_:b646524148 "2"^^ . _:b646523845 . . _:b76341382 _:b76341384 . _:b646524151 "2"^^ . _:b76341382 _:b76341385 . . _:b76341382 _:b76341386 . _:b646524150 "2"^^ . . _:b76341382 _:b76341383 . . . _:b646524145 "2"^^ . _:b646523617 . _:b646524144 "2"^^ . _:b646524024 . . _:b646524147 "2"^^ . _:b76341318 . _:b646524146 "2"^^ . _:b646524157 "2"^^ . _:b646523474 . _:b646524156 "2"^^ . _:b646524256 . _:b646524159 "2"^^ . . _:b646524439 . _:b646524158 "2"^^ . _:b646523630 . _:b646524209 . _:b646524153 "2"^^ . _:b646524152 "2"^^ . _:b646523333 . _:b646524155 "2"^^ . _:b646524253 . _:b646524154 "2"^^ . . _:b646523331 . _:b646524165 "2"^^ . . _:b646524164 "2"^^ . . _:b646524167 "2"^^ . _:b646523551 . _:b646524166 "2"^^ . . _:b646524161 "2"^^ . _:b646524160 "2"^^ . _:b646524163 "2"^^ . _:b646523611 . . . . _:b646524422 . . _:b646524162 "2"^^ . . . _:b646524173 "2"^^ . . . _:b646524172 "2"^^ . . _:b646523461 . _:b646523884 . _:b646523329 . _:b646524175 "2"^^ . _:b646523410 . _:b646524174 "2"^^ . . _:b646524169 "2"^^ . _:b646524168 "2"^^ . . _:b646524171 "2"^^ . _:b646524135 . . . . _:b646524170 "2"^^ . _:b646523087 . _:b646524181 "2"^^ . . _:b646524180 "2"^^ . _:b646524183 "2"^^ . _:b646524128 . _:b646524182 "2"^^ . . . _:b646524177 "2"^^ . _:b646524176 "2"^^ . _:b646524179 "2"^^ . _:b646524178 "2"^^ . _:b646524101 . _:b646524189 "2"^^ . . . _:b646523252 . . _:b646524188 "2"^^ . _:b646524432 . _:b646524191 "2"^^ . . . _:b646524190 "2"^^ . _:b76341266 . _:b646524185 "2"^^ . _:b76341304 . _:b646524184 "2"^^ . _:b646522968 . _:b646524294 . _:b646523057 . _:b646524187 "2"^^ . _:b646523913 . _:b646524186 "2"^^ . . . _:b646524197 "2"^^ . _:b646524196 "2"^^ . _:b646524199 "2"^^ . . . _:b646523317 . _:b646524198 "2"^^ . _:b646524193 "2"^^ . _:b646524353 . _:b646524192 "2"^^ . _:b646523053 . . _:b646524195 "2"^^ . _:b646524194 "2"^^ . . _:b76341240 "While there are numerous DNA repair pathway-targeting drugs currently in clinical trials (>>149<<), their combination with HDACi have yet to be tested." . . _:b646524298 . _:b646524205 "2"^^ . _:b646523789 . _:b646524204 "2"^^ . . . . _:b646524207 "2"^^ . . _:b646522954 . _:b646524206 "2"^^ . . . _:b646523161 . _:b646524201 "2"^^ . _:b646524200 "2"^^ . _:b76341294 . . _:b646524203 "2"^^ . _:b646524420 . _:b646524202 "2"^^ . . . _:b646524213 "2"^^ . . . _:b646523492 . _:b646524212 "2"^^ . _:b76341311 "Although cisplatin treatment results in many cases as an initial therapeutic success, chemoresistance eventually develops particularly in non-germ cell solid tumors (>>25<<, 75, 76). Thus, combining cisplatin with HDACi is a promising strategy to increase the efficacy of cisplatin (25). Concurrent SAHA (vorinostat) therapy has been shown to enhance tumor cell sensitivity to subtoxic doses of cisplatin in" . _:b646524215 "2"^^ . . . . _:b646524214 "2"^^ . _:b646524209 "2"^^ . _:b646524208 "2"^^ . . _:b646524192 . _:b646523073 . _:b646523058 . _:b646524211 "2"^^ . . _:b646524210 "2"^^ . _:b646523775 . _:b646524221 "2"^^ . . _:b646524220 "2"^^ . . _:b646524223 "2"^^ . _:b646523555 . _:b646524425 . _:b646524222 "2"^^ . . _:b646524217 "2"^^ . _:b646524216 "2"^^ . _:b646524219 "2"^^ . . . _:b646524218 "2"^^ . _:b646524086 . _:b646524229 "2"^^ . . . _:b646524228 "2"^^ . _:b646523903 . . _:b646523142 . . _:b646524231 "2"^^ . . _:b646524443 . . _:b646523928 . . _:b646524230 "2"^^ . . _:b646524225 "2"^^ . _:b646524224 "2"^^ . . . _:b646524227 "2"^^ . . _:b646524226 "2"^^ . _:b646523375 . _:b646524237 "2"^^ . . _:b646524236 "2"^^ . _:b646523523 . _:b646524239 "2"^^ . . _:b646524238 "2"^^ . _:b646524233 "2"^^ . . _:b646524232 "2"^^ . _:b646524050 . _:b646524378 . _:b646523798 . _:b646524235 "2"^^ . _:b646523547 . _:b646524234 "2"^^ . _:b646524245 "2"^^ . _:b646524244 "2"^^ . . _:b646524247 "2"^^ . _:b646523724 . . _:b646524246 "2"^^ . _:b646524241 "2"^^ . . . _:b646524240 "2"^^ . _:b646524243 "2"^^ . _:b76341262 "was approved by the FDA in 2014 for the use against peripheral T-cell lymphoma (PTCL) (>>29<<) and panobinostat (Farydak, Novartis Pharmaceuticals) was licensed in 2015 for the treatment of multiple myeloma (30)." . . _:b646524154 . _:b646524242 "2"^^ . _:b646524253 "2"^^ . _:b646524252 "2"^^ . _:b76341298 _:b76341304 . _:b646524255 "2"^^ . . _:b76341298 _:b76341305 . . _:b646524361 . _:b76341298 _:b76341306 . _:b76341298 _:b76341307 . _:b646524368 . _:b76341298 _:b76341300 . _:b646524254 "2"^^ . _:b76341298 _:b76341301 . . _:b76341298 _:b76341302 . _:b76341298 _:b76341303 . _:b646523407 . _:b646524249 "2"^^ . _:b646523159 . _:b646524040 . _:b76341298 _:b76341299 . _:b646524248 "2"^^ . _:b646523131 . _:b646524251 "2"^^ . _:b646523122 . _:b646524250 "2"^^ . _:b76341308 _:b76341309 . _:b76341308 _:b76341310 . _:b76341308 _:b76341311 . _:b646524261 "2"^^ . _:b646524260 "2"^^ . _:b646524263 "2"^^ . _:b646523646 . _:b646524262 "2"^^ . _:b646524257 "2"^^ . . . _:b646524256 "2"^^ . . _:b646524259 "2"^^ . _:b646524258 "2"^^ . . . _:b646524269 "2"^^ . _:b646523007 . _:b76341308 _:b76341316 . _:b646524268 "2"^^ . . _:b76341308 _:b76341317 . _:b76341308 _:b76341318 . _:b76341281 . _:b76341308 _:b76341319 . _:b76341308 _:b76341312 . _:b646524271 "2"^^ . _:b76341308 _:b76341313 . _:b76341308 _:b76341314 . _:b76341308 _:b76341315 . _:b76341244 "The HDAC Classes I, II, and IV are Zn2+-dependent metalloproteins, while Class III HDACs are NAD+-dependent (>>15<<, 16). Class I HDACs are related to yeast RPD3 gene and include HDAC1, 2, 3, and 8. On the other hand, HDACs 4, 5, 7, and 9 are classified as Class IIa HDACs, while HDACs 6 and 10 belong to Class IIb and are related to the yeast Hda1 gene" . _:b646523842 . _:b646524270 "2"^^ . _:b76341308 _:b76341320 . _:b646524265 "2"^^ . _:b76341308 _:b76341321 . _:b76341308 _:b76341322 . _:b646524264 "2"^^ . _:b646524267 "2"^^ . _:b646524119 . _:b646524266 "2"^^ . _:b76341289 _:b76341290 . _:b76341289 _:b76341291 . . _:b646524277 "2"^^ . _:b76341289 _:b76341292 . _:b76341289 _:b76341293 . _:b76341289 _:b76341294 . _:b76341289 _:b76341295 . _:b76341289 _:b76341296 . _:b646524276 "2"^^ . _:b76341289 _:b76341297 . _:b646524279 "2"^^ . . _:b646522963 . _:b646524278 "2"^^ . _:b646522962 . . _:b646524273 "2"^^ . . _:b646523635 . . _:b646524272 "2"^^ . _:b646524275 "2"^^ . _:b646523003 . . _:b646524274 "2"^^ . _:b76341341 . _:b646524285 "2"^^ . _:b76341321 . _:b76341271 _:b76341288 . _:b76341273 "Indeed the selectivity of HDACi in specifically targeting cancer cells can be attributed to HDACi causing DNA damage that normal but not cancer cells can repair (>>43<<, 44). For example, the HDACi vorinostat induces DSBs in normal and LNCaP and A549 cancer cells (43). While \u03B3H2AX levels, a marker for the appearance of DSBs (45), increased in the cancer cells over time, in continued culture with" . _:b646524284 "2"^^ . _:b646524287 "2"^^ . . . _:b646523503 . . _:b646524286 "2"^^ . _:b76341271 _:b76341280 . _:b76341271 _:b76341281 . . _:b76341271 _:b76341282 . _:b76341271 _:b76341283 . _:b76341271 _:b76341284 . _:b646524281 "2"^^ . _:b76341271 _:b76341285 . _:b76341271 _:b76341286 . . _:b646523929 . _:b76341271 _:b76341287 . _:b76341271 _:b76341272 . _:b646524280 "2"^^ . _:b76341271 _:b76341273 . _:b76341271 _:b76341274 . _:b76341271 _:b76341275 . _:b76341271 _:b76341276 . _:b646524283 "2"^^ . . _:b76341271 _:b76341277 . . _:b76341271 _:b76341278 . _:b76341271 _:b76341279 . _:b646524282 "2"^^ . . _:b646524293 "2"^^ . _:b646523385 . . . _:b76341264 _:b76341268 . _:b646524292 "2"^^ . _:b646523198 . _:b76341264 _:b76341269 . . _:b76341264 _:b76341270 . . . . . _:b646524295 "2"^^ . . . _:b76341264 _:b76341265 . _:b76341264 _:b76341266 . _:b646523961 . _:b76341264 _:b76341267 . _:b646524294 "2"^^ . _:b646524290 . _:b646524289 "2"^^ . _:b646524329 . . _:b646524288 "2"^^ . . _:b76341259 _:b76341260 . _:b646524291 "2"^^ . _:b76341259 _:b76341261 . _:b76341364 . _:b76341259 _:b76341262 . _:b76341259 _:b76341263 . _:b646524290 "2"^^ . . . _:b646524301 "2"^^ . . _:b646524300 "2"^^ . _:b646524303 "2"^^ . _:b646524027 . . _:b646524302 "2"^^ . _:b646523399 . _:b646524297 "2"^^ . _:b646524393 . _:b646524296 "2"^^ . _:b646524299 "2"^^ . . _:b646524298 "2"^^ . _:b646523124 . _:b646524309 "2"^^ . _:b646523809 . _:b646524308 "2"^^ . _:b646523708 . _:b646524311 "2"^^ . "10.3389%2Ffonc.2018.00092" . _:b646523562 . _:b646524310 "2"^^ . _:b76341288 . . _:b646524305 "2"^^ . _:b646523126 . _:b646524304 "2"^^ . . _:b646524307 "2"^^ . _:b646524306 "2"^^ . _:b646523282 . . _:b646524317 "2"^^ . _:b646524369 . _:b646523023 . _:b646524316 "2"^^ . _:b646523259 . . . _:b646524319 "2"^^ . . _:b646524318 "2"^^ . _:b76341307 "The authors subsequently carried out a phase I combination trial of vorinostat and doxorubicin in treating patients with metastatic or advanced solid tumors (>>72<<). While a modest clinical effect was observed, this study showed that HDAC2 expression is a potential predictive biomarker and a target for developing isotype-specific inhibitors that may lead to greater inhibition with reduced toxicity" . . _:b646524313 "2"^^ . . _:b646524312 "2"^^ . _:b646524315 "2"^^ . . . _:b76341352 _:b76341356 . _:b646524314 "2"^^ . . _:b76341352 _:b76341357 . _:b76341352 _:b76341358 . . _:b76341352 _:b76341359 . _:b646524325 "2"^^ . _:b76341352 _:b76341353 . _:b76341352 _:b76341354 . _:b76341352 _:b76341355 . _:b646523823 . _:b646524324 "2"^^ . . _:b76341352 _:b76341360 . _:b646524327 "2"^^ . _:b646524326 "2"^^ . . . _:b646524321 "2"^^ . _:b646524320 "2"^^ . . _:b646524323 "2"^^ . _:b646523182 . _:b646524322 "2"^^ . _:b646523610 . . . _:b646524333 "2"^^ . _:b646523838 . . _:b646524332 "2"^^ . _:b76341361 _:b76341362 . _:b76341337 "of HDACi with proteasome inhibitors may additionally be used to treat glioblastomas in order to maximize the therapeutic efficacy and limit the toxicity associated with using proteasome inhibitors as a single agent in this disease (>>102<<). Clinical trials with bortezomib in combination with either vorinostat as a third-line treatment in advanced NSCLC (ClinicalTrial." . . _:b76341361 _:b76341363 . _:b76341361 _:b76341364 . _:b646524335 "2"^^ . _:b76341361 _:b76341365 . _:b76341295 "The novel pan-HDACi, panobinostat (LBH589), is currently being used in phase I and II clinical studies against various hematologic malignancies and solid tumors (>>60<<, 61). In combination with radiotherapy, LBH589 was shown to be an effective regimen for the treatment of prostate cancer in vitro. The authors demonstrated that LBH589 at low concentrations (IC20) in combination with radiation induced" . _:b76341361 _:b76341366 . _:b76341361 _:b76341367 . _:b646524334 "2"^^ . _:b646523806 . _:b646523177 . _:b76341343 . _:b646524182 . _:b646524329 "2"^^ . _:b646524328 "2"^^ . . . _:b646524331 "2"^^ . _:b646522980 . _:b646523790 . . _:b646524330 "2"^^ . _:b646524064 . _:b646523039 . _:b646524341 "2"^^ . _:b646524197 . _:b646524340 "2"^^ . . _:b76341331 . _:b646524343 "2"^^ . . _:b646524342 "2"^^ . _:b76341368 _:b76341372 . _:b76341368 _:b76341373 . _:b76341379 "the reversal of carcinoma immune escape through the induction of ER stress, resulting in the activation of the unfolded response, subsequently leading to immunogenic modulation and increased tumor sensitivity to T-cell mediated lysis (>>141<<)." . _:b76341368 _:b76341374 . _:b76341368 _:b76341375 . _:b646524337 "2"^^ . _:b76341368 _:b76341369 . . _:b76341368 _:b76341370 . _:b646523460 . _:b76341368 _:b76341371 . _:b76341368 _:b76341380 . _:b646524336 "2"^^ . _:b76341368 _:b76341381 . . _:b646523654 . _:b76341323 _:b76341324 . _:b646524339 "2"^^ . _:b76341368 _:b76341376 . _:b76341323 _:b76341325 . _:b76341368 _:b76341377 . _:b76341323 _:b76341326 . _:b646523837 . _:b76341368 _:b76341378 . _:b76341368 _:b76341379 . _:b76341323 _:b76341327 . . _:b646524338 "2"^^ . _:b646524349 "2"^^ . . _:b76341323 _:b76341336 . _:b646524348 "2"^^ . _:b76341323 _:b76341337 . _:b76341323 _:b76341338 . _:b76341323 _:b76341339 . _:b646524351 "2"^^ . _:b76341323 _:b76341328 . _:b646524350 "2"^^ . _:b76341323 _:b76341329 . _:b76341323 _:b76341330 . _:b76341323 _:b76341331 . . _:b646524345 "2"^^ . _:b76341323 _:b76341332 . . _:b76341323 _:b76341333 . _:b76341323 _:b76341334 . _:b646523383 . _:b76341323 _:b76341335 . _:b646524344 "2"^^ . . . . _:b646523424 . _:b646524347 "2"^^ . . . _:b646523313 . . _:b646523416 . _:b646524346 "2"^^ . _:b646523534 . . _:b646523773 . _:b646524357 "2"^^ . . _:b646524356 "2"^^ . _:b646524359 "2"^^ . . _:b646524358 "2"^^ . _:b646524260 . _:b646524353 "2"^^ . _:b646524352 "2"^^ . _:b646524301 . . _:b646524355 "2"^^ . . . _:b646524354 "2"^^ . _:b76341340 _:b76341341 . _:b76341340 _:b76341342 . . _:b76341340 _:b76341343 . _:b646524365 "2"^^ . _:b646524364 "2"^^ . . _:b646524367 "2"^^ . _:b646524410 . _:b646524366 "2"^^ . . _:b646524361 "2"^^ . . . _:b646523598 . _:b646524360 "2"^^ . . _:b646524363 "2"^^ . . _:b646524362 "2"^^ . _:b646524373 "2"^^ . _:b76341340 _:b76341348 . _:b646524372 "2"^^ . . _:b76341340 _:b76341349 . _:b76341340 _:b76341350 . _:b76341335 "The authors showed that the synergism observed was independent of HDAC6 but rather through the induction of ROS-dependent estrogen receptor (ER) stress (>>100<<). The Class I HDACi, MGCD0103, has also been shown to synergize with proteasome inhibitors and induce apoptosis in Hodgkin lymphoma cell lines by an HDAC6-independent mechanism. The authors demonstrated that MGCD0103 resulted in the" . _:b76341340 _:b76341351 . _:b76341340 _:b76341344 . _:b646524375 "2"^^ . _:b76341340 _:b76341345 . . _:b646523095 . _:b76341340 _:b76341346 . _:b76341340 _:b76341347 . _:b646523024 . _:b646524374 "2"^^ . _:b646524369 "2"^^ . _:b646524368 "2"^^ . . _:b646524371 "2"^^ . . _:b646522941 . _:b646524370 "2"^^ . . _:b646524381 "2"^^ . _:b76341291 "HDACi enhance the radiosensitivity of cancer cells (56, >>57<<). HDACi have been shown in vitro to lower a cell\u2019s ability to repair IR-induced DNA damage, by affecting DNA damage signaling and the NHEJ and HR DSB repair pathways (17)." . _:b646524380 "2"^^ . . _:b646523117 . _:b646524383 "2"^^ . _:b646523853 . _:b646524382 "2"^^ . _:b646524377 "2"^^ . . _:b646524376 "2"^^ . . _:b646524379 "2"^^ . . _:b646524378 "2"^^ . _:b646524389 "2"^^ . _:b76341279 . _:b646524388 "2"^^ . . _:b646523919 . . _:b646524391 "2"^^ . . . _:b646522974 . . . . _:b646524390 "2"^^ . _:b646524385 "2"^^ . _:b646524384 "2"^^ . _:b646523727 . . _:b646524387 "2"^^ . _:b646524386 "2"^^ . _:b646524397 "2"^^ . _:b646523821 . _:b646524396 "2"^^ . _:b76341356 "Therefore, the combination of RTK targeted therapies and HDACi represents a novel approach for targeted cancer therapy (>>57<<, 121). Sorafenib (BAY 43-9006) is a novel multikinase inhibitor which has been shown to block the RAS-RAF-MEK-MAPK pathway. Recent work has demonstrated that vorinostat and sorafenib synergistically kill tumor cells (122). Numerous phase" . . _:b646524399 "2"^^ . _:b646522982 . . _:b646524398 "2"^^ . _:b646524393 "2"^^ . _:b646524392 "2"^^ . _:b646523444 . . _:b646524395 "2"^^ . _:b646524394 "2"^^ . . _:b646523188 . _:b646524405 "2"^^ . _:b646523128 . _:b646524404 "2"^^ . _:b646524407 "2"^^ . _:b646524406 "2"^^ . _:b646524415 . _:b646523567 . _:b646524401 "2"^^ . . _:b646524400 "2"^^ . . _:b646524403 "2"^^ . _:b646523364 . . _:b646524402 "2"^^ . . _:b646524076 . _:b646524413 "2"^^ . _:b646524445 . _:b646523586 . _:b646524412 "2"^^ . . . . _:b646523045 . _:b646524415 "2"^^ . _:b646524414 "2"^^ . _:b646523176 . _:b646524409 "2"^^ . _:b646523049 . . _:b646524408 "2"^^ . _:b646523648 . . _:b646524411 "2"^^ . _:b646524356 . _:b646524410 "2"^^ . _:b646524247 . _:b646523397 "3"^^ . . . _:b646523396 "3"^^ . _:b646523739 . _:b646523009 . _:b646523399 "3"^^ . _:b646523398 "3"^^ . . _:b646523393 "3"^^ . . _:b646524268 . _:b646523392 "3"^^ . _:b76341309 . _:b646523395 "3"^^ . . _:b646523394 "3"^^ . _:b646523405 "3"^^ . _:b646523464 . _:b646523349 . . _:b646523879 . . _:b646523404 "3"^^ . . _:b646523164 . _:b646523205 . _:b646523407 "3"^^ . _:b646523406 "3"^^ . . _:b646523401 "3"^^ . _:b76341366 . _:b646523400 "3"^^ . _:b646523271 . . . _:b646523403 "3"^^ . . _:b646523052 . _:b646523402 "3"^^ . _:b646524010 . _:b646523413 "2"^^ . _:b646524292 . . _:b646523412 "3"^^ . _:b646522939 . _:b646523415 "2"^^ . . _:b646524277 . . _:b646523414 "2"^^ . _:b646523409 "3"^^ . . _:b646523408 "3"^^ . _:b646523162 . _:b646523411 "3"^^ . . _:b76341263 "was approved by the FDA in 2014 for the use against peripheral T-cell lymphoma (PTCL) (29) and panobinostat (Farydak, Novartis Pharmaceuticals) was licensed in 2015 for the treatment of multiple myeloma (>>30<<). A summary of HDACi that are currently approved by the FDA and/or are in clinical trials for the treatment of cancer are shown in Table 2." . _:b646523410 "3"^^ . _:b76341365 "This study demonstrated that the combination was safe and resulted in a transient reversal of aberrant epigenetic markers (>>128<<) (ClinicalTrial." . _:b646523421 "2"^^ . . . _:b646523420 "2"^^ . . _:b646523423 "2"^^ . _:b646523422 "2"^^ . _:b646523417 "2"^^ . _:b646523416 "2"^^ . _:b646523419 "2"^^ . _:b646524061 . _:b646523418 "2"^^ . . _:b646523429 "2"^^ . _:b646523428 "2"^^ . _:b76341320 . _:b646524442 . _:b646523431 "2"^^ . _:b646523430 "2"^^ . . _:b646523425 "2"^^ . _:b646523404 . _:b76341348 . _:b646523424 "2"^^ . _:b646523427 "2"^^ . _:b646523426 "2"^^ . _:b646523667 . _:b646523437 "2"^^ . _:b76341340 "combining hdaci with hormonal therapy" . _:b646523436 "2"^^ . _:b646523732 . _:b646524403 . _:b646523982 . _:b646523439 "2"^^ . _:b76341384 "Recent work has demonstrated that knockdown of HDAC1 and not HDAC2 or HDAC3 resulted in an increased resistance to belinostat-induced cell death in HeLa cells (>>146<<). While this data is suggestive for high HDAC1 levels to correlate with sensitivity to HDACi treatment, more experimental data is required to determine whether a tumor-specific HDAC isoenzyme profile may predict the response to individual" . _:b646523438 "2"^^ . _:b646523886 . . . _:b646523433 "2"^^ . . _:b646523778 . _:b646523432 "2"^^ . . _:b646523435 "2"^^ . _:b76341326 "Cancer cells are dependent on the UPS as they are highly proliferative and have an increased requirement for protein synthesis, hence making them more vulnerable to proteasome inhibitors (>>89<<, 90). In 2003, the FDA approved bortezomib (PS-341, Velcade\u2122, Millennium Pharmaceuticals Inc.) to treat relapsed and refractory multiple myeloma (91). However, peripheral neuropathy is often seen and is the most frequently associated dose" . _:b646523413 . . _:b646523296 . _:b646523434 "2"^^ . _:b646523445 "2"^^ . . _:b646523444 "2"^^ . _:b646524165 . . _:b646523447 "2"^^ . _:b646523904 . . _:b646523446 "2"^^ . . . _:b646524003 . _:b646523441 "2"^^ . _:b646523440 "2"^^ . _:b646523568 . . _:b646523443 "2"^^ . _:b646522929 . _:b646523442 "2"^^ . _:b646523453 "2"^^ . . _:b646523452 "2"^^ . _:b646523715 . _:b646523455 "2"^^ . . . . _:b646523454 "2"^^ . . . _:b646523658 . . _:b646523449 "2"^^ . _:b646524223 . _:b646523167 . _:b646524325 . _:b646523448 "2"^^ . . _:b646523451 "2"^^ . _:b646524342 . _:b646523477 . . . _:b646523450 "2"^^ . _:b646523540 . _:b646524341 . _:b646523461 "2"^^ . _:b76341290 . _:b646524333 . _:b646523558 . _:b646523460 "2"^^ . _:b646524212 . _:b646523463 "2"^^ . _:b646523954 . . _:b646523462 "2"^^ . _:b646522956 . _:b646523457 "2"^^ . . _:b646523456 "2"^^ . . _:b646523459 "2"^^ . _:b646523395 . _:b646523458 "2"^^ . _:b646523343 . _:b646523469 "2"^^ . _:b646523468 "2"^^ . . _:b646523471 "2"^^ . _:b646523665 . _:b646523470 "2"^^ . . _:b646523465 "2"^^ . . _:b646523464 "2"^^ . . . _:b646523467 "2"^^ . _:b646523353 . _:b646523986 . . _:b646523466 "2"^^ . _:b646523477 "2"^^ . _:b646523326 . _:b646523476 "2"^^ . _:b646523231 . _:b646523479 "2"^^ . _:b646523258 . _:b646523478 "2"^^ . _:b646523473 "2"^^ . _:b646523756 . _:b646523472 "2"^^ . . _:b646523475 "2"^^ . _:b646523474 "2"^^ . _:b646523485 "2"^^ . . . _:b646523484 "2"^^ . _:b646523487 "2"^^ . . _:b646523486 "2"^^ . _:b646523481 "2"^^ . _:b646523480 "2"^^ . _:b646523952 . _:b646523483 "2"^^ . . _:b646523482 "2"^^ . . _:b76341326 . _:b646523493 "2"^^ . . _:b646523492 "2"^^ . . . _:b646524338 . . _:b646523284 . . _:b646523495 "2"^^ . _:b76341246 . _:b646523494 "2"^^ . . . _:b646523489 "2"^^ . . _:b76341238 . _:b646523488 "2"^^ . _:b646523638 . _:b646523491 "2"^^ . . _:b646523005 . . . _:b646523490 "2"^^ . _:b646523508 . _:b646523693 . _:b646523501 "2"^^ . _:b76341364 "Recent in vitro work has demonstrated that the combination of valproic acid and decitabine synergistically inhibits growth and induces apoptosis in the leukemia cells lines, HL-60, and MOLT4 (>>127<<). A subsequent phase I/II clinical trial with valproic acid and decitabine included 54 patients with leukemia. In the study, 12 patients showed objective responses including 10 complete remissions and a large cytogenetic response was seen" . _:b646523673 . _:b646523239 . . _:b646523500 "2"^^ . _:b646523270 . _:b646523946 . _:b646524206 . _:b646523503 "2"^^ . _:b646523502 "2"^^ . _:b646523497 "2"^^ . _:b646523496 "2"^^ . _:b76341374 "HDACi enhance the immunotherapy response (135) and augment immunotherapy with PD-1 blockade in melanoma cells (>>136<<), inhibit apoptosis of CD4+ T cells within the tumor, upregulate antitumor immune responses and restrict tumor growth (137)." . _:b646523499 "2"^^ . _:b646523498 "2"^^ . _:b646523509 "2"^^ . _:b646523489 . _:b646523508 "2"^^ . _:b646523511 "2"^^ . . _:b646523510 "2"^^ . _:b646523356 . . _:b646523505 "2"^^ . _:b646523406 . _:b646523504 "2"^^ . . _:b646524150 . _:b646523507 "2"^^ . . _:b646523506 "2"^^ . _:b76341257 "HDACi have pleiotropic cellular effects (Figure 2) and induce the expression of pro-apoptotic genes/proteins, cause cellular differentiation and/or cell cycle arrest (13, 15, >>19<<, 25, 26). The classes of HDACs and the HDACi that are targeted against them are summarized in Table 1." . _:b646523517 "2"^^ . . _:b646523767 . _:b646523516 "2"^^ . _:b76341272 "These ends are subsequently modified by Artemis, ligated by ligase IV, and finally stabilized by XRCC4 and XLF (>>39<<\u201342)." . _:b646524202 . _:b646523519 "2"^^ . . _:b646523518 "2"^^ . _:b646523475 . . . _:b646523513 "2"^^ . _:b646523633 . _:b646523512 "2"^^ . . _:b646523515 "2"^^ . _:b646523514 "2"^^ . _:b646523619 . _:b646523525 "2"^^ . _:b646523010 . _:b646523524 "2"^^ . . . . _:b646523527 "2"^^ . . . _:b646523526 "2"^^ . _:b646523521 "2"^^ . _:b646523279 . _:b646524339 . _:b646523520 "2"^^ . _:b646523480 . _:b646523523 "2"^^ . _:b646524181 . _:b646523522 "2"^^ . . . . _:b646523483 . _:b76341324 "The tightly regulated degradation of ubiquitinated proteins by the proteasome is essential in cells and impairment of the ubiquitin-proteasome system (UPS) leads to several pathological diseases (>>86<<). The UPS plays a key role in the cellular protein-degradation machinery and in preventing the accumulation of misfolded proteins (86\u201388)." . . _:b646523533 "2"^^ . . . _:b646523048 . _:b646523532 "2"^^ . _:b76341331 "In several preclinical studies, synergistic antitumor effects were seen in multiple myeloma, when HDACi were combined with proteasome inhibitors, thus providing the rational for combining HDACi with these agents in clinical trials (>>94<<\u201397). The synergistic effect seen with combination of HDACi and proteasome inhibitors may be attributed to the multiple pathways targeting multiple myeloma cell biology. One prominent mechanism may be by disrupting protein degradation by" . _:b646523535 "2"^^ . . _:b76341252 . . _:b646523534 "2"^^ . _:b646523529 "2"^^ . _:b646524017 . _:b646523528 "2"^^ . . _:b646523531 "2"^^ . _:b76341343 "Aberrant acetylation and HDAC expression has been observed in both breast and prostate cancer cell lines and patient tumors (>>107<<, 108). Thus, the combination of HDACi and hormonal therapy is under investigation in both clinical and preclinical settings for the treatment of breast and prostate cancers. While vorinostat as a monotherapy was not found to be effective" . _:b646523081 . _:b646523530 "2"^^ . _:b646523519 . . _:b646523541 "2"^^ . . _:b646523540 "2"^^ . . . _:b646523543 "2"^^ . . _:b646523542 "2"^^ . _:b646523401 . . . . _:b646523537 "2"^^ . . . _:b646523536 "2"^^ . . _:b646523539 "2"^^ . _:b646523538 "2"^^ . _:b646523549 "2"^^ . _:b646522951 . _:b646524310 . _:b646523299 . _:b646523548 "2"^^ . _:b646524048 . . _:b646523551 "2"^^ . _:b646523750 . _:b646523550 "2"^^ . _:b646524090 . _:b646524032 . _:b646523545 "2"^^ . . _:b646524118 . _:b646523544 "2"^^ . _:b646523547 "2"^^ . _:b646523546 "2"^^ . _:b646523677 . _:b646523557 "2"^^ . _:b646523556 "2"^^ . . _:b646523977 . _:b646523684 . _:b646523559 "2"^^ . . _:b646523577 . _:b646523558 "2"^^ . _:b646523553 "2"^^ . _:b646523552 "2"^^ . _:b646523669 . . _:b646523555 "2"^^ . _:b646523554 "2"^^ . _:b646523113 . . _:b646523222 . _:b646523565 "2"^^ . _:b646524340 . . . . _:b646523717 . . _:b646523564 "2"^^ . _:b646524377 . _:b646523567 "2"^^ . . _:b646523566 "2"^^ . . . _:b76341245 "The HDAC Classes I, II, and IV are Zn2+-dependent metalloproteins, while Class III HDACs are NAD+-dependent (15, >>16<<). Class I HDACs are related to yeast RPD3 gene and include HDAC1, 2, 3, and 8. On the other hand, HDACs 4, 5, 7, and 9 are classified as Class IIa HDACs, while HDACs 6 and 10 belong to Class IIb and are related to the yeast Hda1 gene (17)." . _:b646522955 . _:b646523561 "2"^^ . _:b646523560 "2"^^ . _:b646524248 . _:b646523563 "2"^^ . _:b646523562 "2"^^ . _:b646523573 "2"^^ . _:b646524201 . _:b646523572 "2"^^ . . _:b646523575 "2"^^ . _:b646523574 "2"^^ . _:b646523047 . . . _:b646523569 "2"^^ . . . _:b646523568 "2"^^ . . . . _:b646523571 "2"^^ . _:b646523570 "2"^^ . _:b646522934 . _:b646523581 "2"^^ . _:b646523580 "2"^^ . . . _:b646523583 "2"^^ . _:b646523582 "2"^^ . . _:b76341251 "High expression levels of HDAC1, 2, and 3 have been shown to be associated with poor patient outcomes in gastric and ovarian cancers (>>21<<, 22), while high expression of HDAC8 is correlated with poor survival and advanced disease in neuroblastoma (23)." . _:b646523577 "2"^^ . _:b646523152 . _:b646523576 "2"^^ . . _:b646523766 . . . . _:b646523579 "2"^^ . _:b646523578 "2"^^ . . _:b646523589 "2"^^ . . _:b646523470 . _:b646523588 "2"^^ . . _:b646523591 "2"^^ . . _:b646523590 "2"^^ . . . _:b646523585 "2"^^ . _:b646523584 "2"^^ . . _:b646523587 "2"^^ . . _:b646523586 "2"^^ . . _:b76341329 . _:b646523597 "2"^^ . . _:b646523596 "2"^^ . . _:b646523599 "2"^^ . _:b646523308 . _:b646523598 "2"^^ . _:b76341383 . _:b646523593 "2"^^ . . _:b646523592 "2"^^ . . _:b646523595 "2"^^ . . _:b646523594 "2"^^ . _:b646523605 "2"^^ . . . _:b646523604 "2"^^ . _:b646523607 "2"^^ . _:b646524234 . _:b646523606 "2"^^ . . . . _:b646523601 "2"^^ . . _:b646523600 "2"^^ . _:b646523487 . _:b646523603 "2"^^ . _:b646524391 . _:b646523602 "2"^^ . _:b646523243 . _:b646523613 "2"^^ . _:b646523612 "2"^^ . . _:b646523615 "2"^^ . . . _:b646523614 "2"^^ . _:b646523609 "2"^^ . _:b646523608 "2"^^ . _:b646523901 . _:b76341292 "HDACi have been shown in vitro to lower a cell\u2019s ability to repair IR-induced DNA damage, by affecting DNA damage signaling and the NHEJ and HR DSB repair pathways (>>17<<). In preclinical studies, HDACi have shown radiosensitizing effects with glioblastoma multiforme, melanoma, and head and neck squamous, colorectal, non-small cell lung, prostate, and MBCs (58). The first group to publish a case report on" . _:b646523611 "2"^^ . . _:b646523610 "2"^^ . _:b646523613 . _:b646523621 "2"^^ . _:b646523620 "2"^^ . _:b646523623 "2"^^ . . . _:b646523074 . _:b646523622 "2"^^ . _:b646523219 . . . . _:b646523617 "2"^^ . . _:b646523616 "2"^^ . _:b646523704 . _:b646523619 "2"^^ . _:b646523618 "2"^^ . . _:b646523629 "2"^^ . _:b646523628 "2"^^ . _:b646523813 . _:b646523631 "2"^^ . . _:b646523630 "2"^^ . _:b646523625 "2"^^ . _:b646523446 . _:b646523624 "2"^^ . _:b646523211 . _:b646523706 . _:b646523627 "2"^^ . . _:b646523398 . _:b646523109 . _:b646523626 "2"^^ . _:b646524140 . _:b646523013 . _:b76341336 "The subsequent inhibition of NF\u03BAB with proteasome inhibitors enhanced the MGCD0103-induced death of Hodgkin lymphoma cells (>>101<<). The combination of HDACi with proteasome inhibitors may additionally be used to treat glioblastomas in order to maximize the therapeutic efficacy and limit the toxicity associated with using proteasome inhibitors as a single agent in" . _:b646523637 "2"^^ . . . _:b646523636 "2"^^ . _:b646523260 . _:b646522930 . _:b646523639 "2"^^ . _:b646524328 . _:b646523638 "2"^^ . _:b646523633 "2"^^ . _:b646523281 . _:b76341300 "Compared to monotherapy, combination therapies with HDACi and topoisomerase II inhibitors have lead to higher nuclear topoisomerase II inhibitor accumulation, an increase in DNA damage, growth inhibition, and cell death (>>64<<\u201367). Preclinical studies have shown greater efficacy when cells were pretreated with HDACi prior to exposure to DNA damaging agents (64, 68), similar to the decondensation of chromatin seen in cells from breast and other cancers (50, 69)." . _:b646523632 "2"^^ . _:b646523429 . _:b646522971 . _:b646523635 "2"^^ . . _:b646523067 . _:b646523634 "2"^^ . _:b76341292 . . _:b646523645 "2"^^ . . _:b646523644 "2"^^ . _:b646523303 . _:b646523647 "2"^^ . _:b646523646 "2"^^ . _:b76341297 "Additionally, the combination treatment gave rise to more DNA damage and resulted in less activation of NHEJ and HR repair pathways (>>62<<). A phase I clinical trial (ClinicalTrial.gov identifier: NCT00455351) studying the treatment of vorinostat with short-term palliative pelvic radiotherapy showed that both treatments were tolerated in gastrointestinal tract carcinoma" . _:b646524020 . _:b646523641 "2"^^ . _:b646523640 "2"^^ . _:b646524068 . _:b646523643 "2"^^ . _:b646523089 . _:b646523582 . _:b76341277 "Histone deacetylases have been recently shown to play a substantial role in attenuating the activation of ATM following DNA damage (>>46<<). Ataxia-telangiectasia patients, with defective ATM protein, display increased genomic instability, chromatin decondensation, and radiosensitivity (47)." . _:b646523642 "2"^^ . _:b646524231 . _:b646524428 . _:b646523411 . _:b646523653 "2"^^ . _:b646523652 "2"^^ . _:b76341286 "gov identifier: NCT02000622) (>>53<<). Additionally, there is a phase I/II clinical trial underway with the combination of olaparib and vorinostat." . _:b646523106 . _:b646523655 "2"^^ . _:b646523654 "2"^^ . . _:b646523459 . _:b646523290 . _:b646523783 . _:b646523649 "2"^^ . . _:b646523648 "2"^^ . _:b646524111 . _:b76341345 . _:b646523651 "2"^^ . _:b646523096 . _:b646523650 "2"^^ . _:b646523661 "2"^^ . . . _:b646523660 "2"^^ . _:b646523663 "2"^^ . _:b646523344 . _:b646523662 "2"^^ . . _:b646523622 . . . _:b646523657 "2"^^ . _:b646523656 "2"^^ . . _:b646523659 "2"^^ . _:b646523658 "2"^^ . . _:b646523669 "2"^^ . _:b646523668 "2"^^ . _:b646523671 "2"^^ . _:b76341370 "present, there are four immune checkpoint inhibitors approved by the FDA, ipilimumab (an anti-CTLA-4 drug), nivolumab and pembrolizumab (anti-PD-1 drugs), and the anti-PDL1 agents, such as atezolizumab, durvalumab, and avelumab (131, >>132<<). There are over 500 ongoing clinical trials using immune checkpoint inhibitors for the treatment of various cancers including resected, localized, and advanced solid tumors and hematological malignancies." . _:b76341349 . _:b646523670 "2"^^ . _:b646523665 "2"^^ . _:b646523664 "2"^^ . . _:b646523668 . _:b646523667 "2"^^ . _:b646523705 . _:b646523666 "2"^^ . . _:b646523733 . _:b646523677 "2"^^ . . _:b646523676 "2"^^ . _:b76341333 . _:b646523679 "2"^^ . _:b646523263 . _:b646523947 . _:b646523678 "2"^^ . _:b646524213 . . _:b646523673 "2"^^ . _:b646524417 . _:b646523992 . _:b646523672 "2"^^ . _:b646523675 "2"^^ . . _:b646523674 "2"^^ . _:b646523325 . _:b76341331 . _:b646523685 "2"^^ . _:b646523684 "2"^^ . . _:b646524438 . _:b646523687 "2"^^ . _:b646523686 "2"^^ . _:b646523028 . . _:b646524433 . _:b646523681 "2"^^ . _:b646523988 . _:b646523680 "2"^^ . _:b646523683 "2"^^ . . _:b646523682 "2"^^ . . . _:b646523693 "2"^^ . _:b646523336 . _:b646523692 "2"^^ . _:b646524388 . _:b646523936 . . _:b646523695 "2"^^ . . . _:b646523694 "2"^^ . . . _:b646523689 "2"^^ . . _:b646523688 "2"^^ . . _:b646523691 "2"^^ . _:b646523690 "2"^^ . _:b646523701 "2"^^ . _:b76341328 "to treat relapsed and refractory multiple myeloma (>>91<<). However, peripheral neuropathy is often seen and is the most frequently associated dose limiting toxicity." . _:b646523700 "2"^^ . . _:b646523703 "2"^^ . _:b646523528 . _:b646524053 . _:b646523702 "2"^^ . . _:b646523697 "2"^^ . _:b76341253 "levels of HDAC1, 2, and 3 have been shown to be associated with poor patient outcomes in gastric and ovarian cancers (21, 22), while high expression of HDAC8 is correlated with poor survival and advanced disease in neuroblastoma (>>23<<). Additionally, dysregulation of HDAC1 expression was demonstrated to correlate with poor prognosis in multiple myeloma (24)." . _:b646523696 "2"^^ . _:b76341237 . _:b646523699 "2"^^ . . _:b646523698 "2"^^ . . _:b646523709 "2"^^ . _:b646523708 "2"^^ . . _:b646523711 "2"^^ . . . _:b646523710 "2"^^ . _:b646523030 . _:b646523705 "2"^^ . . _:b646523926 . _:b646523704 "2"^^ . _:b646523740 . _:b646523707 "2"^^ . _:b646524262 . _:b646524161 . _:b646523706 "2"^^ . _:b646523249 . _:b646523717 "2"^^ . . _:b646523716 "2"^^ . . _:b646524082 . _:b646523719 "2"^^ . . _:b646523718 "2"^^ . _:b646523713 "2"^^ . . _:b646523712 "2"^^ . _:b646524238 . _:b646523715 "2"^^ . _:b76341329 "However, in phase I and phase II clinical trials, is has been observed that as a single agent, the activity of HDACi have been limited (>>92<<, 93). In several preclinical studies, synergistic antitumor effects were seen in multiple myeloma, when HDACi were combined with proteasome inhibitors, thus providing the rational for combining HDACi with these agents in clinical trials" . . _:b646523714 "2"^^ . "PMC0" . _:b646523725 "2"^^ . _:b646523462 . _:b646523724 "2"^^ . _:b646523438 . _:b646523727 "2"^^ . _:b646523027 . _:b646523726 "2"^^ . _:b646523721 "2"^^ . _:b646523285 . _:b646523720 "2"^^ . _:b646523723 "2"^^ . _:b646523722 "2"^^ . . _:b646523733 "2"^^ . _:b646524296 . _:b646523445 . _:b646523732 "2"^^ . _:b646523735 "2"^^ . _:b646523518 . _:b646523734 "2"^^ . _:b646524399 . _:b646523729 "2"^^ . . . _:b646523728 "2"^^ . _:b646523731 "2"^^ . _:b646523996 . . _:b646523730 "2"^^ . _:b646523741 "2"^^ . _:b646524305 . _:b646523125 . _:b646523740 "2"^^ . _:b646523743 "2"^^ . . _:b646523742 "2"^^ . _:b646523168 . _:b646523737 "2"^^ . . . _:b646523132 . _:b646523191 . . _:b646523736 "2"^^ . _:b646523739 "2"^^ . _:b646523738 "2"^^ . . _:b646523749 "2"^^ . _:b646523581 . _:b646524164 . _:b646523748 "2"^^ . _:b646522970 . _:b646523751 "2"^^ . _:b646523750 "2"^^ . _:b646524141 . _:b646523745 "2"^^ . _:b646523744 "2"^^ . _:b646523747 "2"^^ . . _:b646523226 . _:b646523746 "2"^^ . _:b646523757 "2"^^ . _:b646524029 . _:b646524121 . . _:b646523756 "2"^^ . . _:b646523759 "2"^^ . _:b646524269 . . _:b646523758 "2"^^ . _:b646523753 "2"^^ . _:b646523752 "2"^^ . . . _:b646523755 "2"^^ . . _:b646522921 . _:b646524373 . . _:b646523754 "2"^^ . . . _:b646523765 "2"^^ . _:b646523764 "2"^^ . _:b646523181 . _:b646523767 "2"^^ . _:b646523766 "2"^^ . _:b646524421 . _:b646523761 "2"^^ . . . _:b646524420 . . _:b646523760 "2"^^ . _:b646524423 . _:b646523763 "2"^^ . . . _:b646524422 . _:b646523762 "2"^^ . _:b646524417 . _:b646523773 "2"^^ . _:b646524416 . _:b646522988 . _:b646523772 "2"^^ . _:b76341266 "(ROS)-mediated DNA damage, constitutive activation of NF\u03BAB through p65 acetylation and elevated expression of the signaling proteins, MAPK, PI3K, or STAT3, have additionally been suggested to contribute toward the resistance of HDACi (>>34<<). Furthermore, chromatin and epigenetic alterations, changes in the expression levels of HDACs and changes in drug efflux mechanisms have been implicated as factors in the resistance to HDACi (35)." . _:b646524419 . _:b646523775 "2"^^ . . _:b646524418 . . _:b646523774 "2"^^ . _:b646523569 . _:b76341316 "Trichostatin A was shown to synergistically enhance the antitumor response of cisplatin and additionally resensitize bladder cancer cells that were resistant to cisplatin (>>78<<) and valproic acid was shown to induce apoptosis and p16INK4A upregulation, thereby sensitizing melanoma cells to cisplatin and etoposide treatment (79)." . . _:b646524429 . _:b646523769 "2"^^ . . _:b646524428 . _:b646523768 "2"^^ . . . _:b646524431 . _:b646523771 "2"^^ . _:b646523091 . _:b646524430 . _:b646523770 "2"^^ . _:b646524425 . _:b646523781 "2"^^ . _:b646524424 . _:b646523780 "2"^^ . _:b646524293 . _:b646523473 . _:b646523770 . _:b646524427 . _:b646523783 "2"^^ . _:b646523803 . _:b646524426 . _:b646523782 "2"^^ . . _:b646524437 . _:b646523777 "2"^^ . _:b646523372 . _:b646524436 . _:b646523776 "2"^^ . _:b646524439 . _:b646523779 "2"^^ . . . _:b646524438 . _:b76341299 . _:b646523778 "2"^^ . . _:b646523660 . _:b646524433 . . _:b646523718 . _:b646523789 "2"^^ . _:b646524432 . _:b646523788 "2"^^ . . _:b646524435 . _:b646523791 "2"^^ . _:b646524166 . _:b646524075 . _:b646524434 . _:b646523790 "2"^^ . _:b646524445 . _:b646523785 "2"^^ . _:b646523051 . _:b646524444 . _:b646523784 "2"^^ . _:b646523463 . . _:b646524447 . . _:b646523787 "2"^^ . _:b646524446 . _:b76341288 "When the prostate cancer cells were treated with the HDACi and the DNA damaging agents, bleomycin, doxorubicin, and etoposide, sequentially, the sensitization of the prostate cancer cells was more pronounced (>>55<<). Taken together, the combination of HDACi for sensitizing cancer cells with therapies that induce DNA damage warrants further clinical investigation." . _:b646523786 "2"^^ . _:b646523571 . _:b646524441 . . _:b646523797 "2"^^ . . _:b646523863 . _:b646524440 . _:b646523796 "2"^^ . _:b76341350 . . . _:b646524443 . _:b646524131 . . _:b646523799 "2"^^ . _:b646523597 . _:b646523100 . _:b646524196 . _:b646523697 . _:b646524442 . _:b646523798 "2"^^ . _:b646524358 . . . _:b646523793 "2"^^ . _:b646523792 "2"^^ . _:b646523855 . . _:b646523795 "2"^^ . _:b646523479 . _:b646523277 . _:b646523794 "2"^^ . _:b646523072 . _:b646524136 . _:b646522936 . . . _:b646523805 "2"^^ . _:b646523804 "2"^^ . _:b646523840 . _:b646523807 "2"^^ . _:b646524398 . . _:b646523806 "2"^^ . . . _:b646523801 "2"^^ . . . _:b646523800 "2"^^ . _:b76341284 "Olaparib is approved for the treatment of germline BRCA-mutated advanced ovarian cancer in patients who have received prior chemotherapy (>>51<<, 52). A recently reported phase III clinical trial has demonstrated that olaparib monotherapy is significantly superior to physicians choice of chemotherapy in the treatment of metastatic breast cancer (MBC) patients with germline BRAC1/2" . . _:b646523803 "2"^^ . _:b646524115 . _:b646523802 "2"^^ . _:b646523813 "2"^^ . _:b646523812 "2"^^ . . _:b646523815 "2"^^ . _:b646523814 "2"^^ . . _:b646524447 . _:b646523657 . _:b646523359 . _:b646523809 "2"^^ . _:b646522981 . _:b76341369 . . _:b646523671 . . _:b646523722 . _:b646523808 "2"^^ . _:b76341372 "The combination of immune checkpoint inhibitors with HDACi has shown promising results both in vitro and in vivo (133, >>134<<). HDACi enhance the immunotherapy response (135) and augment immunotherapy with PD-1 blockade in melanoma cells (136), inhibit apoptosis of CD4+ T cells within the tumor, upregulate antitumor immune responses and restrict tumor growth" . _:b646523811 "2"^^ . _:b76341334 "by disrupting protein degradation by inhibiting both the proteasome and aggresome with HDAC6i, resulting in the accumulation of significantly more polyubiquitinated proteins and causing increased cellular stress and apoptosis (94, 98, >>99<<). In addition to multiple myeloma, investigators have demonstrated that combination therapy with bortezomib and the Class I HDACi, MS275, apicidin, and romidepsin, resulted in apoptosis in vitro and in vivo of nasopharyngeal carcinoma" . _:b646523484 . _:b646523680 . _:b646523810 "2"^^ . . _:b646523640 . _:b646523821 "2"^^ . _:b646523760 . _:b646523820 "2"^^ . _:b646523823 "2"^^ . . _:b76341355 . _:b646523822 "2"^^ . _:b646523897 . _:b646523817 "2"^^ . . _:b646524102 . . _:b646523816 "2"^^ . . _:b646523819 "2"^^ . _:b76341347 "gov identifier: NCT00365599) (>>67<<). This study was for advanced breast cancer patients who progressed on prior hormone therapy, as an approach to restore hormone sensitivity to tamoxifen." . _:b646524157 . _:b646523189 . . _:b646523662 . . _:b646523418 . _:b646523818 "2"^^ . _:b76341383 . . _:b646524316 . _:b76341310 . _:b646523829 "2"^^ . . _:b646523314 . _:b646523828 "2"^^ . _:b646523831 "2"^^ . _:b76341344 . _:b646523830 "2"^^ . _:b646523779 . _:b646523825 "2"^^ . _:b646523150 . _:b646523824 "2"^^ . _:b646523827 "2"^^ . _:b646523626 . . _:b646523826 "2"^^ . _:b646523312 . . _:b646523183 . . _:b646523837 "2"^^ . . . _:b646523836 "2"^^ . _:b646523209 . _:b646523585 . _:b646523839 "2"^^ . _:b646524363 . _:b646523065 . . _:b646523838 "2"^^ . _:b76341312 "Although cisplatin treatment results in many cases as an initial therapeutic success, chemoresistance eventually develops particularly in non-germ cell solid tumors (25, >>75<<, 76). Thus, combining cisplatin with HDACi is a promising strategy to increase the efficacy of cisplatin (25). Concurrent SAHA (vorinostat) therapy has been shown to enhance tumor cell sensitivity to subtoxic doses of cisplatin in oral" . _:b76341260 "In 2006, SAHA (Vorinostat, Zolinza\u2122, Merck & Co, Inc., USA) became the first HDACi to be approved by the FDA for the treatment of cutaneous T-cell lymphoma (CTCL) (>>27<<). FK228 (Romidepsin, Istodax\u2122, Celgene Corp., USA), a cyclic peptide was later approved in 2009 for treating CTCL in patients who had received at least one prior systemic therapy (28)." . . _:b646523935 . . _:b646523833 "2"^^ . . _:b646523832 "2"^^ . . . . _:b646523835 "2"^^ . _:b646523834 "2"^^ . _:b646523845 "2"^^ . . _:b646524214 . _:b646523381 . _:b646523844 "2"^^ . _:b646523847 "2"^^ . _:b646523641 . _:b646523846 "2"^^ . . _:b646523318 . _:b646523170 . _:b646523841 "2"^^ . . _:b646524364 . _:b646523840 "2"^^ . _:b76341286 . . _:b646523843 "2"^^ . _:b646524285 . _:b646523842 "2"^^ . _:b646523225 . _:b646522993 . _:b646523655 . _:b646523853 "2"^^ . . _:b646523852 "2"^^ . _:b646523855 "2"^^ . _:b646524186 . _:b646523854 "2"^^ . . . _:b646523694 . _:b646523450 . _:b646523849 "2"^^ . . _:b646523848 "2"^^ . . . _:b646523166 . _:b646523851 "2"^^ . _:b76341272 . _:b646523850 "2"^^ . . _:b646523861 "2"^^ . . . _:b646523860 "2"^^ . _:b646523863 "2"^^ . _:b76341247 . . _:b646523862 "2"^^ . _:b646524184 . . _:b646523857 "2"^^ . . _:b76341374 . . _:b646523856 "2"^^ . _:b76341347 . _:b646522952 . _:b646523859 "2"^^ . . _:b646523858 "2"^^ . _:b646522960 . _:b646523869 "2"^^ . _:b76341257 . . _:b646523868 "2"^^ . . _:b76341249 "Histone deacetylases are often dysregulated in numerous disorders, including cancer, thereby influencing gene transcription and affecting normal cellular behavior (>>13<<, 20). High expression levels of HDAC1, 2, and 3 have been shown to be associated with poor patient outcomes in gastric and ovarian cancers (21, 22), while high expression of HDAC8 is correlated with poor survival and advanced disease in" . . _:b646523871 "2"^^ . . _:b646523870 "2"^^ . . . _:b646523865 "2"^^ . . _:b646523864 "2"^^ . . _:b646523867 "2"^^ . . _:b646523866 "2"^^ . _:b646523877 "2"^^ . _:b646523876 "2"^^ . _:b646524313 . _:b76341248 . . _:b646523879 "2"^^ . . _:b646523592 . _:b646523878 "2"^^ . . _:b646523532 . _:b646524272 . _:b646524273 . _:b646523873 "2"^^ . . _:b646524274 . . _:b646523384 . _:b646524275 . _:b646524276 . _:b646524277 . _:b646523872 "2"^^ . _:b646524278 . _:b646524279 . _:b646524280 . _:b646524281 . _:b646524354 . _:b646523875 "2"^^ . _:b646524282 . _:b646524283 . _:b646524284 . _:b646524285 . _:b646523874 "2"^^ . _:b646524286 . . _:b646524287 . _:b646524431 . _:b646523819 . _:b646524256 . _:b646524257 . _:b646523885 "2"^^ . _:b646524258 . _:b646524259 . _:b646524260 . _:b646524261 . _:b646523884 "2"^^ . _:b646523672 . _:b646524262 . _:b646524263 . _:b646524264 . _:b646524265 . _:b646523887 "2"^^ . _:b646524266 . . _:b646524267 . _:b646524268 . _:b646524269 . _:b646523886 "2"^^ . . _:b646524270 . _:b646524271 . _:b646524240 . . _:b646523881 "2"^^ . _:b646524241 . _:b646524242 . _:b646523396 . _:b646524243 . _:b646524183 . _:b646524244 . _:b646522986 . _:b646524245 . _:b646524370 . _:b646523880 "2"^^ . . _:b646524246 . _:b646524247 . . _:b646524248 . _:b646524249 . _:b646523883 "2"^^ . _:b646524250 . _:b646524251 . _:b646524252 . _:b646523556 . . _:b646523882 "2"^^ . _:b646524253 . _:b646524254 . _:b646524255 . _:b646524224 . _:b646524246 . _:b646524225 . _:b646523893 "2"^^ . _:b646524226 . _:b646524227 . _:b646524228 . _:b646524229 . _:b646524249 . _:b646523892 "2"^^ . _:b646524230 . _:b646524231 . _:b646523409 . _:b646524232 . _:b646524233 . _:b646523895 "2"^^ . _:b646524234 . . _:b646524235 . _:b646524236 . _:b646524237 . _:b646524158 . _:b646523894 "2"^^ . _:b646524238 . _:b646524239 . _:b646524208 . . _:b646523889 "2"^^ . _:b646524209 . _:b646524210 . _:b646524211 . _:b76341269 . _:b646524212 . _:b646524213 . _:b76341300 . _:b646523888 "2"^^ . _:b646524214 . _:b646523309 . _:b646524215 . _:b646524216 . . _:b646524217 . _:b646523891 "2"^^ . _:b646523888 . _:b646524218 . _:b646523499 . _:b646524219 . _:b646524220 . _:b646524221 . _:b646523890 "2"^^ . _:b646524222 . _:b646524223 . _:b646524192 . _:b646524193 . _:b646523901 "2"^^ . _:b646524194 . _:b646524195 . _:b646524196 . _:b646524197 . _:b646523900 "2"^^ . . _:b646524198 . _:b646524199 . _:b646524331 . _:b646524200 . . _:b646524201 . _:b646523903 "2"^^ . _:b646524202 . . _:b646524203 . _:b646524204 . _:b646524205 . _:b646523902 "2"^^ . _:b646524206 . _:b646524207 . _:b646524176 . _:b646524177 . _:b646523897 "2"^^ . _:b646523298 . _:b646524178 . _:b646524179 . _:b646523292 . _:b646524180 . _:b646524181 . _:b646523896 "2"^^ . _:b646524182 . _:b646524183 . _:b646524184 . _:b646523035 . _:b646523899 "2"^^ . _:b646524185 . _:b646524186 . _:b76341335 . _:b646524187 . _:b646524188 . _:b76341314 "Thus, combining cisplatin with HDACi is a promising strategy to increase the efficacy of cisplatin (>>25<<). Concurrent SAHA (vorinostat) therapy has been shown to enhance tumor cell sensitivity to subtoxic doses of cisplatin in oral squamous cell carcinoma cell lines (77). The authors showed that the combination of both drugs synergistically" . _:b646524189 . _:b646523898 "2"^^ . _:b646524190 . _:b646524191 . _:b646524160 . _:b646524170 . . _:b646523107 . _:b646524161 . _:b646524162 . _:b646524163 . _:b646524065 . _:b646524164 . _:b646524165 . . _:b646524166 . _:b646524167 . _:b646524168 . . _:b646524169 . _:b646524170 . _:b646522990 . _:b646524171 . _:b646524172 . _:b646524173 . _:b646524174 . . _:b646524175 . _:b646524400 . _:b646523294 . _:b646524401 . _:b646524402 . _:b646524403 . . . _:b646524404 . _:b646524405 . _:b646524406 . _:b646524407 . _:b646524408 . _:b646524409 . _:b76341325 . _:b646524410 . _:b646524411 . _:b646524412 . _:b646524413 . _:b76341324 . _:b646524414 . . _:b646524415 . _:b646524384 . _:b646524385 . _:b646524386 . _:b646523283 . _:b646524387 . _:b646524388 . _:b646524389 . _:b646524390 . . _:b646524391 . _:b646524392 . . _:b646524393 . _:b76341300 . _:b646524394 . _:b646524395 . _:b646524396 . . _:b646524397 . _:b646524398 . _:b646523676 . _:b646524399 . _:b646524368 . _:b646524369 . _:b646524370 . _:b646524371 . _:b646524372 . _:b646523016 . _:b646524373 . _:b646524374 . _:b646524375 . _:b646524376 . _:b646524377 . _:b646524378 . _:b646524379 . _:b646524380 . _:b646524381 . _:b646524382 . _:b646524383 . _:b646524352 . _:b646524149 . _:b646523899 . _:b646524353 . _:b646524354 . _:b646524355 . _:b646524356 . _:b646524357 . _:b646524358 . . _:b646524359 . _:b646524360 . . _:b646524361 . _:b646524362 . _:b646524363 . _:b646524364 . . _:b646524365 . _:b646523805 . _:b646524366 . _:b646524367 . _:b646524336 . _:b76341299 "While type I topoisomerases cleave one strand of the DNA double helix reversibly, type II enzymes mediate strand passage through a double-strand DNA gate (>>63<<). Compared to monotherapy, combination therapies with HDACi and topoisomerase II inhibitors have lead to higher nuclear topoisomerase II inhibitor accumulation, an increase in DNA damage, growth inhibition, and cell death (64\u201367)." . . _:b646524337 . _:b646524338 . . _:b646523287 . . _:b646524339 . _:b646524340 . . _:b646524341 . _:b646524342 . _:b646524343 . . _:b646524344 . _:b646524345 . _:b646524346 . _:b646524279 . . . _:b646524347 . _:b646524348 . _:b646524349 . _:b646524350 . _:b646524351 . _:b646524320 . _:b646524321 . _:b646524322 . _:b646524323 . _:b646523026 . . _:b646524324 . _:b646524325 . _:b646524326 . _:b646524327 . _:b646523695 . _:b646524328 . _:b646524329 . _:b646524330 . . _:b646524331 . _:b646524332 . _:b646524333 . _:b646524334 . _:b646524335 . . _:b646524304 . _:b646524305 . _:b646524306 . _:b646524307 . . _:b646524308 . _:b646524309 . . _:b646524310 . _:b646524311 . _:b646524312 . . _:b646524313 . _:b646524314 . _:b646524315 . . _:b646524316 . _:b646524317 . _:b646523104 . _:b646524318 . _:b646524319 . _:b646524288 . _:b646524289 . _:b646524290 . _:b646524404 . _:b646524056 . . _:b646524291 . _:b646524292 . _:b646524203 . . _:b646524293 . _:b646524294 . _:b76341282 "HDAC2 has been additionally shown to regulate the expression of chromatin remodeling proteins, including SMC1, an ATM substrate (>>50<<). More recently, research has shown that HDACs regulate ATM-mediated DNA damage signaling and established that HDAC1 and HDAC2 function as part of the DDR (46). The authors demonstrated that HDACi resulted in a reduced activation of ATM" . _:b646524295 . _:b646524296 . . _:b646524297 . _:b646524298 . _:b646524299 . _:b646524300 . _:b646524301 . _:b646524302 . _:b646524303 . _:b646523153 . _:b646524016 . _:b646524017 . . _:b646524018 . _:b646523373 . _:b646524019 . _:b646524020 . _:b646523346 . _:b646524021 . _:b646524022 . _:b646524023 . _:b646524024 . _:b646522942 . _:b646524025 . _:b646524026 . _:b646524027 . _:b646524028 . . . _:b646524029 . _:b646524088 . _:b646524030 . _:b646524031 . _:b646524000 . _:b646524001 . _:b646523703 . _:b646523430 . _:b646524002 . _:b646524003 . _:b646524004 . _:b646524005 . . _:b646524006 . _:b646524007 . _:b646524008 . _:b646524009 . _:b646524010 . _:b646523829 . _:b646524011 . _:b646524012 . _:b646522922 "18"^^ . _:b646524013 . _:b646524014 . _:b646524015 . _:b646524435 . _:b646524396 . _:b646522923 "17"^^ . _:b646523984 . _:b646522921 "25"^^ . _:b646523985 . _:b646523986 . _:b646523987 . _:b646522924 "17"^^ . _:b646523988 . _:b646523989 . _:b646524069 . _:b646523990 . _:b646523991 . _:b646522925 "17"^^ . _:b646523812 . _:b646523992 . _:b646523256 . _:b646523993 . _:b646522926 "14"^^ . _:b646523994 . _:b646523995 . _:b646523996 . _:b646522927 "14"^^ . _:b646523997 . _:b646523998 . _:b646523999 . _:b646523968 . _:b646522928 "14"^^ . _:b646523969 . _:b646523970 . . . _:b646523971 . . _:b646522934 "9"^^ . _:b646523972 . _:b646523973 . _:b646523974 . _:b646523975 . _:b646522935 "9"^^ . _:b646523976 . _:b646523977 . _:b646523978 . _:b646523979 . _:b646523980 . _:b646522932 "10"^^ . _:b646523981 . _:b646523982 . _:b76341250 "Histone deacetylases are often dysregulated in numerous disorders, including cancer, thereby influencing gene transcription and affecting normal cellular behavior (13, >>20<<). High expression levels of HDAC1, 2, and 3 have been shown to be associated with poor patient outcomes in gastric and ovarian cancers (21, 22), while high expression of HDAC8 is correlated with poor survival and advanced disease in" . _:b646523983 . . _:b646523247 . _:b646523952 . _:b646522933 "9"^^ . _:b646523953 . _:b646522931 "11"^^ . _:b646523632 . _:b646523954 . _:b646523955 . _:b646523956 . . _:b646523498 . _:b646523957 . _:b646523958 . _:b646522930 "12"^^ . _:b646523959 . _:b646523960 . _:b646523961 . _:b646523962 . _:b646523963 . . _:b646523964 . _:b646522929 "13"^^ . _:b646523965 . _:b646523966 . _:b646523967 . _:b646523936 . _:b646523937 . _:b646523938 . _:b646522942 "8"^^ . _:b646523939 . _:b646523940 . _:b646523014 . _:b646523941 . . . _:b646523942 . _:b646522943 "8"^^ . _:b646523943 . _:b646523944 . _:b646524334 . _:b646523827 . _:b646523945 . _:b76341239 "conclusion and future directions" . _:b646523946 . _:b646522940 "8"^^ . _:b646523947 . _:b646523764 . _:b646523948 . _:b646523949 . _:b646523950 . _:b646522941 "8"^^ . _:b646523951 . . _:b646523920 . _:b646523921 . _:b646523922 . _:b646522938 "8"^^ . _:b76341371 . _:b646523923 . _:b646523924 . _:b646523925 . _:b646523926 . _:b646522939 "8"^^ . _:b646523927 . _:b646523928 . . _:b646523929 . . _:b646523930 . _:b76341367 "This study showed that the molecular mechanism responsible for responses to DNA methyltransferase and HDACi combination therapy might include the reversal of aberrant epigenetic gene silencing (>>130<<) (ClinicalTrial." . . _:b646523931 . _:b646522936 "9"^^ . _:b646523932 . _:b646523933 . _:b646523934 . _:b646522937 "8"^^ . _:b646523935 . _:b646523904 . _:b646523905 . _:b646522950 "7"^^ . _:b646523906 . _:b646523907 . _:b646523908 . _:b646523909 . _:b646522951 "7"^^ . _:b646523910 . _:b646523911 . _:b646523912 . _:b646523913 . _:b646522948 "7"^^ . _:b646523914 . _:b646523915 . _:b646523916 . . _:b646523210 . _:b646523917 . _:b646522949 "7"^^ . _:b646523973 . _:b646523918 . _:b646523919 . _:b646524144 . _:b646524145 . _:b646523196 . _:b646524146 . _:b646522946 "8"^^ . _:b646523924 . _:b646524147 . _:b646524148 . . _:b646524149 . _:b646524150 . _:b646522947 "8"^^ . _:b646524151 . _:b646524152 . _:b646523141 . _:b646524153 . _:b646524154 . _:b646522944 "8"^^ . _:b646524155 . _:b646524156 . . _:b646524157 . _:b646524158 . _:b646522945 "8"^^ . _:b646524036 . _:b646524159 . _:b646524128 . . _:b646524129 . _:b646522958 "7"^^ . _:b646524130 . _:b646524131 . . _:b646524132 . _:b646524133 . _:b646522959 "7"^^ . _:b646523238 . _:b646524134 . _:b646524135 . . _:b646524136 . _:b646524137 . _:b646522956 "7"^^ . _:b646524138 . . _:b646524139 . _:b646524140 . _:b646524141 . . _:b646524142 . _:b646522957 "7"^^ . _:b646524143 . _:b646524112 . _:b646524113 . _:b646522954 "7"^^ . _:b646524114 . _:b646524115 . _:b646524116 . _:b646524117 . _:b646522955 "7"^^ . _:b646523515 . _:b646524118 . _:b646524119 . _:b646524120 . _:b646524163 . _:b646524121 . _:b646522952 "7"^^ . _:b646524122 . . _:b646524123 . _:b646524124 . _:b76341293 . _:b646524125 . _:b646522953 "7"^^ . _:b646524126 . _:b646524127 . . _:b646524096 . _:b646522966 "6"^^ . _:b646524097 . _:b646524098 . _:b646524099 . _:b646524100 . _:b646522967 "6"^^ . . _:b646524101 . _:b646524102 . _:b646524103 . _:b646524104 . _:b646522964 "6"^^ . _:b76341357 "Therefore, the combination of RTK targeted therapies and HDACi represents a novel approach for targeted cancer therapy (57, >>121<<). Sorafenib (BAY 43-9006) is a novel multikinase inhibitor which has been shown to block the RAS-RAF-MEK-MAPK pathway. Recent work has demonstrated that vorinostat and sorafenib synergistically kill tumor cells (122). Numerous phase I" . _:b646524105 . _:b646524106 . _:b646524107 . _:b646524108 . . _:b646522965 "6"^^ . _:b646524109 . _:b646524110 . _:b646524111 . . _:b646524080 . _:b646522962 "6"^^ . _:b646524081 . _:b646524082 . . _:b646523338 . _:b646524083 . _:b646524084 . _:b646522963 "6"^^ . _:b646524085 . _:b646524086 . _:b646524087 . _:b646524088 . _:b646522960 "6"^^ . _:b646524089 . _:b646524090 . _:b646524091 . _:b646524324 . _:b646524092 . _:b646522961 "6"^^ . _:b76341354 . _:b646524093 . _:b646524094 . _:b646524095 . _:b646524064 . . _:b646522974 "6"^^ . _:b646524065 . _:b646524066 . _:b646524067 . _:b646524068 . _:b646522975 "6"^^ . _:b646524069 . _:b646524070 . _:b646524071 . . _:b646524072 . _:b646522972 "6"^^ . _:b646524073 . . _:b646524074 . _:b646524075 . _:b646524076 . _:b646523468 . . _:b646524077 . _:b646522973 "6"^^ . _:b646524078 . _:b646524079 . _:b646523022 . _:b646524048 . _:b646522970 "6"^^ . _:b646524049 . _:b646524050 . _:b646524051 . _:b646524052 . _:b646522971 "6"^^ . _:b646524053 . _:b646524054 . _:b646524055 . _:b646524056 . _:b76341258 "HDACi have pleiotropic cellular effects (Figure 2) and induce the expression of pro-apoptotic genes/proteins, cause cellular differentiation and/or cell cycle arrest (13, 15, 19, >>25<<, 26). The classes of HDACs and the HDACi that are targeted against them are summarized in Table 1." . . _:b646524057 . _:b646522968 "6"^^ . _:b646524058 . _:b646524059 . _:b646524060 . _:b646522969 "6"^^ . _:b646524061 . _:b646524062 . _:b646524063 . . _:b646523650 . _:b646524032 . _:b646522982 "6"^^ . _:b646524033 . _:b646524034 . _:b646524035 . _:b646524036 . _:b646522983 "6"^^ . _:b646524037 . _:b646524038 . _:b646524039 . _:b646524040 . _:b646522980 "6"^^ . _:b646524041 . _:b646524042 . _:b646524106 . _:b646524043 . _:b646524044 . _:b646522981 "6"^^ . _:b646524045 . _:b646524046 . _:b646524093 . _:b646524047 . _:b646522978 "6"^^ . _:b646523623 . _:b646522979 "6"^^ . . _:b76341267 . _:b646522976 "6"^^ . . . _:b646522977 "6"^^ . . _:b646522990 "6"^^ . . _:b646522988 "6"^^ . _:b646523832 . _:b646522991 "5"^^ . _:b646522989 "6"^^ . . . . _:b646522986 "6"^^ . . . _:b646522987 "6"^^ . _:b76341303 "Preclinical studies have shown greater efficacy when cells were pretreated with HDACi prior to exposure to DNA damaging agents (64, 68), similar to the decondensation of chromatin seen in cells from breast and other cancers (>>50<<, 69). The first human phase I dose-escalation clinical study combining valproic acid and the topoisomerase II inhibitor, epirubicin, in solid malignancies has recently been performed (70). This study showed that valproic acid is well" . . . _:b646522984 "6"^^ . _:b76341270 . _:b646522985 "6"^^ . . _:b646523220 . _:b646522997 "5"^^ . _:b646523466 . . _:b646524095 . . _:b646522996 "5"^^ . _:b646524198 . _:b646522999 "5"^^ . _:b646522998 "5"^^ . _:b646524165 . _:b646522993 "5"^^ . _:b646524164 . _:b646522992 "5"^^ . _:b646524167 . . _:b646524299 . _:b646522995 "5"^^ . _:b646524166 . . _:b646523974 . _:b646522994 "5"^^ . _:b76341313 . _:b646524161 . _:b646523005 "5"^^ . _:b646524160 . . _:b76341281 "For instance, ATM has been shown to interact both in vitro and in vivo with HDAC1 and this interaction increases post-irradiation (46, >>49<<). HDAC2 has been additionally shown to regulate the expression of chromatin remodeling proteins, including SMC1, an ATM substrate (50). More recently, research has shown that HDACs regulate ATM-mediated DNA damage signaling and" . . _:b646523004 "5"^^ . _:b646524163 . . _:b646523828 . _:b76341285 . . _:b646524162 . _:b646523007 "5"^^ . _:b646524266 . . _:b646524173 . _:b646523006 "5"^^ . _:b646523550 . _:b646523001 "5"^^ . _:b646524172 . _:b646524113 . _:b646523000 "5"^^ . _:b646524175 . . _:b646523003 "5"^^ . _:b646524174 . _:b646523002 "5"^^ . _:b646524169 . . _:b646523013 "5"^^ . _:b646524168 . . _:b646523012 "5"^^ . _:b646524171 . . _:b646524261 . _:b646523015 "5"^^ . _:b646524170 . . _:b646523014 "5"^^ . _:b646524181 . _:b646524083 . _:b646523009 "5"^^ . _:b646524180 . _:b646523702 . _:b646523008 "5"^^ . _:b646524183 . _:b646523011 "5"^^ . _:b646524182 . _:b646523891 . . _:b76341349 . _:b646523010 "5"^^ . _:b646524177 . . _:b646523021 "5"^^ . _:b646524176 . _:b646523020 "5"^^ . _:b646524179 . _:b646523273 . _:b646523023 "5"^^ . _:b646524178 . . _:b646523022 "5"^^ . _:b646524189 . . _:b646523890 . _:b646523017 "5"^^ . _:b646524188 . _:b646523397 . _:b646523016 "5"^^ . _:b646524191 . . _:b646523714 . _:b646523976 . . _:b646523019 "5"^^ . _:b646524190 . . _:b646523670 . _:b646523018 "5"^^ . _:b646524185 . . _:b646523029 "5"^^ . _:b646524184 . _:b646523388 . _:b646523028 "5"^^ . _:b646524187 . _:b646522926 . _:b646523031 "5"^^ . _:b646524186 . _:b646523227 . _:b646523366 . _:b646523538 . _:b646524197 . _:b646523030 "5"^^ . _:b76341259 "hdaci that have been approved by the usa fda" . _:b646523025 "5"^^ . _:b646524196 . . . _:b646523024 "5"^^ . _:b646524199 . . _:b646523027 "5"^^ . _:b646524198 . _:b646523661 . . _:b646524193 . _:b646523026 "5"^^ . _:b646523876 . . _:b646523037 "5"^^ . _:b646524192 . . _:b646524286 . _:b646523036 "5"^^ . _:b646524195 . _:b646523039 "5"^^ . _:b646524194 . _:b646523038 "5"^^ . _:b646524205 . _:b646524288 . _:b646523033 "5"^^ . _:b646524204 . _:b646523428 . _:b646523032 "5"^^ . _:b646524207 . . _:b646523860 . _:b646523035 "5"^^ . _:b646524206 . . _:b646523034 "5"^^ . _:b646524201 . _:b646523833 . . _:b646523045 "4"^^ . _:b646524200 . _:b646523044 "4"^^ . _:b646524203 . _:b646524335 . _:b646523047 "4"^^ . _:b646524202 . _:b646523046 "4"^^ . _:b646524213 . . . _:b646523041 "4"^^ . _:b646524212 . _:b646523846 . _:b646523040 "5"^^ . _:b646524215 . _:b646523043 "4"^^ . _:b646524214 . _:b646524200 . _:b646524289 . _:b646523335 . _:b646523042 "4"^^ . _:b646524209 . . _:b646523053 "4"^^ . _:b646524208 . _:b646523589 . _:b646523179 . _:b646523052 "4"^^ . . . _:b646524211 . _:b646523055 "4"^^ . _:b646524210 . _:b646523054 "4"^^ . _:b646524221 . _:b646523049 "4"^^ . _:b646524217 . _:b646524220 . _:b646524436 . _:b646523048 "4"^^ . _:b646524223 . _:b646523051 "4"^^ . _:b646523255 . _:b646524222 . _:b646523069 . _:b646523050 "4"^^ . _:b646524217 . _:b646523061 "4"^^ . . _:b646524216 . _:b646523883 . _:b646523060 "4"^^ . _:b646524219 . _:b646523063 "4"^^ . . _:b646524218 . _:b646523902 . . _:b646523062 "4"^^ . . _:b646524229 . . . _:b646523006 . _:b646523057 "4"^^ . _:b646524228 . _:b646524127 . _:b646523056 "4"^^ . _:b646523212 . _:b646523133 . _:b646524231 . _:b646523059 "4"^^ . _:b646523147 . _:b646523155 . _:b646524230 . _:b646523058 "4"^^ . _:b646524225 . _:b646523322 . _:b76341349 "While HDACi as a monotherapy in prostate cancer has not shown promise in clinical trials (110\u2013112), in combination with the antiandrogen, bicalutamide, a synergistic cytotoxicity was observed in preclinical models (>>113<<\u2013115). There have been two completed trials evaluating the combination of HDACi and hormonal therapy in prostate cancer (116)." . _:b646523069 "4"^^ . _:b646524224 . _:b76341305 . . _:b646523068 "4"^^ . _:b646524227 . . _:b646523071 "4"^^ . _:b646524226 . _:b646523070 "4"^^ . _:b646524432 . _:b76341369 "At present, there are four immune checkpoint inhibitors approved by the FDA, ipilimumab (an anti-CTLA-4 drug), nivolumab and pembrolizumab (anti-PD-1 drugs), and the anti-PDL1 agents, such as atezolizumab, durvalumab, and avelumab (>>131<<, 132). There are over 500 ongoing clinical trials using immune checkpoint inhibitors for the treatment of various cancers including resected, localized, and advanced solid tumors and hematological malignancies." . _:b646524237 . _:b646524433 . _:b646524434 . _:b646523065 "4"^^ . _:b646524435 . _:b646524436 . _:b646524236 . _:b646524437 . _:b646524067 . _:b646524438 . _:b646523064 "4"^^ . _:b646524439 . _:b646524440 . _:b646524239 . _:b646524441 . _:b646524442 . . _:b646523067 "4"^^ . _:b646524443 . _:b646524444 . _:b646524238 . _:b646524445 . _:b646524446 . _:b646523526 . _:b646524012 . _:b646524447 . _:b646523066 "4"^^ . _:b646524416 . _:b646524233 . . _:b76341362 "The hypomethylating agents, azacitidine and decitabine, are active anticancer drugs currently FDA approved for treating AML, chronic myelomonocytic leukemia, and myelodysplatic syndromes (MDSs) (>>125<<, 126). The dual inhibition of HDACi with DNA-hypomethylating agents is a growing area of interest in the clinic. Recent in vitro work has demonstrated that the combination of valproic acid and decitabine synergistically inhibits growth" . _:b646524417 . _:b646524418 . _:b646523077 "4"^^ . _:b646523997 . _:b646524419 . _:b646524420 . _:b646524232 . _:b646524421 . _:b646524422 . . _:b646524423 . _:b646523076 "4"^^ . _:b646524424 . _:b646524235 . _:b646524425 . _:b646524426 . _:b646523079 "4"^^ . _:b646524427 . _:b646524428 . _:b646524234 . _:b646524429 . . _:b646524430 . _:b646523078 "4"^^ . _:b646523229 . _:b646524431 . _:b646524245 . _:b646523073 "4"^^ . . _:b646524244 . _:b646523072 "4"^^ . _:b646524247 . _:b646523075 "4"^^ . _:b646524246 . _:b646523743 . _:b646523074 "4"^^ . _:b646524241 . _:b646523085 "4"^^ . . _:b646524240 . _:b646523785 . _:b646523084 "4"^^ . _:b646524243 . _:b646523546 . _:b646523087 "4"^^ . _:b646524242 . . . _:b646523086 "4"^^ . _:b646524253 . _:b646524243 . _:b646523081 "4"^^ . _:b646524252 . . _:b646523080 "4"^^ . . _:b646524255 . _:b646523083 "4"^^ . _:b646524254 . _:b646524221 . _:b646523082 "4"^^ . _:b646524249 . _:b646523687 . _:b646523063 . _:b646523093 "4"^^ . _:b646524248 . _:b646523092 "4"^^ . _:b646524251 . . _:b646523095 "4"^^ . _:b646524250 . _:b646523094 "4"^^ . . _:b646524261 . . . _:b646523089 "4"^^ . _:b646523771 . _:b646524260 . _:b646523088 "4"^^ . _:b646524263 . _:b646523091 "4"^^ . _:b646524262 . _:b646523090 "4"^^ . _:b646524257 . _:b646523101 "4"^^ . _:b646524218 . _:b646523469 . _:b646524256 . _:b646523100 "4"^^ . _:b646523240 . _:b646524259 . _:b646523103 "4"^^ . _:b646524258 . _:b646523102 "4"^^ . _:b646524269 . . _:b646524049 . _:b646523097 "4"^^ . _:b646523324 . _:b646524268 . . . _:b646523096 "4"^^ . . _:b646524271 . _:b646523099 "4"^^ . . _:b646524270 . . . . . _:b646523098 "4"^^ . . _:b646524265 . . _:b646523109 "4"^^ . . _:b646524264 . _:b646523108 "4"^^ . _:b646523741 . _:b646524267 . . _:b646523111 "4"^^ . _:b646524266 . _:b646523110 "4"^^ . _:b646524228 . _:b646523248 . _:b646524277 . _:b646523249 . _:b646523250 . . _:b646523251 . _:b646523105 "4"^^ . . _:b646523252 . _:b646524276 . _:b646523253 . _:b646523254 . _:b646523104 "4"^^ . _:b646523255 . _:b646523256 . _:b646524279 . _:b646523257 . . _:b646523258 . _:b646523107 "4"^^ . . _:b646523259 . _:b646523260 . _:b646524278 . _:b646523261 . _:b646523262 . _:b646523106 "4"^^ . _:b646523263 . _:b646523232 . _:b646524273 . . _:b646523233 . _:b646523234 . _:b646523117 "4"^^ . _:b646523235 . _:b646523236 . _:b646524272 . _:b646523237 . . _:b646523942 . _:b646523238 . _:b646522935 . _:b646523239 . _:b646523116 "4"^^ . . _:b76341331 . _:b646524275 . . _:b646523240 . _:b646523241 . _:b646524189 . _:b646523242 . _:b76341275 . _:b646523119 "4"^^ . _:b76341253 . _:b646523243 . _:b646523244 . _:b646524274 . _:b646523245 . _:b646523246 . _:b646523118 "4"^^ . _:b646523247 . _:b646523216 . _:b646524285 . _:b646523217 . _:b646523218 . _:b76341273 . _:b646523113 "4"^^ . _:b646523219 . _:b646523220 . _:b646524284 . _:b646523221 . _:b646523222 . _:b646523112 "4"^^ . _:b646523223 . _:b646523224 . _:b646524287 . . _:b646523225 . _:b646523226 . _:b646523115 "4"^^ . _:b646523227 . _:b646523228 . _:b646524286 . _:b646523229 . _:b646523206 . _:b646523230 . _:b646523114 "4"^^ . _:b646523231 . _:b646523200 . _:b646524281 . _:b76341368 "combining hdaci with immune checkpoint inhibitors" . _:b646523201 . _:b646523202 . _:b646523125 "4"^^ . _:b646523203 . _:b646523204 . _:b646524280 . _:b646523205 . _:b646523206 . . . _:b646523207 . _:b646523124 "4"^^ . _:b646523208 . _:b646524283 . . _:b646523209 . _:b646523210 . . _:b646523211 . _:b646523127 "4"^^ . _:b646523215 . _:b646523698 . _:b646524282 . . _:b646523212 . _:b646523628 . _:b646523213 . _:b646523214 . _:b646523126 "4"^^ . _:b646523215 . _:b646523184 . _:b76341380 "Of the 47 patients who took part in the study, an objective response of 37% was observed, a 13.8-month median progression-free survival as seen and 65.3\u2009months was the overall survival (>>142<<). Additionally, a phase III trial evaluating endocrine therapy with the HDACi, entinostat, or placebo in hormone receptor-positive breast cancer patients is about to commence (ClinicalTrial.gov identifier: NCT02115282) (140)." . _:b646524293 . _:b646523185 . _:b646523186 . _:b646523121 "4"^^ . _:b76341356 . _:b646523301 . _:b646523187 . _:b646523188 . _:b646524292 . . _:b646523189 . _:b646523190 . . _:b646523191 . _:b646523120 "4"^^ . _:b646523192 . _:b646524295 . . _:b646523193 . _:b646523194 . _:b646523123 "4"^^ . _:b646523666 . _:b646523195 . _:b646523196 . _:b646524294 . _:b646524098 . _:b646523197 . _:b646523198 . _:b646523122 "4"^^ . _:b646523199 . _:b646523168 . _:b646524289 . _:b646522973 . _:b646523169 . . _:b646523170 . _:b646523133 "4"^^ . _:b646523171 . _:b646523172 . _:b646524288 . _:b646523173 . _:b646523174 . _:b646523132 "4"^^ . _:b646523175 . _:b646523176 . _:b646524291 . _:b646523177 . _:b646523080 . _:b646523178 . _:b646523135 "4"^^ . _:b76341346 . _:b646523179 . _:b646523180 . _:b646524290 . _:b646523181 . _:b646523645 . _:b646523182 . _:b646524156 . _:b646523134 "4"^^ . _:b646523183 . _:b646523152 . _:b646524301 . . . _:b646523153 . _:b646523154 . _:b76341312 . _:b646524295 . _:b646523129 "4"^^ . _:b646523155 . _:b76341239 _:b76341240 . _:b76341239 _:b76341241 . _:b646524300 . _:b646523156 . _:b646523157 . _:b646523158 . _:b646523128 "4"^^ . _:b646523159 . _:b646523160 . _:b646524303 . _:b646523161 . _:b646523162 . _:b646523131 "4"^^ . _:b646523163 . _:b646523164 . _:b646524302 . _:b646523165 . _:b646523166 . _:b646523130 "4"^^ . _:b646523167 . _:b646523136 . _:b646524297 . _:b646523137 . _:b646523138 . _:b646523141 "4"^^ . . _:b646523352 . _:b646523139 . _:b646523140 . _:b646524296 . _:b646523141 . _:b646523142 . _:b646523140 "4"^^ . _:b76341375 "HDACi enhance the immunotherapy response (135) and augment immunotherapy with PD-1 blockade in melanoma cells (136), inhibit apoptosis of CD4+ T cells within the tumor, upregulate antitumor immune responses and restrict tumor growth (>>137<<). It was recently shown in mice that cancers resistant to the immune checkpoint inhibitors, anti-PD-1 and anti-CTLA-4, could be cured by eliminating myeloid-derived suppressor cells (MDSCs) (138)." . _:b646523143 . _:b646523144 . _:b646524299 . _:b646523145 . . _:b646523146 . _:b646523143 "4"^^ . _:b646523147 . _:b646523148 . _:b646524298 . _:b646523149 . _:b646523150 . _:b646523142 "4"^^ . _:b646523151 . _:b76341235 _:b76341236 . _:b76341235 _:b76341237 . _:b646524309 . _:b646523376 . _:b76341235 _:b76341238 . _:b646523377 . _:b646523378 . _:b646523137 "4"^^ . _:b646523379 . _:b646523380 . _:b646524308 . _:b646523184 . _:b646523381 . . _:b646523382 . _:b646523136 "4"^^ . _:b646523383 . _:b646522938 . _:b646524311 . _:b646523384 . _:b646523385 . . _:b646523386 . _:b646523127 . _:b646523387 . _:b646523139 "4"^^ . _:b646523388 . _:b646524310 . _:b646523816 . _:b646523025 . _:b646523389 . _:b646523405 . _:b646523390 . _:b646523138 "4"^^ . _:b646524357 . _:b646523391 . _:b646523360 . _:b646524305 . _:b646523916 . _:b646523361 . _:b646523362 . _:b646523149 "4"^^ . _:b646523925 . _:b646523363 . _:b76341242 _:b76341244 . _:b646523605 . _:b646524304 . _:b646523364 . _:b76341242 _:b76341245 . _:b76341242 _:b76341246 . _:b646523365 . . _:b646523366 . _:b76341242 _:b76341247 . _:b646523148 "4"^^ . _:b646523367 . _:b646523368 . _:b646524307 . _:b646522931 . _:b646523369 . _:b76341242 _:b76341243 . _:b646523370 . _:b646523151 "4"^^ . _:b646524224 . _:b646523371 . _:b646523372 . _:b646524306 . _:b646523373 . _:b646523374 . _:b646523150 "4"^^ . _:b646523375 . _:b646523344 . _:b646524317 . _:b646523345 . . _:b646523912 . _:b646523346 . _:b646523145 "4"^^ . _:b646523347 . _:b646523348 . _:b646524316 . _:b646523349 . _:b646523021 . _:b646523350 . _:b646523144 "4"^^ . _:b646524001 . _:b646523351 . _:b646523352 . _:b646524319 . _:b646523353 . _:b646523389 . _:b646523354 . . _:b76341327 . _:b646523355 . _:b646523147 "4"^^ . _:b646523356 . _:b646524318 . _:b646522985 . _:b646523357 . _:b646523358 . . _:b646523359 . _:b646523146 "4"^^ . . _:b646524313 . _:b646523328 . _:b646523286 . _:b646522977 . _:b646523329 . _:b646523157 "3"^^ . _:b646523330 . _:b646523331 . _:b646523332 . _:b646524312 . _:b646523333 . _:b646523156 "3"^^ . _:b646523334 . _:b646523335 . _:b646523336 . _:b646524315 . _:b646523337 . _:b646523159 "3"^^ . _:b646523338 . . _:b646523339 . _:b646523340 . _:b646524314 . _:b646523341 . _:b646523158 "3"^^ . . _:b646523342 . _:b646523343 . _:b646523312 . _:b646524325 . _:b646523313 . _:b646523314 . _:b646523782 . _:b646523153 "4"^^ . _:b646523315 . _:b646523316 . _:b646524324 . . _:b646523317 . . _:b646523318 . _:b646523152 "4"^^ . _:b646523319 . . _:b646524327 . _:b646523320 . _:b646523321 . _:b646523155 "3"^^ . _:b646523322 . _:b646523323 . . _:b646523324 . _:b646524326 . _:b646523325 . _:b646523326 . _:b646524320 . _:b646524259 . _:b646523154 "4"^^ . _:b646523327 . _:b646523296 . _:b646524321 . _:b646523297 . _:b646523165 "3"^^ . _:b646523298 . _:b646523299 . _:b646523300 . _:b646524320 . _:b646523301 . . _:b646523164 "3"^^ . _:b646523302 . _:b646523675 . _:b646523303 . _:b646523304 . _:b646524323 . _:b646523305 . . _:b646523306 . _:b646523167 "3"^^ . . . _:b646523307 . . _:b646524322 . _:b646523308 . _:b646523309 . _:b646523166 "3"^^ . _:b646523932 . _:b646523310 . _:b646523311 . _:b646523280 . _:b646524333 . _:b646523281 . _:b646523161 "3"^^ . _:b646523282 . _:b646523283 . _:b646523284 . _:b646524332 . . _:b646523285 . _:b646523160 "3"^^ . _:b646523286 . _:b646523287 . _:b646523288 . _:b646524437 . _:b646524335 . _:b646523289 . _:b646523163 "3"^^ . _:b646523290 . _:b646523291 . . _:b646524334 . _:b646523292 . _:b646523293 . _:b646523378 . _:b646523162 "3"^^ . _:b646524274 . _:b646523294 . _:b646522957 . _:b646523295 . . . _:b646524329 . _:b646523264 . _:b646523265 . _:b646523040 . _:b646523266 . _:b646523173 "3"^^ . . _:b646523267 . _:b646523268 . _:b646524328 . _:b646523759 . _:b646523269 . . _:b646523270 . _:b646523172 "3"^^ . _:b646523271 . _:b646523272 . _:b646524331 . . _:b76341274 . _:b646523273 . _:b646523175 "3"^^ . _:b646523274 . _:b646523275 . _:b646523276 . _:b646524330 . _:b646523277 . _:b646523174 "3"^^ . _:b646523951 . _:b646523278 . _:b646523279 . _:b646522992 . _:b646524341 . _:b646524039 . _:b646522993 . _:b646523520 . _:b646523169 "3"^^ . . _:b646522994 . _:b646522995 . . _:b646524340 . _:b646522996 . _:b646522997 . _:b646523762 . _:b646522998 . _:b646523168 "3"^^ . _:b646522999 . _:b646523000 . _:b646524343 . _:b646523001 . _:b646523171 "3"^^ . _:b646523002 . _:b646523003 . _:b646523004 . _:b646524342 . _:b646523005 . _:b646523170 "3"^^ . _:b646523006 . _:b646523007 . _:b646522976 . _:b646524337 . _:b646522977 . _:b646523181 "3"^^ . . _:b646522978 . _:b646522979 . _:b646522980 . _:b646524336 . _:b646522981 . _:b76341376 "It was recently shown in mice that cancers resistant to the immune checkpoint inhibitors, anti-PD-1 and anti-CTLA-4, could be cured by eliminating myeloid-derived suppressor cells (MDSCs) (>>138<<). The authors demonstrated that the HDACi, entinostat, targeted the mouse granulocytic MDSCs, responsible for the resistance to immune checkpoint blockade seen. In a mouse model of lung and renal cell carcinoma, entinostat was" . _:b646523180 "3"^^ . _:b646522982 . . _:b646522983 . _:b646522984 . _:b646524339 . _:b646522985 . . _:b646523183 "3"^^ . _:b646522986 . _:b646523400 . _:b646522987 . _:b646522988 . _:b646524338 . _:b646522989 . _:b646523182 "3"^^ . _:b646522990 . _:b646522991 . _:b646522960 . _:b646524349 . _:b646523362 . _:b646522961 . _:b646523177 "3"^^ . _:b646522962 . _:b646522963 . _:b76341236 . . _:b646522964 . _:b646524348 . _:b646523711 . _:b646522965 . _:b646523176 "3"^^ . _:b646522966 . _:b646522967 . _:b646522968 . _:b646524351 . _:b646522969 . _:b76341342 . . _:b646522970 . _:b646523179 "3"^^ . _:b646522971 . _:b646522972 . _:b646524350 . _:b646523793 . _:b646522973 . _:b646523178 "3"^^ . _:b646523920 . _:b646522974 . _:b646522975 . _:b646522944 . _:b646524345 . _:b646522945 . _:b646523189 "3"^^ . . _:b646522946 . _:b646522947 . . _:b646524344 . _:b646522948 . . _:b646522949 . _:b646523188 "3"^^ . _:b646522950 . _:b646522951 . _:b76341291 . _:b646522952 . _:b76341313 "Although cisplatin treatment results in many cases as an initial therapeutic success, chemoresistance eventually develops particularly in non-germ cell solid tumors (25, 75, >>76<<). Thus, combining cisplatin with HDACi is a promising strategy to increase the efficacy of cisplatin (25). Concurrent SAHA (vorinostat) therapy has been shown to enhance tumor cell sensitivity to subtoxic doses of cisplatin in oral" . _:b646524347 . _:b646522953 . _:b646523191 "3"^^ . _:b646522954 . _:b646522955 . _:b646522956 . _:b646524346 . . _:b646522957 . _:b646523190 "3"^^ . _:b646523980 . _:b646522958 . _:b646522959 . _:b646522928 . _:b646524357 . _:b646522929 . _:b646523802 . _:b646523755 . _:b646523185 "3"^^ . _:b646522930 . _:b646522931 . _:b646522932 . _:b646524356 . _:b646522933 . _:b646523184 "3"^^ . _:b646522934 . _:b646522935 . _:b646523505 . _:b646522936 . _:b646524359 . _:b646522937 . _:b646523187 "3"^^ . _:b646524284 . _:b646522938 . . _:b646522939 . _:b646522940 . _:b646524358 . _:b646522941 . _:b646523579 . _:b646523186 "3"^^ . _:b646522942 . _:b646522943 . _:b646522948 . _:b646524353 . _:b646523572 . _:b646523197 "3"^^ . _:b646524352 . _:b646523196 "3"^^ . _:b646524355 . _:b646522921 . _:b646523199 "3"^^ . _:b646522922 . _:b646522923 . _:b646524137 . _:b646522924 . _:b646524354 . _:b646522925 . _:b646523198 "3"^^ . _:b646522926 . _:b646522927 . . . _:b646524365 . _:b646523193 "3"^^ . _:b76341342 "Strategies inhibiting estrogen and androgen signaling in breast and prostate cancers, respectively, have shown clinical success (105, >>106<<). Aberrant acetylation and HDAC expression has been observed in both breast and prostate cancer cell lines and patient tumors (107, 108). Thus, the combination of HDACi and hormonal therapy is under investigation in both clinical and" . . _:b646523564 . _:b646524364 . . _:b646524263 . _:b646523192 "3"^^ . _:b646524367 . _:b646523195 "3"^^ . . _:b646524366 . _:b646523194 "3"^^ . _:b76341237 "Indeed, as cytotoxic drugs target naturally regenerating tissues, mainly the bone marrow and gastrointestinal tract, the formation of secondary hematologic and solid tumors may be seen many years following treatment (>>4<<\u20137). Combining anticancer drugs with other chemotherapeutic agents is often used to maximize efficacy, while reducing toxicity and resistance by administering lower drug doses, and their combination has shown synergistic or additive" . _:b646524361 . _:b646523720 . _:b646523205 "3"^^ . _:b646524360 . _:b646524314 . _:b646523204 "3"^^ . _:b646524363 . . _:b646523207 "3"^^ . _:b646523486 . _:b646524362 . . _:b646523206 "3"^^ . _:b76341254 "Additionally, dysregulation of HDAC1 expression was demonstrated to correlate with poor prognosis in multiple myeloma (>>24<<). HDACi are currently used in the clinic as anticancer agents and are a powerful new class of small-molecular therapeutics that alters the regulation of histone and non-histone proteins. HDACi increase the acetylation of core histones," . _:b646524219 . _:b646523120 . _:b646524373 . _:b646523121 . _:b646523940 . _:b646523201 "3"^^ . _:b646523122 . _:b646523123 . . _:b646524372 . _:b646523124 . _:b646523774 . _:b646523125 . . _:b646523200 "3"^^ . _:b646523126 . _:b646523127 . _:b646523128 . _:b646524375 . _:b646523129 . _:b646523203 "3"^^ . _:b646523130 . _:b646523131 . _:b646523864 . . _:b646524374 . _:b646523132 . _:b646523186 . _:b646523133 . . _:b646523134 . _:b646523202 "3"^^ . _:b646523135 . _:b646523104 . _:b646524369 . _:b646523599 . _:b646524272 . _:b646523105 . _:b646523213 "3"^^ . _:b646523106 . _:b646523107 . _:b646523108 . _:b646524368 . _:b646523109 . _:b646523212 "3"^^ . _:b646523110 . _:b646523111 . _:b646523112 . _:b646524371 . _:b646523113 . _:b76341337 . _:b646523215 "3"^^ . _:b646523114 . _:b646523115 . _:b646524379 . _:b646523116 . _:b646524370 . _:b646523117 . _:b646523214 "3"^^ . _:b646523118 . _:b646523119 . _:b646523088 . _:b646524381 . _:b646523761 . _:b646523089 . _:b646523209 "3"^^ . _:b646523090 . _:b646523091 . _:b646523092 . _:b646524380 . _:b646523093 . _:b646523208 "3"^^ . _:b646523094 . _:b646523095 . _:b646524123 . _:b646523096 . _:b646524383 . _:b646523097 . . _:b646523098 . _:b646523211 "3"^^ . _:b646523099 . _:b646523100 . _:b646524382 . _:b646523101 . _:b76341317 . _:b646524222 . _:b646523210 "3"^^ . _:b646523102 . _:b646523103 . _:b646523072 . _:b646524377 . _:b646523073 . . _:b646523074 . _:b646523221 "3"^^ . _:b646523075 . _:b646523251 . _:b646524376 . _:b646523076 . _:b646523077 . _:b646523220 "3"^^ . _:b76341383 "Indeed, prior to FDA approval, there were six deaths in patients treated with romidepsin (>>143<<\u2013145). In order to minimize the off-target toxicity of HDACi, tissue and cell targeted delivery of HDACi and the identification of isoform selective HDACi will become the focus of future research into HDACi." . _:b646523078 . _:b646523079 . _:b646523080 . _:b646524379 . . . _:b646523081 . _:b646523223 "3"^^ . _:b646523082 . _:b646523083 . _:b646523084 . _:b646524378 . _:b646524019 . _:b646523085 . _:b646523105 . _:b646523086 . _:b646523222 "3"^^ . _:b646523087 . _:b646523056 . _:b646524389 . _:b646523160 . _:b646523057 . _:b646523217 "3"^^ . _:b646523058 . _:b646523059 . . _:b646523060 . _:b646524388 . _:b646523061 . _:b646523216 "3"^^ . _:b646523062 . _:b646523063 . _:b646523064 . _:b646524391 . _:b646523065 . _:b646524169 . _:b646523219 "3"^^ . _:b646523066 . _:b646523067 . _:b646523068 . _:b646524390 . . _:b646523069 . . _:b646523218 "3"^^ . _:b646523070 . _:b646523071 . . _:b646524385 . _:b646523040 . _:b646523041 . . _:b646523229 "3"^^ . _:b646523042 . _:b646523043 . _:b646523044 . _:b646524384 . . _:b646523045 . . _:b646523998 . _:b646523046 . _:b646523228 "3"^^ . _:b646523047 . _:b646523048 . _:b646524387 . . _:b646523049 . _:b646523231 "3"^^ . _:b646523050 . . _:b646523051 . _:b646523052 . _:b646524386 . . _:b646523053 . _:b646523230 "3"^^ . _:b646523054 . _:b646523055 . _:b646523024 . _:b646524397 . _:b646524005 . _:b646523025 . _:b646523225 "3"^^ . _:b646524229 . _:b646523026 . _:b646523027 . _:b646523028 . _:b646524396 . _:b646523029 . _:b646523224 "3"^^ . _:b646523030 . . _:b646523031 . _:b646523032 . _:b646524399 . _:b646523033 . _:b646523077 . _:b646523034 . _:b646523227 "3"^^ . _:b646523035 . _:b646523351 . _:b646524398 . . _:b646523036 . _:b646523037 . _:b646523226 "3"^^ . _:b76341385 . _:b646523038 . _:b646523039 . _:b646523008 . _:b646524393 . _:b646523009 . _:b646523237 "3"^^ . _:b646523010 . _:b646523011 . _:b646523012 . _:b646524392 . _:b646523013 . _:b646523350 . _:b646523288 . _:b646523014 . _:b646523236 "3"^^ . _:b646523015 . _:b646523016 . _:b646524395 . . _:b646523394 . _:b646523017 . _:b646523239 "3"^^ . _:b646523018 . _:b646523019 . _:b646523020 . _:b646524394 . _:b646522949 . _:b646523021 . . _:b646523238 "3"^^ . _:b646523022 . _:b646523023 . _:b646523760 . _:b646524405 . _:b646523761 . . _:b646523762 . _:b646523233 "3"^^ . _:b646523763 . _:b646523854 . _:b646523764 . _:b646524404 . _:b646523765 . _:b646523232 "3"^^ . _:b646523766 . _:b646523767 . _:b646523768 . _:b646524407 . _:b646523769 . . _:b646523235 "3"^^ . _:b646523770 . _:b646523771 . _:b646523772 . _:b646524406 . _:b646523773 . _:b646523234 "3"^^ . _:b646523774 . . _:b646523775 . . _:b646523744 . _:b646524401 . _:b646523745 . _:b646523245 "3"^^ . _:b646523746 . . _:b646523747 . _:b646523674 . _:b646523748 . _:b646524400 . _:b646523749 . _:b646523244 "3"^^ . _:b646523750 . _:b646523751 . _:b646523752 . _:b646524403 . _:b646523753 . _:b646523247 "3"^^ . _:b646523754 . _:b646523755 . _:b646523756 . _:b646524402 . _:b646523757 . _:b646523246 "3"^^ . _:b646523758 . _:b646523759 . _:b646523728 . _:b646524413 . _:b646523729 . _:b646523241 "3"^^ . _:b646523730 . _:b646523731 . . _:b646524412 . _:b646523732 . _:b646523733 . _:b646523240 "3"^^ . _:b646523734 . _:b646523735 . _:b646523736 . _:b646524415 . _:b646523737 . _:b646523243 "3"^^ . _:b646523738 . _:b646523739 . _:b646523995 . _:b646523740 . _:b646524414 . _:b646523741 . . _:b646523742 . _:b646523242 "3"^^ . _:b646523743 . _:b76341345 "While vorinostat as a monotherapy was not found to be effective against the treatment of MBC (>>109<<), in combination therapy with the anti-estrogen, tamoxifen, it has shown great promise (57)." . _:b646523712 . _:b646524409 . _:b646523713 . _:b646523253 "3"^^ . _:b646523714 . _:b646523715 . _:b646523716 . _:b646524408 . _:b646524162 . _:b646523717 . _:b646523252 "3"^^ . _:b646524254 . _:b646523718 . _:b646523719 . _:b646523720 . _:b646524411 . _:b646523721 . _:b646524077 . _:b646523255 "3"^^ . _:b646523722 . _:b646523723 . _:b646523724 . _:b646524410 . _:b646523725 . _:b646523254 "3"^^ . _:b646523726 . _:b646523727 . _:b646523180 . _:b646523909 . _:b646523696 . _:b646523697 . _:b646523249 "3"^^ . _:b646523698 . _:b646523699 . _:b646523700 . _:b646523908 . _:b646523701 . _:b646523248 "3"^^ . _:b646523702 . _:b646523703 . _:b646523704 . _:b646523911 . . _:b646523705 . _:b646523251 "3"^^ . _:b646523706 . _:b646523707 . _:b646524138 . . _:b646523910 . _:b646523708 . _:b646523709 . _:b646523250 "3"^^ . _:b646523710 . . _:b646523711 . _:b646523680 . _:b646523905 . _:b646522922 . _:b646523681 . _:b646523261 "3"^^ . _:b646523862 . _:b646523682 . _:b646523683 . _:b646523684 . _:b646523904 . . _:b646523685 . _:b646523260 "3"^^ . _:b646523686 . _:b646523687 . _:b646523688 . _:b646523907 . . _:b646523689 . _:b646523263 "3"^^ . _:b646523690 . _:b646523691 . _:b646523692 . _:b646523906 . _:b646523693 . _:b646523604 . _:b646523694 . _:b646523262 "3"^^ . _:b646523695 . _:b646523664 . _:b76341350 "There have been two completed trials evaluating the combination of HDACi and hormonal therapy in prostate cancer (>>116<<). The initial trial was a phase II trial with vorinostat in combination with bicalutamide and radical prostatectomy, in patients with localized prostate cancer (ClinicalTrial.gov identifier: NCT00589472) (117). The second clinical trial" . _:b646523917 . _:b646523665 . _:b646523257 "3"^^ . _:b646523666 . _:b646523245 . _:b646523667 . _:b646523668 . _:b646523916 . _:b646523669 . _:b646523256 "3"^^ . _:b646523670 . _:b646523671 . _:b646523672 . _:b646523919 . _:b646523673 . _:b646523259 "3"^^ . _:b646523674 . _:b646523675 . _:b646523676 . _:b646523918 . . _:b646523677 . . _:b646523258 "3"^^ . _:b646523678 . _:b646523679 . _:b646523648 . _:b646523913 . _:b646523649 . _:b646524014 . _:b646523269 "3"^^ . _:b646523650 . _:b646523651 . _:b646523652 . _:b646523912 . _:b646523653 . _:b646523268 "3"^^ . _:b646523654 . _:b646523655 . _:b646523656 . _:b646523915 . _:b646523657 . _:b646523271 "3"^^ . _:b646523658 . _:b646523659 . . _:b646523914 . _:b646523660 . _:b646523661 . _:b646523270 "3"^^ . _:b646523662 . _:b646523663 . . . _:b646523925 . _:b646523888 . _:b646523889 . _:b646523265 "3"^^ . _:b646523890 . _:b646523891 . _:b646523892 . _:b646523924 . . _:b76341278 "Ataxia-telangiectasia patients, with defective ATM protein, display increased genomic instability, chromatin decondensation, and radiosensitivity (>>47<<). Interestingly, cells treated with HDACi display a similar phenotype (48). There is increasing evidence to suggest that HDACs regulate ATM. For instance, ATM has been shown to interact both in vitro and in vivo with HDAC1 and this" . _:b646523893 . _:b646523264 "3"^^ . _:b646523894 . _:b646523895 . _:b646523896 . _:b646523927 . _:b646523512 . _:b646523897 . _:b646523267 "3"^^ . _:b646523898 . _:b646523899 . _:b646523525 . _:b646523926 . _:b646523900 . . _:b646523901 . _:b646523266 "3"^^ . _:b646523902 . _:b646523903 . _:b646523872 . _:b646523921 . _:b646523873 . _:b646523277 "3"^^ . _:b646523874 . _:b646523875 . _:b646523876 . _:b646523920 . _:b646523877 . _:b646523276 "3"^^ . _:b646523878 . _:b646523879 . _:b646523880 . _:b646523923 . _:b646523881 . _:b646523279 "3"^^ . _:b646523882 . _:b646523883 . _:b76341256 . _:b646523884 . _:b646523922 . _:b646523885 . _:b646523873 . _:b646523278 "3"^^ . _:b646523886 . _:b646523887 . _:b646523856 . _:b76341243 . _:b646523933 . . _:b646523857 . _:b646523273 "3"^^ . _:b646524282 . _:b646523858 . _:b646523859 . _:b646523860 . _:b646523932 . _:b646523861 . _:b646523272 "3"^^ . _:b646523862 . _:b646523863 . _:b646523545 . _:b646523935 . _:b646523864 . _:b646523865 . _:b646523533 . _:b646523275 "3"^^ . _:b646523866 . _:b646523867 . _:b646523868 . _:b646523934 . _:b646523869 . _:b646523274 "3"^^ . _:b646523870 . _:b646523871 . _:b646524278 . . _:b646523929 . _:b646523840 . _:b646523841 . _:b646523285 "3"^^ . _:b646523842 . _:b646523843 . _:b646523849 . _:b646523844 . _:b646523928 . _:b646523845 . _:b646523284 "3"^^ . _:b76341293 "In preclinical studies, HDACi have shown radiosensitizing effects with glioblastoma multiforme, melanoma, and head and neck squamous, colorectal, non-small cell lung, prostate, and MBCs (>>58<<). The first group to publish a case report on use of an HDACi with radiotherapy used valproic acid in combination with cisplatin and doxorubicin, 40\u2009Gy radiation, and surgery to successfully treat a patient with anaplastic thyroid" . _:b646523846 . _:b646523847 . _:b646523848 . _:b646523931 . _:b646523849 . _:b646523287 "3"^^ . _:b646523850 . _:b646523851 . _:b646523852 . _:b646523930 . . _:b646523853 . _:b646524023 . _:b646523286 "3"^^ . _:b646523854 . _:b646523855 . _:b646523824 . _:b646523941 . _:b646523825 . . _:b646523281 "3"^^ . _:b646523826 . _:b646523827 . _:b646523651 . _:b646523940 . _:b646523828 . _:b646523829 . _:b646523280 "3"^^ . _:b646523830 . _:b646523831 . _:b76341260 . . _:b646523943 . _:b646523832 . . _:b646523833 . _:b646523283 "3"^^ . _:b646523834 . _:b646523835 . _:b646523836 . _:b646523942 . _:b646523837 . _:b646523282 "3"^^ . _:b646523838 . _:b646523839 . _:b646523808 . _:b646523937 . _:b646523809 . _:b646523293 "3"^^ . _:b646523994 . _:b646523810 . _:b646523811 . _:b646523812 . _:b646524060 . _:b646523936 . _:b646523813 . _:b646523990 . _:b646523292 "3"^^ . _:b646523814 . _:b646523815 . _:b646523201 . _:b646523939 . . _:b646523816 . _:b646523817 . _:b646524096 . _:b646523295 "3"^^ . _:b646523818 . _:b646523819 . _:b646523820 . _:b646523938 . _:b646523821 . . _:b646523822 . _:b646523294 "3"^^ . _:b646523590 . _:b646523823 . _:b646523792 . _:b646523949 . . _:b646523793 . _:b646523289 "3"^^ . _:b646523794 . . _:b646523795 . _:b646523796 . _:b646523948 . _:b646523797 . _:b646523288 "3"^^ . _:b646523798 . . _:b646523799 . _:b646523800 . _:b646523951 . _:b646523801 . _:b646523291 "3"^^ . _:b646523371 . _:b646523802 . _:b646523803 . _:b646523804 . _:b646523950 . . _:b646523805 . _:b646523614 . . _:b646523806 . _:b646523290 "3"^^ . _:b646523807 . _:b646523776 . _:b646523945 . _:b646523777 . _:b646523301 "3"^^ . _:b646523778 . . _:b646523779 . _:b646523780 . _:b646523944 . _:b646523781 . _:b646523831 . _:b646523300 "3"^^ . _:b646523782 . _:b646523783 . . _:b646523947 . _:b646523784 . _:b646523785 . _:b646524326 . _:b646523303 "3"^^ . _:b646523786 . _:b646523787 . _:b646523788 . _:b646523946 . _:b646523789 . . _:b646523790 . _:b646523302 "3"^^ . . _:b646523791 . _:b646523504 . _:b646523957 . _:b646523505 . _:b646523297 "3"^^ . _:b646523506 . _:b646523507 . _:b646523508 . _:b646523956 . . _:b646523509 . _:b646523296 "3"^^ . _:b646523510 . _:b646523511 . _:b646523512 . _:b646523959 . _:b646523513 . _:b646523299 "3"^^ . _:b646524337 . _:b646523514 . _:b646523515 . _:b646523516 . _:b646523958 . _:b646523887 . _:b646523517 . _:b646523298 "3"^^ . _:b646523518 . _:b646523519 . _:b646523488 . _:b76341380 . _:b646523953 . _:b646523489 . _:b646523309 "3"^^ . _:b646523490 . _:b646523491 . . _:b646523952 . _:b646523492 . _:b646523493 . _:b646523308 "3"^^ . _:b646523494 . _:b646523495 . _:b646523496 . _:b646523955 . _:b646523497 . _:b646523311 "3"^^ . _:b646523498 . _:b646523499 . _:b646523500 . _:b646523954 . _:b646523501 . _:b646523310 "3"^^ . _:b646523502 . . . _:b646523712 . _:b646523503 . _:b646523472 . _:b646523965 . _:b646523473 . . _:b646523474 . _:b646523305 "3"^^ . _:b646523475 . _:b646523476 . _:b646523964 . _:b646523477 . _:b646523272 . _:b646523478 . _:b646523304 "3"^^ . _:b646523479 . _:b646523480 . _:b646523967 . _:b646523481 . _:b646523307 "3"^^ . _:b646523482 . _:b646523483 . _:b646523484 . _:b646523966 . _:b646523485 . _:b646523017 . _:b646523486 . _:b646523306 "3"^^ . _:b646523487 . _:b646523456 . _:b646523961 . _:b646523457 . _:b646523317 "3"^^ . _:b646523458 . . _:b646524255 . _:b646523459 . _:b646523460 . _:b646524444 . _:b646523960 . . _:b646523461 . _:b646523316 "3"^^ . _:b646523462 . _:b646523463 . _:b646523464 . _:b76341280 "For instance, ATM has been shown to interact both in vitro and in vivo with HDAC1 and this interaction increases post-irradiation (>>46<<, 49). HDAC2 has been additionally shown to regulate the expression of chromatin remodeling proteins, including SMC1, an ATM substrate (50). More recently, research has shown that HDACs regulate ATM-mediated DNA damage signaling and" . _:b646523963 . _:b646523465 . _:b646523319 "3"^^ . _:b646523466 . . _:b646523379 . _:b646523054 . _:b646523467 . _:b646523468 . _:b646523962 . _:b646523469 . _:b646523893 . _:b646523318 "3"^^ . _:b646523470 . _:b646523713 . _:b646523471 . _:b646523440 . _:b646523973 . _:b646523441 . _:b646523313 "3"^^ . _:b646523442 . _:b646523443 . _:b646523444 . _:b646523972 . . _:b646523445 . _:b646523312 "3"^^ . _:b646523446 . _:b646523447 . _:b646523541 . _:b646523975 . _:b646523448 . _:b646523449 . _:b646523315 "3"^^ . _:b646523450 . _:b646523451 . _:b646523452 . _:b646523974 . _:b646523453 . _:b646523314 "3"^^ . _:b646523454 . _:b646523455 . _:b646523574 . _:b646523969 . _:b646523424 . _:b646523425 . . _:b646523426 . _:b646523325 "3"^^ . _:b646523427 . _:b646523428 . _:b646523968 . _:b646523429 . _:b646523917 . _:b646523324 "3"^^ . _:b646523430 . _:b646523431 . . _:b646523971 . _:b646523432 . _:b646523433 . _:b646523327 "3"^^ . _:b646523434 . _:b646523435 . _:b646523825 . _:b646523436 . _:b646523970 . _:b646523437 . _:b646523326 "3"^^ . _:b646523438 . _:b646523439 . _:b646523408 . _:b646524152 . _:b646523981 . _:b646523409 . _:b646523321 "3"^^ . _:b646523410 . . _:b646523411 . _:b646523412 . _:b646523980 . _:b646523413 . _:b646523320 "3"^^ . _:b646523414 . _:b646523415 . _:b646523416 . _:b646523983 . _:b646523169 . . _:b646523417 . _:b646523323 "3"^^ . _:b646523418 . _:b646523419 . _:b646523420 . _:b646523982 . _:b646523421 . _:b646523322 "3"^^ . _:b646523422 . _:b646523423 . _:b646523392 . _:b76341255 . _:b646523977 . _:b646523393 . _:b646523333 "3"^^ . _:b646523394 . _:b646523395 . _:b646523396 . _:b646523976 . . _:b646523397 . _:b76341382 "side effects and the search for biomarkers of hdaci" . _:b646523398 . _:b646523332 "3"^^ . _:b646523399 . . _:b76341249 . _:b646523979 . _:b646523400 . _:b646523401 . _:b646523335 "3"^^ . _:b646523402 . _:b646523403 . _:b646523404 . _:b646523978 . _:b646523405 . _:b646523334 "3"^^ . _:b646524207 . _:b646523406 . _:b646523407 . _:b646523632 . _:b646523989 . _:b646523633 . _:b646523329 "3"^^ . _:b646523634 . _:b646523635 . _:b646523636 . _:b646523988 . _:b646523637 . _:b646523328 "3"^^ . _:b646523638 . _:b646523639 . _:b646523640 . _:b646523991 . _:b646523641 . _:b646523331 "3"^^ . _:b646523642 . _:b646523643 . . _:b646523990 . _:b646523644 . _:b646523645 . _:b646523330 "3"^^ . _:b646523646 . _:b646523647 . _:b646523616 . _:b646523985 . _:b646523826 . _:b646523617 . _:b646523341 "3"^^ . _:b646523618 . _:b646523619 . _:b646523620 . _:b646523984 . . _:b646523621 . . _:b646523622 . _:b646523340 "3"^^ . _:b646523623 . _:b646523624 . _:b646523987 . _:b646523625 . _:b646523343 "3"^^ . . _:b646523626 . _:b646523627 . . _:b646523986 . _:b646523628 . . _:b646523629 . _:b646523342 "3"^^ . _:b646523630 . _:b646523631 . _:b646523600 . _:b646523997 . . _:b646523601 . _:b646523337 "3"^^ . _:b646523602 . _:b646523603 . _:b646523604 . _:b646523996 . _:b646523605 . . _:b646523336 "3"^^ . _:b646523606 . _:b646523607 . . _:b646523999 . _:b646523608 . _:b646523609 . _:b646523339 "3"^^ . _:b646523610 . . _:b646523611 . _:b646523612 . _:b646523998 . _:b646523613 . _:b646523338 "3"^^ . _:b646523614 . _:b646523615 . _:b646523056 . _:b646523993 . _:b646523584 . . _:b646523585 . _:b646523349 "3"^^ . _:b646523586 . _:b646523587 . _:b646523588 . _:b646524252 . _:b646523992 . _:b646523589 . _:b646523348 "3"^^ . _:b646523590 . _:b646523591 . _:b76341242 _:b76341256 . _:b646523995 . _:b646523592 . _:b76341242 _:b76341257 . _:b646524303 . _:b646523593 . _:b646523351 "3"^^ . _:b646523594 . _:b76341242 _:b76341258 . _:b646523595 . _:b76341242 _:b76341252 . _:b646523994 . _:b646523596 . . _:b646523597 . _:b76341242 _:b76341253 . _:b646523350 "3"^^ . _:b646523598 . _:b76341242 _:b76341254 . _:b76341242 _:b76341255 . _:b646523599 . _:b76341242 _:b76341248 . _:b646524005 . _:b646523568 . _:b76341242 _:b76341249 . _:b646523569 . _:b646523345 "3"^^ . _:b646524016 . _:b646523570 . _:b76341242 _:b76341250 . _:b76341242 _:b76341251 . _:b646523571 . _:b646523572 . _:b646524240 . _:b646524004 . _:b646523573 . _:b646523344 "3"^^ . _:b646523574 . _:b646523575 . _:b646523576 . _:b646524007 . _:b646523577 . _:b646523347 "3"^^ . _:b646523578 . _:b646523579 . _:b646523580 . _:b646524006 . _:b646523581 . _:b646523346 "3"^^ . _:b646523582 . . _:b646523583 . _:b646523552 . _:b646524001 . _:b646523553 . _:b646523357 "3"^^ . _:b646523554 . _:b646523555 . _:b646523556 . _:b646524000 . _:b646523557 . _:b646523356 "3"^^ . _:b646523558 . _:b646523559 . _:b646523560 . _:b646524003 . . _:b76341307 . _:b646523561 . _:b646523359 "3"^^ . _:b646523562 . _:b646523157 . _:b646523563 . _:b646523564 . _:b646524002 . _:b646523565 . _:b646523358 "3"^^ . _:b646523566 . _:b646523123 . _:b646523567 . _:b646523536 . _:b646524085 . _:b646524013 . . _:b646523537 . _:b646523353 "3"^^ . _:b646523538 . _:b646523539 . . _:b646524012 . _:b646523540 . _:b646523541 . _:b646523352 "3"^^ . _:b646523542 . . _:b646523543 . _:b646523544 . _:b646524015 . . _:b646523545 . . _:b646523546 . _:b646523355 "3"^^ . _:b646523547 . _:b646523548 . _:b76341265 "High levels of Bcl-2, Trx, and peroxiredoxins have previously been implicated with resistance of transformed cells to chemotherapy and may form the basis of resistance seen with HDACi (>>31<<\u201333). Increased expression of the cell cycle protein, p21, elevated levels of thioredoxin leading to lower reactive-oxygen species (ROS)-mediated DNA damage, constitutive activation of NF\u03BAB through p65 acetylation and elevated expression" . _:b646524014 . . _:b646523549 . _:b646523354 "3"^^ . _:b646524044 . _:b646523550 . _:b646523363 . _:b646523551 . _:b646523520 . _:b646524009 . _:b646523521 . _:b646523365 "3"^^ . _:b646523522 . _:b646523523 . _:b646523524 . _:b646524008 . . _:b646523525 . . _:b646523526 . _:b646523364 "3"^^ . _:b646523527 . _:b646523810 . _:b646523528 . _:b646524011 . _:b646523529 . _:b646523367 "3"^^ . _:b646523991 . _:b646523530 . _:b646523531 . _:b646523532 . _:b646524010 . . _:b646523533 . _:b646523366 "3"^^ . _:b646523534 . _:b646523535 . _:b646524021 . _:b646522996 . _:b646523361 "3"^^ . _:b646524020 . _:b646523178 . _:b646523360 "3"^^ . _:b646524023 . _:b646523363 "3"^^ . _:b646523921 . _:b646524022 . _:b646524033 . _:b646523362 "3"^^ . _:b646524017 . _:b646523373 "3"^^ . _:b646524016 . _:b646523372 "3"^^ . _:b646523339 . _:b646523020 . . _:b646524019 . _:b646523151 . _:b646523375 "3"^^ . . . _:b646524018 . . _:b646523682 . _:b646523374 "3"^^ . . _:b646524029 . _:b646523369 "3"^^ . _:b646524028 . _:b646523368 "3"^^ . _:b646524031 . _:b646523371 "3"^^ . _:b646524441 . . _:b646524030 . . . _:b646523370 "3"^^ . . _:b646524025 . . . _:b646523381 "3"^^ . _:b646523993 . _:b646524024 . _:b646523380 "3"^^ . _:b646524027 . _:b646523521 . _:b646523383 "3"^^ . _:b646524026 . _:b646524058 . _:b646523382 "3"^^ . _:b646524037 . _:b646523454 . _:b646524130 . _:b646523267 . _:b646523377 "3"^^ . . _:b646524036 . _:b646523376 "3"^^ . _:b76341352 "combination of hdaci with tyrosine kinase pathway inhibitors" . _:b646523134 . _:b646524002 . _:b646524039 . _:b646523379 "3"^^ . . _:b646524038 . . _:b646523765 . . _:b646523378 "3"^^ . . _:b646524033 . . _:b646523389 "3"^^ . . _:b646524032 . . _:b646523388 "3"^^ . . _:b76341279 "Interestingly, cells treated with HDACi display a similar phenotype (>>48<<). There is increasing evidence to suggest that HDACs regulate ATM." . _:b646524035 . _:b646523403 . _:b646523391 "3"^^ . _:b646524347 . _:b646524034 . _:b646523390 "3"^^ . _:b646524045 . . _:b646523385 "3"^^ . _:b646523892 . _:b646524044 . _:b646523384 "3"^^ . _:b646524047 . _:b76341354 "Therefore, RTKs are promising therapeutic targets (118, >>119<<). Activation of RTK has been demonstrated to activate RAS-RAF-MEK-MAPK and PI3K-AKT pathways among others." . _:b646522947 . . _:b646523387 "3"^^ . _:b646524046 . _:b646523386 "3"^^ . _:b646523836 . . _:b646524041 . _:b76341373 . . . _:b646524040 . _:b76341272 . . _:b646524390 . _:b646523253 . _:b76341385 "The study identified a nine-gene RNA expression signature useful in predicting trichostatin A or vorinostat-induced apoptosis and may lead to individualized treatment for patients with NSCLC (>>147<<). Additionally, further studies showed increased nuclear STAT1 and phospho-STAT3 staining in CTCL cells was associated with a lack of clinical response to vorinostat. The authors concluded that blocking this pathway may lead to" . _:b646524043 . . _:b646522928 . . . _:b646523595 . _:b646524042 . . _:b646524053 . _:b646524052 . _:b646523062 . _:b646524055 . _:b646524073 . _:b646524051 . _:b646523495 . _:b646524054 . _:b646524049 . . _:b646524048 . _:b646524051 . _:b646523264 . . _:b646524050 . . _:b646523146 . . . _:b646524061 . _:b646524060 . _:b646524063 . . _:b646524062 . _:b646523679 . _:b646524057 . _:b646524056 . . _:b646524059 . _:b646524058 . _:b646524028 . _:b646524069 . . . . _:b646523747 . _:b646524068 . _:b646524300 . . _:b646524071 . _:b646524070 . . _:b646524065 . . _:b646523510 . _:b646523130 . . _:b646524064 . . _:b646524125 . . . _:b646524067 . _:b646523953 . . _:b646524120 . _:b646524066 . . . _:b646524077 . . _:b646524076 . _:b76341302 . _:b646523749 . . . _:b646524079 . _:b646524078 . _:b646524073 . _:b646524072 . . . _:b646524075 . . . _:b646524074 . . . _:b646524085 . _:b646524084 . _:b646524009 . . . _:b646524087 . _:b646523972 . _:b646524086 . . _:b646524081 . . _:b76341251 . _:b646524080 . . . _:b646524083 . . _:b646524082 . _:b646524093 . . . _:b646524092 . _:b646524095 . . . . _:b646524094 . . _:b646524089 . _:b646524304 . _:b646523485 . _:b646524088 . _:b646524063 . . _:b646524091 . _:b646522972 . _:b646524319 . . _:b646524090 . _:b646524101 . _:b646524100 . _:b646524241 . . . _:b646524280 . _:b646524103 . _:b646523419 . _:b646524102 . _:b646524097 . _:b646523019 . _:b646524096 . . . _:b646524099 . . _:b646524062 . _:b646524098 . . _:b646524109 . _:b646524400 . _:b646523524 . _:b646524215 . . _:b646524094 . _:b646524108 . _:b646523121 . . _:b646524111 . _:b646524110 . . _:b76341317 "Carboplatin (cyclobutane-1,1-dicarboxylate-O,O\u2032) was developed as an analog of cisplatin that results in less nephron and neurotoxicity than cisplatin, but results in the same DNA adducts (>>80<<). A phase I clinical study was carried out to determine the safety and pharmacokinetics of the HDACi, belinostat, with carboplatin and/or paclitaxel in solid tumors." . _:b646523652 . _:b646524105 . _:b646523950 . _:b646524104 . _:b646524107 . . _:b646524106 . _:b76341323 "combining hdaci and proteasome inhibitors" . _:b646524117 . . _:b646524116 . . _:b646524119 . _:b646523938 . . _:b646524118 . _:b646523513 . _:b646524113 . _:b646523815 . _:b646524112 . _:b646524115 . _:b646524114 . _:b646524125 . . _:b646524124 . _:b646523076 . _:b646523064 . _:b646524127 . _:b646523763 . . _:b646524126 . _:b646524121 . . _:b646524120 . _:b646523139 . . _:b646524123 . . _:b646524047 . . _:b646524122 . . _:b646524021 . _:b646524133 . _:b646523814 . _:b646523433 . _:b646524132 . . . _:b646524135 . _:b646524134 . _:b646524424 . _:b646524129 . _:b646524128 . _:b646524131 . . _:b646524130 . _:b646524141 . _:b646524140 . . _:b646524348 . . _:b646524143 . _:b646524142 . _:b646524351 . _:b646524137 . _:b646523542 . . _:b646524136 . _:b646524139 . _:b646524070 . _:b646523824 . _:b646524138 . _:b646524208 . _:b76341304 "Preclinical studies have shown greater efficacy when cells were pretreated with HDACi prior to exposure to DNA damaging agents (64, 68), similar to the decondensation of chromatin seen in cells from breast and other cancers (50, >>69<<). The first human phase I dose-escalation clinical study combining valproic acid and the topoisomerase II inhibitor, epirubicin, in solid malignancies has recently been performed (70)." . _:b646524149 . _:b646523001 . . _:b646524148 . _:b646524151 . _:b646523476 . _:b646524150 . _:b646524145 . _:b646524144 . _:b646524147 . . . _:b646524146 . . . _:b646524157 . . _:b646523927 . _:b646524156 . . _:b76341236 . _:b646524159 . . _:b646523307 . _:b646524158 . . . . _:b646524153 . _:b646522966 . _:b646524152 . _:b646524155 . . _:b76341319 . _:b646524154 . _:b646523653 . _:b646523652 . . . _:b646523361 . . _:b646524401 . _:b646523655 . . _:b646523654 . _:b646523649 . _:b646523949 . _:b646523649 . . _:b646523648 . . _:b646523651 . _:b646523650 . _:b646523661 . _:b76341371 "The combination of immune checkpoint inhibitors with HDACi has shown promising results both in vitro and in vivo (>>133<<, 134). HDACi enhance the immunotherapy response (135) and augment immunotherapy with PD-1 blockade in melanoma cells (136), inhibit apoptosis of CD4+ T cells within the tumor, upregulate antitumor immune responses and restrict tumor" . . _:b646523660 . _:b646523808 . _:b646523663 . . _:b646523662 . _:b646523856 . . _:b646523657 . . _:b646523656 . _:b76341255 "HDACi have pleiotropic cellular effects (Figure 2) and induce the expression of pro-apoptotic genes/proteins, cause cellular differentiation and/or cell cycle arrest (>>13<<, 15, 19, 25, 26)." . _:b646523726 . _:b646523456 . _:b646523659 . _:b646523910 . . _:b646523658 . _:b646523079 . _:b646523669 . . _:b646523174 . _:b646524367 . _:b76341363 "The hypomethylating agents, azacitidine and decitabine, are active anticancer drugs currently FDA approved for treating AML, chronic myelomonocytic leukemia, and myelodysplatic syndromes (MDSs) (125, >>126<<). The dual inhibition of HDACi with DNA-hypomethylating agents is a growing area of interest in the clinic. Recent in vitro work has demonstrated that the combination of valproic acid and decitabine synergistically inhibits growth and" . _:b646523668 . . . _:b646523671 . . . _:b646523670 . _:b646523796 . _:b646523665 . _:b646523664 . _:b646523667 . . _:b646522998 . _:b76341237 . _:b646523666 . _:b646523677 . _:b646523676 . . _:b646524283 . _:b646523679 . _:b646523678 . . _:b76341341 "Strategies inhibiting estrogen and androgen signaling in breast and prostate cancers, respectively, have shown clinical success (>>105<<, 106). Aberrant acetylation and HDAC expression has been observed in both breast and prostate cancer cell lines and patient tumors (107, 108). Thus, the combination of HDACi and hormonal therapy is under investigation in both clinical and" . _:b646523278 . _:b646523673 . _:b646523448 . . _:b646523672 . _:b646523675 . . _:b646524276 . _:b646523674 . . _:b646523685 . . . _:b646523684 . . _:b646523731 . _:b646523560 . _:b646523687 . _:b646523686 . _:b646523681 . _:b646523848 . _:b76341252 "High expression levels of HDAC1, 2, and 3 have been shown to be associated with poor patient outcomes in gastric and ovarian cancers (21, >>22<<), while high expression of HDAC8 is correlated with poor survival and advanced disease in neuroblastoma (23)." . . _:b646523680 . . _:b646523502 . _:b646523683 . _:b646523237 . . . _:b646523682 . . _:b646523693 . _:b646523563 . _:b646523044 . _:b646523692 . _:b646523695 . _:b646522984 . _:b646523694 . _:b646523689 . _:b646524035 . _:b646523688 . . . _:b646523691 . . _:b646523690 . _:b646523289 . _:b646523701 . _:b646523700 . _:b646524194 . _:b646523071 . _:b646523136 . _:b646523493 . _:b646522927 . _:b646523703 . _:b646523702 . _:b76341296 . _:b646524418 . _:b646523844 . _:b646523697 . _:b76341290 "HDACi enhance the radiosensitivity of cancer cells (>>56<<, 57). HDACi have been shown in vitro to lower a cell\u2019s ability to repair IR-induced DNA damage, by affecting DNA damage signaling and the NHEJ and HR DSB repair pathways (17)." . _:b646523696 . _:b646523516 . _:b646523699 . _:b646523036 . . . _:b646523698 . . _:b646523709 . . _:b646523708 . _:b646523711 . _:b76341322 "Overall, this study demonstrated that vorinostat enhanced the efficacy of carboplatin and paclitaxel in patients with NSCLC patients (84, >>85<<); however, the phase III trial with this combination was terminated due to lack of efficacy (ClinicalTrial." . _:b646523148 . _:b646522991 . _:b646524025 . _:b76341238 . _:b646523710 . _:b646524220 . _:b646523591 . _:b646523705 . . _:b646523704 . . . _:b646523707 . _:b646524041 . . _:b646523370 . _:b646523706 . _:b646523983 . _:b646523717 . _:b646524092 . . _:b646523015 . . _:b646523716 . . _:b646523719 . _:b646524430 . _:b646523718 . . _:b646523713 . _:b646523712 . _:b646523914 . _:b646524408 . _:b646523616 . _:b646523715 . _:b646522933 . . _:b646523965 . _:b646523714 . _:b646523319 . _:b646523725 . _:b646524302 . _:b646523310 . . . _:b646523724 . . . _:b646523727 . _:b646523268 . . _:b646523726 . _:b646523721 . _:b646524018 . _:b646523696 . _:b646523720 . . _:b646523099 . _:b646523723 . _:b646523722 . _:b646523391 . . . _:b646523733 . _:b646523732 . . _:b646523735 . _:b646523734 . . _:b646523729 . _:b646522953 . . _:b646523345 . . _:b646523728 . _:b646523731 . _:b76341284 . _:b646523730 . _:b646523741 . _:b646523740 . _:b646523894 . _:b76341383 . . _:b646523743 . _:b646523781 . _:b646523742 . . _:b646523737 . _:b646523736 . . _:b646523739 . . _:b646523348 . _:b646523548 . _:b646523738 . _:b646523421 . . _:b646523749 . _:b646523748 . _:b76341236 . . _:b646523751 . _:b646523750 . _:b646524133 . . . _:b646523745 . _:b646523432 . _:b646523744 . . _:b646523747 . _:b646523746 . _:b646523757 . . _:b646524103 . _:b646523756 . _:b646523759 . . _:b646523758 . _:b646524145 . . _:b646523753 . . _:b646523752 . _:b646523481 . _:b646524446 . . _:b646523755 . _:b76341241 . . _:b76341358 "Recent work has demonstrated that vorinostat and sorafenib synergistically kill tumor cells (>>122<<). Numerous phase I clinical trials have been conducted with the combination of sorafenib and HDACi for treating patients with advanced/metastatic solid malignancies and refractory/relapsed acute myeloid leukemia (AML), soft tissue" . _:b646523754 . _:b646523765 . _:b646523764 . _:b646522944 . _:b646523767 . _:b646523766 . _:b646523274 . _:b646523761 . . _:b646523760 . _:b646523763 . _:b646523871 . _:b646523236 . _:b646523762 . . _:b646523773 . _:b646524114 . _:b646523772 . . _:b646523775 . _:b646524242 . . _:b646523774 . _:b646523769 . . _:b646523768 . . . _:b646523771 . . _:b646523770 . . . _:b646523781 . . . _:b646523780 . _:b646523719 . . _:b646523783 . _:b646523527 . _:b646523332 . _:b76341240 . . _:b646523782 . . . _:b646523777 . . _:b646524287 . _:b646523776 . . _:b646523032 . _:b646523779 . _:b646523955 . _:b646523778 . _:b646522925 . _:b646524151 . _:b646523789 . _:b646524172 . _:b646524006 . _:b646523788 . . _:b646523791 . _:b646523790 . _:b646523785 . _:b646523784 . . _:b646523787 . _:b646523786 . . _:b646523797 . _:b646523796 . _:b76341360 "Studies have demonstrated that gefitinib combined with HDACi synergistically induces growth inhibition and apoptosis in gefitinib-resistant NSCLC cells (>>124<<). Currently, there is a phase I/II clinical trial combining Gefitinib and vorinostat in relapsed/refractory patients with advanced NSCLC (ClinicalTrial.gov identifier: NCT01027676) and phase I study of vorinostat combined with gefitinib" . _:b646523799 . _:b646523959 . _:b646524079 . . _:b646523798 . . _:b76341334 . _:b646524230 . . _:b646523482 . _:b646523793 . _:b646523620 . _:b646523792 . _:b76341338 . _:b646523269 . _:b646523795 . . . _:b646523794 . _:b76341386 . _:b646523442 . _:b646523805 . _:b646522992 . . . . _:b646523878 . _:b646523804 . _:b646523529 . _:b646523807 . _:b646523806 . . _:b646524107 . _:b646523501 . _:b646523374 . _:b646523801 . _:b646523244 . _:b76341241 "As epigenetic changes that occur during the development of cancer are reversible and amenable to pharmacological intervention, HDACi provide a unique avenue of treating cancers (>>150<<). Over the last few years we have witnessed the approval of HDACi by the FDA, the approval of the PARP inhibitor, olaparib, the proteasome inhibitor, cafilzomib, and in 2011 the approval of the first immune checkpoint inhibitor," . _:b646523800 . _:b646523941 . _:b646523803 . . _:b646523802 . . _:b646524168 . _:b646523804 . _:b646523813 . _:b76341268 "Hence, the identification of these mutations may enable the selective targeting of individual cancers susceptible to HDACi (>>36<<). Despite the approval by the FDA for the treatment of certain cancers, HDACi have been shown to have a limited therapeutic efficacy against solid tumors as a single therapeutic agent. HDACi have, however, been shown to function" . _:b646523812 . _:b646524236 . _:b646523815 . . . _:b646523814 . _:b646523029 . _:b646523800 . . _:b646523809 . _:b646523354 . _:b646523966 . _:b646523414 . _:b646523808 . . _:b646523811 . _:b646523744 . _:b646523810 . _:b646523012 . _:b646524336 . _:b646523735 . _:b646523821 . . _:b646523820 . . _:b646523823 . . _:b646523822 . _:b646523817 . _:b646523729 . _:b76341339 . _:b646523816 . . _:b646523342 . _:b646524108 . _:b646523819 . . . _:b646524000 . . _:b646523818 . . _:b646523829 . . _:b646523828 . . _:b76341370 . _:b646523831 . _:b646523830 . _:b646523233 . _:b646523975 . . _:b646523825 . . _:b646523824 . _:b646523827 . . _:b646523631 . _:b646523826 . _:b646523566 . _:b646523837 . . _:b646523443 . _:b646523836 . _:b646523839 . _:b646524423 . _:b646523699 . _:b646523838 . . _:b646523833 . . _:b646523832 . . _:b646523835 . _:b646523834 . _:b646523896 . _:b646524235 . _:b646523543 . _:b646523845 . _:b646523844 . _:b646524142 . . _:b646523088 . _:b646523847 . _:b646523846 . . _:b76341349 . _:b646523511 . _:b646523447 . _:b646523841 . . _:b646523840 . _:b646523843 . _:b76341309 "Cis-diamminedichloroplatinum(II) (cisplatin) was first approved in 1978 for the treatment of bladder and testicular cancer (>>73<<, 74). Cisplatin has since been used as a first-line therapy for many different solid malignancies, including head and neck, ovarian, bladder, testicular, colorectal, bladder, cervical, and lung cancers, as a monotherapy or in combination" . _:b646523842 . _:b646523316 . _:b646523853 . . _:b646523664 . _:b76341280 . _:b646523852 . . _:b646523777 . _:b646523855 . . . _:b646523854 . _:b76341373 "HDACi enhance the immunotherapy response (>>135<<) and augment immunotherapy with PD-1 blockade in melanoma cells (136), inhibit apoptosis of CD4+ T cells within the tumor, upregulate antitumor immune responses and restrict tumor growth (137)." . _:b646524362 . _:b76341283 . _:b646523849 . _:b76341330 . _:b646523848 . . . _:b646523851 . _:b646523850 . _:b646523116 . _:b646523861 . _:b646523341 . _:b646523860 . _:b646523060 . . _:b646523863 . _:b646523439 . _:b646523862 . . . _:b646523857 . . . _:b646523856 . _:b646523859 . _:b646523659 . _:b646523858 . _:b76341306 . _:b646523869 . . _:b646524057 . _:b646523488 . _:b646523868 . . _:b646524281 . . . _:b646523871 . _:b646524026 . . _:b646523870 . _:b646523865 . _:b646523830 . _:b646524110 . _:b646523864 . . _:b646523653 . _:b76341237 . . _:b646523867 . _:b646523866 . _:b646524187 . _:b646523877 . _:b646523978 . . _:b646523876 . _:b646523879 . _:b646524322 . _:b646523878 . _:b646524084 . _:b646523873 . . _:b646524148 . _:b646523872 . _:b646523875 . . . _:b646523874 . _:b646523895 . _:b76341271 "hdaci in combination with drugs that target dna repair pathways" . _:b646523885 . _:b646523884 . _:b646523887 . _:b646523700 . _:b646523886 . _:b646523881 . _:b646523880 . _:b646523822 . _:b646523883 . _:b646523882 . _:b646523033 . _:b646524126 . _:b646523893 . _:b646524066 . _:b646523791 . . _:b646523892 . _:b76341285 "Olaparib is approved for the treatment of germline BRCA-mutated advanced ovarian cancer in patients who have received prior chemotherapy (51, >>52<<). A recently reported phase III clinical trial has demonstrated that olaparib monotherapy is significantly superior to physicians choice of chemotherapy in the treatment of metastatic breast cancer (MBC) patients with germline BRAC1/2" . _:b646523895 . . _:b646523930 . _:b646523894 . . _:b646522924 . _:b646523889 . _:b76341339 "Carfilzomib is a second-generation proteasome inhibitor that was recently approved by the FDA for the treatment of relapsed and refractory multiple myeloma, in patients who were given at least two prior therapies (103, >>104<<). There is an ongoing phase I/II clinical trial with panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma (ClinicalTrial." . _:b646524406 . _:b646523888 . _:b76341265 . _:b76341277 . _:b646523891 . . . _:b76341238 . _:b646524112 . _:b646523890 . _:b646523901 . _:b646523900 . . _:b646523903 . _:b646523869 . _:b646523902 . . _:b646523897 . _:b76341295 . _:b646523896 . _:b646524402 . . _:b646523899 . _:b646523898 . _:b646524307 . _:b646523204 . . _:b646524081 . _:b646523397 . . _:b646523129 . _:b646523396 . _:b646524434 . . _:b76341269 "Combining HDACi with other cancer therapeutics may thus be an avenue to achieve their full therapeutic potential (>>19<<, 37, 38)." . _:b646523399 . . _:b646523398 . _:b646523794 . _:b646523393 . . _:b646523392 . _:b646523234 . _:b646523395 . _:b646523467 . _:b76341300 . _:b646523394 . . . _:b646523405 . _:b646523197 . _:b646523404 . _:b646523407 . _:b646523981 . _:b646523406 . . _:b646523401 . _:b646523037 . _:b646523400 . _:b646523471 . _:b646523403 . _:b646523402 . _:b646524271 . _:b646523588 . _:b646523413 . _:b646523412 . _:b646524389 . _:b76341325 . _:b646523415 . . _:b646523943 . . _:b646523414 . _:b646523573 . . . _:b76341296 "The novel pan-HDACi, panobinostat (LBH589), is currently being used in phase I and II clinical studies against various hematologic malignancies and solid tumors (60, >>61<<). In combination with radiotherapy, LBH589 was shown to be an effective regimen for the treatment of prostate cancer in vitro. The authors demonstrated that LBH589 at low concentrations (IC20) in combination with radiation induced more" . _:b646523409 . _:b76341376 . _:b646523408 . . _:b646523411 . _:b646523618 . _:b646523321 . _:b76341357 . _:b646523410 . _:b646523427 . _:b646523514 . . _:b646523421 . _:b646523748 . _:b646523772 . _:b646523420 . _:b646523423 . _:b646523422 . . _:b646523417 . . _:b646523416 . _:b646523419 . . . _:b646523418 . _:b646523429 . _:b76341361 "hdaci in combination with other epigenetic modifiers" . _:b646523115 . _:b646524265 . _:b646523428 . . _:b646523431 . . _:b646524380 . _:b646524350 . _:b646523430 . . _:b646522979 . _:b646523425 . _:b646523424 . _:b646524185 . . _:b646523427 . _:b646523723 . _:b646524372 . _:b646523426 . _:b646523686 . _:b646523452 . . . _:b646523437 . . _:b646523436 . . _:b646523224 . . . _:b646523439 . _:b646523390 . _:b646524273 . _:b646523438 . _:b646522994 . . . . _:b646523433 . _:b76341331 . _:b646523432 . _:b646523158 . _:b646523875 . _:b76341338 "Carfilzomib is a second-generation proteasome inhibitor that was recently approved by the FDA for the treatment of relapsed and refractory multiple myeloma, in patients who were given at least two prior therapies (>>103<<, 104). There is an ongoing phase I/II clinical trial with panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma (ClinicalTrial." . _:b76341244 . _:b646523435 . _:b646524407 . _:b76341377 . _:b646523434 . . _:b646523445 . _:b76341243 . _:b646523444 . _:b646523447 . _:b646523446 . _:b76341332 . . _:b76341365 . . _:b646523441 . _:b646523440 . . . _:b646523443 . . _:b646523442 . _:b76341336 . _:b76341305 "The first human phase I dose-escalation clinical study combining valproic acid and the topoisomerase II inhibitor, epirubicin, in solid malignancies has recently been performed (>>70<<). This study showed that valproic acid is well tolerated and can be used in a clinical setting. The combination of valproic acid followed by epirubicin, resulted in an objective response rate of 22% and, additionally, 39% of patients had" . _:b646523453 . _:b646523452 . . _:b646523455 . . _:b646523454 . _:b646523449 . _:b646524239 . . . _:b646523448 . _:b646524117 . _:b646523451 . _:b646523154 . _:b646523450 . _:b646523461 . _:b646523460 . . _:b646523463 . . . . _:b646523462 . _:b646523451 . . _:b646523881 . _:b646523457 . _:b76341325 "The UPS plays a key role in the cellular protein-degradation machinery and in preventing the accumulation of misfolded proteins (>>86<<\u201388). Cancer cells are dependent on the UPS as they are highly proliferative and have an increased requirement for protein synthesis, hence making them more vulnerable to proteasome inhibitors (89, 90). In 2003, the FDA approved bortezomib" . _:b646523456 . . _:b646523459 . _:b646523769 . _:b76341242 "histone deacetylases (hdacs) and hdaci" . _:b646523458 . _:b646524365 . . _:b646523469 . _:b646524421 "2"^^ . . _:b646523468 . _:b646524420 "2"^^ . _:b646522975 . _:b646523232 . _:b646523471 . _:b646524423 "2"^^ . _:b646523367 . . _:b646523470 . _:b646524422 "2"^^ . . _:b646523465 . _:b646524417 "2"^^ . _:b76341333 "be by disrupting protein degradation by inhibiting both the proteasome and aggresome with HDAC6i, resulting in the accumulation of significantly more polyubiquitinated proteins and causing increased cellular stress and apoptosis (94, >>98<<, 99). In addition to multiple myeloma, investigators have demonstrated that combination therapy with bortezomib and the Class I HDACi, MS275, apicidin, and romidepsin, resulted in apoptosis in vitro and in vivo of nasopharyngeal carcinoma" . _:b646523464 . _:b646524416 "2"^^ . . _:b646524419 "2"^^ . _:b646523467 . _:b646523466 . _:b646524418 "2"^^ . _:b646523477 . _:b646524429 "2"^^ . _:b646523476 . _:b646524428 "2"^^ . . _:b646523479 . _:b646524431 "2"^^ . _:b646523478 . _:b646524430 "2"^^ . _:b646523305 . . _:b646523473 . _:b646524425 "2"^^ . _:b646524004 . _:b646523852 . _:b646523472 . _:b646524424 "2"^^ . . _:b646524190 . _:b646523475 . _:b646524427 "2"^^ . _:b646524134 . _:b646523474 . _:b646524426 "2"^^ . . _:b646523485 . _:b646524437 "2"^^ . . _:b646522945 . _:b646523484 . _:b646524436 "2"^^ . _:b646523300 . _:b646523487 . _:b646524439 "2"^^ . _:b646524421 . _:b646523486 . _:b646524438 "2"^^ . _:b646523458 . . _:b646523481 . _:b646524433 "2"^^ . _:b646524043 . . . _:b646524432 "2"^^ . _:b646523480 . _:b646523262 . _:b646523483 . _:b646524435 "2"^^ . . . _:b646524434 "2"^^ . _:b646523482 . _:b646523493 . _:b646524445 "2"^^ . _:b646523492 . _:b646524444 "2"^^ . _:b76341289 "combination of hdaci and radiotherapy" . _:b646523725 . . _:b646524447 "2"^^ . _:b646523495 . . _:b646524344 . . _:b646523494 . _:b646524446 "2"^^ . _:b646522965 . . . _:b646524441 "2"^^ . . _:b646523489 . . _:b646523847 . _:b646523488 . _:b646524440 "2"^^ . _:b646523114 . _:b646523491 . _:b646524443 "2"^^ . _:b646523478 . . _:b646523490 . _:b646524442 "2"^^ . . . . . _:b646523501 . . . _:b646523500 . . _:b646524321 . _:b646523503 . _:b646523502 . _:b646523497 . _:b76341325 . _:b646523496 . _:b646523999 . _:b646524052 . _:b646523075 . _:b646523752 . _:b646523499 . _:b646524414 . _:b646523498 . _:b646523334 . _:b646523549 . . _:b646523509 . . _:b646523143 . _:b76341250 . _:b646523508 . . . _:b646523967 . _:b646523797 . _:b646523261 . _:b646523511 . _:b646523817 . . _:b646523971 . . _:b646523510 . . _:b646523505 . . _:b646523504 . _:b646523507 . _:b646524210 . _:b646523506 . _:b646523839 . _:b646523923 . _:b646523517 . _:b646523516 . _:b646523519 . _:b646523518 . _:b646523513 . . . _:b646523512 . . . _:b646523515 . . _:b646523514 . _:b646523644 . _:b646523525 . . _:b646523524 . _:b646523050 . . . _:b646523527 . _:b646523526 . . . _:b646523521 . _:b646523678 . _:b646523520 . . _:b646523523 . _:b646523522 . _:b646524071 . . _:b646523533 . _:b646523380 . . _:b646523532 . . _:b646523535 . _:b646524013 . _:b646523534 . _:b646523578 . . . _:b646523529 . _:b646522959 . _:b646523528 . _:b646523979 . . . _:b646523531 . . _:b646523530 . . _:b646523541 . _:b646523787 . _:b646523540 . _:b646523543 . _:b646523933 . _:b646523542 . . . . . _:b646523537 . . _:b76341278 . . _:b646524199 . _:b646523536 . _:b646523402 . _:b646523539 . _:b646523538 . _:b76341314 . . _:b646523549 . _:b646523552 . _:b646523548 . _:b76341381 "Additionally, a phase III trial evaluating endocrine therapy with the HDACi, entinostat, or placebo in hormone receptor-positive breast cancer patients is about to commence (ClinicalTrial.gov identifier: NCT02115282) (>>140<<)." . . _:b646523551 . _:b646523266 . . _:b646523550 . _:b646524385 . . . _:b646523545 . _:b646523734 . . _:b646523544 . . _:b646523547 . . _:b646524291 . . _:b646523546 . _:b646523213 . _:b646523557 . _:b646523556 . _:b646523559 . _:b646524264 . _:b646523558 . _:b646522961 . _:b646523553 . . _:b646523552 . . . _:b646523555 . . _:b646523554 . _:b646523868 . _:b646523565 . _:b646524124 . . _:b646523564 . _:b646523567 . . _:b646523436 . _:b646523566 . _:b646524173 . _:b646523627 . _:b646523561 . _:b646523560 . _:b646523563 . _:b76341247 "Class III (sirtuins) include SIRT1\u20137 and are related the Sir2 gene while Class IV contains HDAC11 (>>18<<, 19)." . _:b646523562 . _:b646523315 . _:b646523573 . _:b646523572 . _:b646523575 . _:b76341235 . _:b646523575 . _:b76341359 "Gefitinib (Iressa) is a selective, first generation, reversible EGFR tyrosine kinase inhibitor (>>123<<). Studies have demonstrated that gefitinib combined with HDACi synergistically induces growth inhibition and apoptosis in gefitinib-resistant NSCLC cells (124). Currently, there is a phase I/II clinical trial combining Gefitinib and" . _:b646523574 . _:b76341239 . . . _:b646523957 . _:b646523569 . _:b76341242 . . . . _:b646523568 . _:b646523328 . _:b646523571 . . . _:b646523570 . _:b646523751 . . _:b646523581 . _:b646523580 . . _:b646523583 . _:b646523582 . _:b76341294 "first group to publish a case report on use of an HDACi with radiotherapy used valproic acid in combination with cisplatin and doxorubicin, 40\u2009Gy radiation, and surgery to successfully treat a patient with anaplastic thyroid carcinoma (>>59<<). The novel pan-HDACi, panobinostat (LBH589), is currently being used in phase I and II clinical studies against various hematologic malignancies and solid tumors (60, 61)." . . _:b646523577 . . . _:b646523576 . . _:b646523579 . _:b646523119 . _:b646524412 . _:b646522964 . _:b76341261 "FK228 (Romidepsin, Istodax\u2122, Celgene Corp., USA), a cyclic peptide was later approved in 2009 for treating CTCL in patients who had received at least one prior systemic therapy (>>28<<). More recently, belinostat (PXD101, BELEODAQ\u2122, Spectrum Pharmaceuticals, Inc.) was approved by the FDA in 2014 for the use against peripheral T-cell lymphoma (PTCL) (29) and panobinostat (Farydak, Novartis Pharmaceuticals) was licensed" . _:b646523578 . _:b646523589 . _:b646523588 . . _:b646523591 . . _:b646523590 . . _:b646523585 . . . . . . _:b646523584 . _:b646523911 . . _:b646523587 . . _:b646523960 . _:b646523235 . _:b646523565 . _:b646522937 . . _:b646523586 . _:b646523265 . _:b646523597 . _:b646523596 . . _:b646523599 . _:b646523598 . . _:b646523593 . _:b646523984 . _:b646523592 . _:b646523595 . _:b646523594 . _:b76341379 . _:b646523605 . _:b646523604 . _:b646523745 . _:b646523607 . _:b76341236 . _:b76341311 . _:b646523606 . _:b646523776 . _:b76341237 . _:b646523601 . _:b76341238 . _:b646523600 . _:b646523434 . _:b76341239 . _:b646523603 . . _:b646523002 . _:b76341316 . _:b646523602 . _:b646522943 . _:b646523358 . . _:b646523613 . _:b646523195 . . . _:b646523612 . _:b646523070 . . . _:b646523615 . _:b76341235 . . _:b76341244 . _:b646523614 . _:b76341245 . _:b646523647 . _:b76341272 . _:b646524143 . _:b646523609 . . _:b646523093 . _:b76341246 . _:b646523608 . _:b646524323 . _:b76341247 . _:b646523611 . _:b76341240 . _:b646523610 . _:b646523135 . _:b76341241 . _:b76341258 . . _:b646523621 . . _:b646523931 . _:b76341242 . _:b646523620 . _:b76341243 . _:b646523623 . . _:b646523622 . _:b76341315 "Concurrent SAHA (vorinostat) therapy has been shown to enhance tumor cell sensitivity to subtoxic doses of cisplatin in oral squamous cell carcinoma cell lines (>>77<<). The authors showed that the combination of both drugs synergistically induced cytotoxicity and apoptosis in the oral squamous cell carcinoma cells, compared to SAHA or cisplatin treatment alone. Trichostatin A was shown to" . _:b646523795 . . _:b646523788 . _:b646523617 . _:b646523616 . . _:b646523619 . _:b646523618 . _:b646524011 . _:b646523629 . _:b646523628 . . _:b646523631 . _:b76341254 . _:b646523630 . _:b646523625 . . _:b646523624 . _:b646523627 . _:b646523626 . . _:b646523637 . _:b646523945 . _:b646524359 . . _:b646523636 . . _:b646524046 . _:b646523639 . _:b646524426 . . _:b646523638 . . . _:b646523633 . _:b646524191 . . . _:b646523632 . . _:b646524195 . . _:b646523140 . _:b646523635 . _:b76341243 "This opposing action of HATs and HDACs enable the regulation of gene expression in response to the environment (Figure 1) (>>12<<\u201315). To date, in humans there are 18 HDACs that have been identified which are classified according to their homology to yeast HDACs. The HDAC Classes I, II, and IV are Zn2+-dependent metalloproteins, while Class III HDACs are" . _:b646523799 . . _:b76341377 "In a mouse model of lung and renal cell carcinoma, entinostat was additionally shown to improve the antitumor effect of PD-1 targeting by inhibiting MDSC function (>>139<<). Furthermore, in breast cancer patients, entinostat reduced MDSCs and the modulation of MDSC CD40 expression and additionally, increased HLA-DR expression on CD14+ monocytes in the cancer patients. These results establish a rationale for" . _:b646523634 . _:b646523061 . _:b646523645 . _:b646523250 . _:b646524034 . . _:b646523644 . _:b646523647 . . _:b646523646 . _:b646524167 . . _:b646523641 . . _:b646523640 . _:b76341287 . . _:b646523496 . . _:b646523643 . _:b646523323 . . _:b646523642 . . _:b646523141 . _:b646523870 . _:b646522969 . _:b646523199 . _:b76341261 . _:b646523140 . _:b76341348 "While HDACi as a monotherapy in prostate cancer has not shown promise in clinical trials (>>110<<\u2013112), in combination with the antiandrogen, bicalutamide, a synergistic cytotoxicity was observed in preclinical models (113\u2013115)." . _:b646523143 . _:b646523142 . _:b646523522 . _:b646523615 . _:b646523600 . _:b646523137 . _:b646523355 . _:b646523609 . . _:b646523136 . _:b646524204 . _:b646524031 . _:b646523139 . _:b646523987 . _:b646523138 . . _:b646523149 . . _:b646523148 . _:b646524257 . _:b646523151 . _:b646524440 . . _:b646523150 . _:b646523145 . _:b646523144 . _:b646523422 . _:b646523147 . . _:b646524059 . _:b646523858 . _:b646523146 . . . . _:b646523612 . _:b646523157 . _:b646523145 . _:b646523156 . . _:b646523159 . _:b76341274 "Indeed the selectivity of HDACi in specifically targeting cancer cells can be attributed to HDACi causing DNA damage that normal but not cancer cells can repair (43, >>44<<). For example, the HDACi vorinostat induces DSBs in normal and LNCaP and A549 cancer cells (43). While \u03B3H2AX levels, a marker for the appearance of DSBs (45), increased in the cancer cells over time, in continued culture with vorinostat," . _:b646523158 . _:b646523340 . . _:b646523153 . _:b646524258 . . _:b646523152 . . _:b646523155 . _:b646523607 . _:b646523958 . _:b646523154 . _:b646524030 . _:b646523165 . . _:b646523164 . _:b76341362 . _:b646523167 . _:b646523208 . _:b646523386 . _:b646523166 . . _:b646523161 . . _:b646523160 . _:b646523163 . _:b646523084 . _:b646523162 . _:b646523327 . _:b646523173 . _:b646523137 . _:b646523172 . _:b646523175 . _:b646523174 . _:b646523934 . _:b646523169 . _:b646523989 . . _:b76341384 . . _:b646523168 . _:b646523347 . _:b646523000 . _:b646523171 . . _:b646523170 . _:b646524132 . _:b646523181 . _:b646523180 . . _:b646523183 . _:b646523038 . _:b646523182 . . . _:b646523177 . _:b646523176 . _:b646523110 . . _:b646523179 . _:b76341318 "Overall, belinostat with carboplatin and paclitaxel was well tolerated with no evidence of a pharmacokinetic interaction (>>81<<). A phase I pharmacokinetic study was additionally carried out with vorinostat in combination with carboplatin and paclitaxel for advanced solid malignancies (82, 83). This study demonstrated that this combination was tolerated well and" . _:b76341328 . _:b646523178 . _:b646523034 . _:b646523189 . . _:b646523008 . _:b646523188 . _:b646523191 . _:b646523190 . _:b646523964 . _:b646523185 . _:b646523500 . _:b646524392 . _:b646523184 . _:b76341263 . . _:b76341287 "In addition to their histone substrates, HDACi act on non-histone proteins including p53, Ku70, HSP90, NF\u03BAB, and \u03B1-tubulin (>>54<<). Thus, the acetylation of both histone and non-histone proteins give rise to the pleiotropic antitumor effects seen with HDACi at both epigenetic and cellular levels." . _:b646523187 . _:b76341245 . _:b646523186 . _:b76341348 . . _:b646523642 . . _:b646523197 . _:b646523196 . _:b646523199 . . _:b646524297 . _:b646523198 . _:b646523859 . _:b646523306 . _:b646523193 . . . _:b646523192 . _:b646524045 . _:b646523195 . . _:b646523194 . _:b646524312 . _:b646523205 . _:b646523426 . _:b646523204 . _:b646524309 . . _:b646523066 . _:b646523207 . . _:b646523206 . _:b646523201 . . _:b646523637 . . _:b646523200 . _:b646523203 . _:b646523786 . _:b646523202 . _:b646524332 . . _:b646523213 . . _:b76341238 "anticancer drugs with other chemotherapeutic agents is often used to maximize efficacy, while reducing toxicity and resistance by administering lower drug doses, and their combination has shown synergistic or additive antitumor effects (>>8<<\u201311). This review focuses on research thus far on histone deacetylase inhibitors (HDACi) in combination therapy with other chemotherapeutic agents and how this understanding can be utilized to optimize their application as anticancer" . _:b646523212 . _:b646522987 . _:b646523215 . . . _:b646523242 . . _:b646523214 . _:b646523209 . . _:b646523208 . _:b646523716 . _:b646524180 . _:b646524177 . _:b646523211 . _:b646523210 . . _:b646523494 . _:b646523221 . . _:b646523220 . _:b646523223 . _:b646523222 . _:b646523304 . _:b646523530 . _:b646523217 . _:b646523792 . . _:b646523004 . _:b646523216 . . _:b646523455 . . _:b646523219 . _:b646523944 . . _:b646523218 . _:b646523544 . _:b646523229 . _:b646523962 . . _:b646523228 . _:b646524159 . _:b646523584 . _:b646523231 . . _:b646524349 . _:b646523230 . . . . _:b646523225 . _:b646523224 . . . . _:b646524237 . _:b646523227 . _:b646523226 . . . _:b646523237 . _:b646523163 . _:b646523236 . _:b646523850 . _:b646524382 . _:b646524211 . . _:b76341321 "Overall, this study demonstrated that vorinostat enhanced the efficacy of carboplatin and paclitaxel in patients with NSCLC patients (>>84<<, 85); however, the phase III trial with this combination was terminated due to lack of efficacy (ClinicalTrial." . _:b646523239 . _:b646523172 . _:b646523238 . . _:b646524105 . _:b646523233 . . _:b646523232 . _:b646523889 . _:b76341378 "These results establish a rationale for combination therapy between entinostat and immune checkpoint inhibitors (>>140<<). It was recently shown that the prostate cell line, LNCAP, and the breast cell line, MDA-MB-231, were more sensitive to T-cell mediated lysis following treatment with the HDACi, entinostat, or vorinostat. The authors demonstrated that" . _:b646523235 . _:b76341367 . _:b646523234 . _:b646523707 . _:b646523245 . _:b646523244 . _:b646523041 . _:b646523112 . _:b646523247 . _:b646523882 . _:b76341270 "Combining HDACi with other cancer therapeutics may thus be an avenue to achieve their full therapeutic potential (19, >>37<<, 38)." . _:b646523246 . _:b646523392 . . . _:b646524327 . _:b646523241 . . _:b646522946 . . _:b646523240 . . _:b646523243 . . . _:b646523242 . . _:b646523253 . _:b646522967 . _:b646523252 . _:b646523851 . . _:b646523255 . _:b646523254 . . _:b646523249 . . _:b646523248 . _:b646523251 . _:b646523018 . _:b646523685 . _:b646523250 . _:b646523963 . _:b646523261 . . _:b646523214 . _:b646523621 . _:b646523260 . _:b646524386 . . _:b646523834 . _:b646523263 . _:b646523262 . . _:b646523257 . . _:b646523256 . _:b646524251 . . _:b646523259 . _:b646523218 . _:b76341322 . _:b646523258 . . _:b646523269 . . _:b646524091 . . . _:b646523268 . _:b646523254 . . . _:b646523271 . _:b646523270 . _:b76341332 "may be by disrupting protein degradation by inhibiting both the proteasome and aggresome with HDAC6i, resulting in the accumulation of significantly more polyubiquitinated proteins and causing increased cellular stress and apoptosis (>>94<<, 98, 99). In addition to multiple myeloma, investigators have demonstrated that combination therapy with bortezomib and the Class I HDACi, MS275, apicidin, and romidepsin, resulted in apoptosis in vitro and in vivo of nasopharyngeal" . _:b646524232 . _:b646523265 . _:b646523264 . _:b646523267 . . _:b646523266 . _:b646523818 . _:b646523758 . _:b646523277 . _:b646524245 . _:b646523276 . _:b646523279 . _:b646523753 . _:b646523297 . _:b646523278 . _:b76341346 "While vorinostat as a monotherapy was not found to be effective against the treatment of MBC (109), in combination therapy with the anti-estrogen, tamoxifen, it has shown great promise (>>57<<). Hormone therapy resistance is a challenging issue for treating ER positive breast cancers and thus, combination therapy with HDACi has been studied. Researchers carried out the first clinical trial combining vorinostat and tamoxifen for" . _:b646523784 . _:b646523437 . . _:b76341353 "Therefore, RTKs are promising therapeutic targets (>>118<<, 119). Activation of RTK has been demonstrated to activate RAS-RAF-MEK-MAPK and PI3K-AKT pathways among others." . _:b646523273 . _:b646524146 . _:b646523272 . . _:b646523275 . _:b76341276 . _:b76341276 "While \u03B3H2AX levels, a marker for the appearance of DSBs (>>45<<), increased in the cancer cells over time, in continued culture with vorinostat, they were found to decrease in the control, non-cancerous cells." . _:b646523274 . _:b646524147 . . _:b646523285 . _:b646523284 . _:b646523867 . . _:b646523287 . _:b646523286 . _:b646524227 . _:b646523629 . . _:b646523281 . _:b646523730 . _:b646523280 . _:b646523283 . _:b646523282 . . _:b646524042 . _:b646523293 . _:b646523754 . _:b646523292 . . . . _:b646523295 . _:b646523580 . _:b646523294 . . _:b646523289 . _:b646523288 . . _:b646523291 . . _:b646524397 . . . _:b646523290 . _:b646523937 . _:b646523301 . _:b646523393 . _:b646523192 . _:b646523300 . _:b646524318 . _:b646523360 . _:b646524381 . _:b646523531 . _:b76341319 "A phase I pharmacokinetic study was additionally carried out with vorinostat in combination with carboplatin and paclitaxel for advanced solid malignancies (>>82<<, 83). This study demonstrated that this combination was tolerated well and of the 19 patients with NSCLC, 10 had partial responses and 4 patients showed stable disease. This study subsequently led to a phase II clinical study involving 94" . _:b646523303 . _:b646523387 . . _:b76341238 . _:b646523302 . _:b646523011 . . . _:b646523297 . _:b646523435 . . _:b646523296 . _:b646523811 . _:b646523299 . _:b646523298 . _:b646524311 . _:b646523309 . _:b646523970 . . . . _:b646523308 . . _:b646524171 . _:b646523311 . _:b76341267 "Furthermore, chromatin and epigenetic alterations, changes in the expression levels of HDACs and changes in drug efflux mechanisms have been implicated as factors in the resistance to HDACi (>>35<<). It was recently speculated that the resistance to HDACi is a critical evolutionary consequence of environmental exposure to HDACi and that cancers that respond to HDACi have developed mutations that alters how the cancer cell responds" . _:b646523310 . _:b646523709 . _:b646524411 . _:b646523305 . _:b646524226 . _:b646523420 . _:b646523376 . _:b646523304 . _:b646523307 . . _:b646523306 . _:b646523317 . . _:b646523316 . _:b646523319 . _:b76341375 . _:b76341237 . . _:b646523318 . _:b646523601 . _:b646523602 . _:b646523313 . _:b646523223 . _:b76341272 . _:b646523312 . _:b646523194 . _:b76341353 . _:b646523315 . _:b646524345 . _:b646524409 . . _:b76341363 . _:b646523314 . _:b646524122 . _:b646523325 . . . _:b646523324 . _:b646524007 . _:b646523327 . _:b646523083 . . _:b646523326 . . _:b646523321 . . _:b646523320 . . _:b646523323 . _:b646523322 . _:b646523333 . _:b646523332 . _:b646523335 . _:b646524144 . _:b646523334 . . . _:b646523329 . _:b646523328 . _:b646523331 . _:b646523746 . _:b76341351 . _:b646523330 . . . _:b646523341 . _:b646523302 . _:b646524270 . _:b646523340 . . . _:b646524355 . _:b646523343 . _:b646523342 . _:b646523337 . _:b646524099 . _:b646523336 . . _:b646523339 . _:b646523338 . . . _:b646523349 . . _:b646523348 . . _:b646523351 . . _:b646523350 . _:b76341283 "More recently, research has shown that HDACs regulate ATM-mediated DNA damage signaling and established that HDAC1 and HDAC2 function as part of the DDR (>>46<<). The authors demonstrated that HDACi resulted in a reduced activation of ATM and its expression and decreased p53 activation both in vitro and in vivo. Thus, addition of HDACi followed by a subsequent treatment with DNA damaging agents" . _:b646523570 . _:b76341265 . _:b646523345 . _:b646523440 . _:b76341355 "Monoclonal antibodies or RTK inhibitors of these pathways may block cell cycle progression, inhibit production of pro-angiogenic factors and induce apoptosis in various in vitro and xenograft models (>>120<<). Interestingly, cyclin D1 interacts with class I/II HDACs and HDACs regulate the expression of c-Myc and cyclin D1. Additionally, cell treatments with HDACi reduced cyclin D1 transcription and increased c-Myc degradation. Therefore, the" . _:b76341327 "Cancer cells are dependent on the UPS as they are highly proliferative and have an increased requirement for protein synthesis, hence making them more vulnerable to proteasome inhibitors (89, >>90<<). In 2003, the FDA approved bortezomib (PS-341, Velcade\u2122, Millennium Pharmaceuticals Inc.) to treat relapsed and refractory multiple myeloma (91). However, peripheral neuropathy is often seen and is the most frequently associated dose" . _:b646523344 . . _:b646523347 . . _:b646523042 . _:b646523692 . _:b646523346 . _:b646524416 . _:b76341248 "Class III (sirtuins) include SIRT1\u20137 and are related the Sir2 gene while Class IV contains HDAC11 (18, >>19<<)." . _:b646523922 . _:b646523103 . _:b646523357 . . . . _:b646524174 . . _:b646523356 . _:b646523359 . _:b646523843 . . _:b646523358 . . _:b646523353 . . . _:b646523352 . _:b646523355 . _:b646524054 . _:b646523354 . . . _:b646523365 . . . _:b646524374 . . _:b646523364 . _:b646523367 . _:b646523366 . . _:b646523361 . _:b646523280 . _:b646523360 . _:b646524153 . _:b646523363 . . _:b646523362 . _:b646523373 . . . . _:b646523372 . _:b646523375 . _:b646523098 . _:b646523374 . _:b646523603 . _:b646523369 . . _:b646523368 . _:b646524080 . _:b646523371 . . _:b646523539 . _:b646523370 . . _:b646523381 . . _:b646523865 . _:b646523369 . _:b646523380 . . _:b646523383 . _:b646523536 . . _:b646523431 . . _:b646523382 . . _:b646523377 . _:b646523376 . _:b646523701 . . _:b646523379 . _:b646523377 . _:b646523378 . . . _:b76341386 "The authors concluded that blocking this pathway may lead to improvements in the response to vorinostat and may indeed be predictive of response of CTCL patients to the agent (>>148<<)." . _:b646524413 . _:b646523389 . _:b646524179 . _:b646523388 . . . _:b646523391 . _:b646523688 . . _:b646524387 . _:b646523390 . . _:b646523385 . . _:b76341315 . . . . _:b646523509 . _:b646523384 . _:b646524097 . _:b646523387 . _:b646523386 . . _:b646524360 . . _:b76341372 . _:b646523636 . . _:b646523031 . _:b76341310 "Cis-diamminedichloroplatinum(II) (cisplatin) was first approved in 1978 for the treatment of bladder and testicular cancer (73, >>74<<). Cisplatin has since been used as a first-line therapy for many different solid malignancies, including head and neck, ovarian, bladder, testicular, colorectal, bladder, cervical, and lung cancers, as a monotherapy or in combination with" . _:b646523906 . . _:b646523625 . _:b646524375 . _:b646524275 . . . _:b646524155 . . _:b76341301 . _:b76341348 . . _:b76341300 . . . . _:b646524308 . . . _:b646523757 . . . . _:b646523337 . _:b646523880 . _:b76341243 . . . . . _:b646524352 . _:b646522978 . . . . . _:b646524175 . _:b76341256 "HDACi have pleiotropic cellular effects (Figure 2) and induce the expression of pro-apoptotic genes/proteins, cause cellular differentiation and/or cell cycle arrest (13, >>15<<, 19, 25, 26)." . . _:b646523465 . . _:b76341344 "Aberrant acetylation and HDAC expression has been observed in both breast and prostate cancer cell lines and patient tumors (107, >>108<<). Thus, the combination of HDACi and hormonal therapy is under investigation in both clinical and preclinical settings for the treatment of breast and prostate cancers. While vorinostat as a monotherapy was not found to be effective" . _:b646523583 . . _:b646524395 . _:b646523207 . _:b646523506 . . . _:b646523608 . . _:b646523043 . _:b76341382 . . . _:b646524315 . _:b646523576 . _:b646523939 . _:b646523780 . _:b646523918 . . . _:b646522925 . _:b646522958 . . _:b646522924 . . _:b646523738 . _:b646524394 . _:b646523736 . _:b646522927 . _:b646523877 . _:b646523408 . _:b646522926 . . . _:b646523874 . . _:b76341297 . _:b646522921 . _:b646524176 . _:b646523293 . _:b76341275 "For example, the HDACi vorinostat induces DSBs in normal and LNCaP and A549 cancer cells (>>43<<). While \u03B3H2AX levels, a marker for the appearance of DSBs (45), increased in the cancer cells over time, in continued culture with vorinostat, they were found to decrease in the control, non-cancerous cells. Additionally, the authors" . _:b646523587 . . _:b646522923 . _:b646522922 . . _:b646522933 . _:b646522932 . _:b646523841 . . _:b76341359 . _:b646522935 . _:b646523643 . _:b646522934 . _:b646523857 . . _:b646522929 . _:b646522928 . _:b646522931 . . _:b646522930 . _:b646522941 . _:b646523517 . _:b76341306 "gov identifier: NCT01010854) (>>71<<). The authors subsequently carried out a phase I combination trial of vorinostat and doxorubicin in treating patients with metastatic or advanced solid tumors (72)." . _:b646522989 . _:b646524419 . _:b646522940 . . _:b646522943 . _:b646522942 . _:b76341289 . _:b646522937 . _:b646523241 . . _:b646522936 . _:b76341298 . . _:b646523144 . _:b646522939 . . . _:b646522938 . _:b646523078 . _:b646522949 . . _:b76341308 . _:b646522948 . _:b646524022 . _:b646523120 . _:b646522951 . _:b646522950 . . . _:b646522945 . _:b76341259 . _:b646524129 . _:b646522944 . _:b76341264 . _:b646522947 . . _:b646523175 . _:b646522946 . _:b76341271 . . _:b646522957 . _:b646523909 "2"^^ . _:b646522950 . _:b646522956 . _:b646523908 "2"^^ . _:b646522959 . _:b646523911 "2"^^ . _:b646522958 . _:b646523910 "2"^^ . _:b646523291 . _:b76341352 . . _:b646522953 . _:b646523905 "2"^^ . . _:b646522952 . _:b646523904 "2"^^ . _:b76341361 . _:b646523634 . _:b646522955 . _:b646524193 . _:b646523907 "2"^^ . _:b646522954 . _:b646523906 "2"^^ . _:b76341368 . _:b646522965 . _:b646523917 "2"^^ . . . . _:b646522964 . _:b646523916 "2"^^ . . _:b646522967 . _:b646523919 "2"^^ . _:b646523710 . . . _:b646522966 . _:b646523918 "2"^^ . _:b646523728 . _:b646523913 "2"^^ . _:b76341323 . _:b646522961 . _:b646522960 . _:b646523912 "2"^^ . _:b646522963 . _:b646523915 "2"^^ . . _:b646523276 . _:b646523914 "2"^^ . . _:b646522962 . . _:b646522973 . _:b646523925 "2"^^ . _:b76341340 . . _:b646522972 . _:b646523924 "2"^^ . _:b646524188 . . _:b646522975 . _:b646523927 "2"^^ . . _:b76341252 . _:b646522974 . _:b646523926 "2"^^ . _:b646523221 . _:b76341253 . _:b646522969 . _:b646523921 "2"^^ . _:b646523885 . _:b76341254 . . . . _:b646522968 . _:b646523920 "2"^^ . _:b76341255 . . _:b646522971 . _:b646523923 "2"^^ . . . . _:b76341248 . _:b646524384 . _:b646524405 . _:b646523537 . _:b76341262 . _:b646522970 . _:b646523922 "2"^^ . _:b76341249 . _:b646522981 . _:b646523933 "2"^^ . _:b76341250 . _:b646522980 . _:b646523932 "2"^^ . . _:b646523497 . _:b76341251 . _:b76341330 "However, in phase I and phase II clinical trials, is has been observed that as a single agent, the activity of HDACi have been limited (92, >>93<<). In several preclinical studies, synergistic antitumor effects were seen in multiple myeloma, when HDACi were combined with proteasome inhibitors, thus providing the rational for combining HDACi with these agents in clinical trials" . _:b646522983 . _:b646523935 "2"^^ . _:b76341260 . . _:b646522982 . _:b646523934 "2"^^ . _:b76341261 . . _:b646522977 . _:b646523929 "2"^^ . _:b646523097 . _:b646523441 . _:b76341262 . . _:b646523203 . _:b646522976 . _:b646523928 "2"^^ . _:b76341263 . _:b646522979 . _:b646523931 "2"^^ . _:b76341256 . _:b646522978 . _:b646523930 "2"^^ . _:b646523721 . . _:b76341257 . . _:b646522989 . _:b646523941 "2"^^ . _:b76341258 . _:b646522999 . _:b646523940 "2"^^ . _:b646522988 . . _:b76341259 . _:b646522991 . _:b646523943 "2"^^ . _:b646523968 . _:b76341268 . _:b646522990 . _:b646523942 "2"^^ . _:b646524037 . _:b76341269 . _:b646522985 . _:b646523937 "2"^^ . _:b76341270 . _:b646523417 . _:b646522984 . _:b646523936 "2"^^ . . _:b76341271 . _:b646522987 . _:b646523939 "2"^^ . _:b76341264 . . _:b646522986 . _:b646523938 "2"^^ . . _:b646523055 . _:b76341265 . _:b76341246 "On the other hand, HDACs 4, 5, 7, and 9 are classified as Class IIa HDACs, while HDACs 6 and 10 belong to Class IIb and are related to the yeast Hda1 gene (>>17<<). Class III (sirtuins) include SIRT1\u20137 and are related the Sir2 gene while Class IV contains HDAC11 (18, 19)." . _:b646522997 . _:b646523949 "2"^^ . _:b76341266 . _:b646522996 . _:b646523948 "2"^^ . _:b76341267 . _:b646522999 . _:b646523951 "2"^^ . _:b76341276 . _:b646522998 . _:b646523950 "2"^^ . _:b76341277 . . _:b646522993 . _:b646523945 "2"^^ . _:b76341278 . _:b646522992 . _:b646523944 "2"^^ . _:b646524317 . _:b76341279 . _:b646522995 . _:b646523947 "2"^^ . . _:b76341272 . _:b646523118 . _:b646522994 . _:b646523946 "2"^^ . . _:b76341273 . _:b646523046 . _:b646523005 . _:b646523957 "2"^^ . . _:b76341274 . _:b646522976 . _:b646523004 . _:b646523956 "2"^^ . _:b76341275 . _:b646523007 . _:b646523959 "2"^^ . _:b646523216 . _:b76341284 . _:b646523006 . _:b646523958 "2"^^ . _:b76341285 . _:b76341303 . _:b646523504 . _:b646523001 . _:b646523953 "2"^^ . . _:b76341286 . . _:b646523000 . _:b646523952 "2"^^ . . _:b76341287 . _:b646523003 . _:b646523955 "2"^^ . . _:b76341280 . _:b646523311 . _:b646523663 . _:b646523002 . _:b646523954 "2"^^ . _:b76341281 . _:b646523013 . _:b646523965 "2"^^ . . _:b76341282 . _:b646523200 . _:b646523012 . _:b646523964 "2"^^ . _:b646523948 . _:b646524089 . _:b76341283 . _:b646523866 . _:b646523015 . _:b646523967 "2"^^ . _:b76341292 . _:b646523412 . _:b646523966 "2"^^ . _:b646523014 . _:b646523085 . _:b76341293 . _:b646523009 . _:b646523961 "2"^^ . _:b76341294 . _:b646523008 . _:b646523960 "2"^^ . _:b646523423 . _:b76341295 . _:b646523681 . _:b646523011 . _:b646523963 "2"^^ . . _:b76341288 . _:b646523010 . _:b646523962 "2"^^ . _:b76341289 . _:b646523021 . _:b646523973 "2"^^ . _:b76341290 . _:b646523020 . _:b646523972 "2"^^ . _:b76341291 . _:b646523023 . _:b646523975 "2"^^ . . _:b76341300 . . . _:b646523022 . _:b646523974 "2"^^ . . _:b76341301 . _:b646523017 . _:b646523969 "2"^^ . _:b76341302 . _:b646523016 . _:b646523968 "2"^^ . _:b646523330 . _:b76341303 . . _:b646524160 . _:b646523019 . _:b646523971 "2"^^ . . . _:b76341296 . _:b76341282 . . _:b646523970 "2"^^ . _:b646523018 . . _:b76341297 . . _:b646523029 . _:b646523981 "2"^^ . . _:b76341298 . _:b646524216 . . _:b646523028 . _:b646523980 "2"^^ . _:b76341299 . _:b646523031 . _:b646523983 "2"^^ . . _:b76341308 . _:b646523553 . _:b646524116 . _:b646523030 . _:b646523982 "2"^^ . _:b76341309 . _:b646523102 . _:b646523025 . _:b646523977 "2"^^ . _:b76341310 . _:b646523024 . _:b646523976 "2"^^ . _:b76341311 . _:b646523027 . _:b646523979 "2"^^ . _:b76341304 . . _:b646523026 . _:b646523978 "2"^^ . _:b646524233 . _:b76341305 . _:b646523037 . _:b646523989 "2"^^ . _:b76341306 . _:b646523036 . _:b646524178 . _:b646523988 "2"^^ . _:b646522995 . _:b76341307 . _:b646523039 . _:b646523991 "2"^^ . . _:b76341316 . . _:b646523038 . _:b646523990 "2"^^ . _:b76341317 . _:b646523033 . _:b646523985 "2"^^ . _:b646523656 . _:b76341318 . _:b76341320 "A phase I pharmacokinetic study was additionally carried out with vorinostat in combination with carboplatin and paclitaxel for advanced solid malignancies (82, >>83<<). This study demonstrated that this combination was tolerated well and of the 19 patients with NSCLC, 10 had partial responses and 4 patients showed stable disease. This study subsequently led to a phase II clinical study involving 94" . _:b646523032 . _:b646523984 "2"^^ . _:b646523082 . _:b76341319 . _:b646523035 . _:b646523987 "2"^^ . _:b646524346 . _:b76341312 . _:b646523165 . . _:b646523034 . _:b646523986 "2"^^ . _:b646523368 . _:b76341313 . _:b76341360 . . _:b646523045 . _:b646523997 "2"^^ . . _:b76341314 . _:b76341298 "dual combination of hdaci and topoisomerase inhibitors" . . _:b646523996 "2"^^ . _:b646523044 . _:b76341315 . _:b646523047 . _:b646523999 "2"^^ . . _:b76341324 . . _:b646523415 . _:b646523046 . _:b646523998 "2"^^ . _:b76341325 . . _:b646523041 . _:b646523993 "2"^^ . _:b76341326 . . _:b646523068 . _:b646522923 . . _:b646523040 . _:b646523992 "2"^^ . _:b76341327 . _:b646523835 . _:b646523043 . _:b646523995 "2"^^ . . . _:b76341320 . _:b646523969 . _:b646524038 . _:b646523042 . _:b646523994 "2"^^ . _:b76341321 . _:b646523053 . _:b646524005 "2"^^ . . _:b646523059 . _:b76341322 . . _:b646523052 . _:b646524004 "2"^^ . . _:b76341323 . . _:b646523055 . _:b646524007 "2"^^ . _:b76341332 . _:b646523054 . _:b646524006 "2"^^ . _:b76341333 . _:b646523246 . _:b646523049 . _:b646524001 "2"^^ . . _:b76341334 . _:b646523048 . _:b646524000 "2"^^ . . _:b76341335 . _:b646523051 . _:b646524003 "2"^^ . _:b646523561 . _:b76341328 . _:b646523050 . _:b646524002 "2"^^ . _:b76341329 . _:b646523737 . _:b646523061 . _:b646524013 "2"^^ . . _:b76341330 . _:b76341301 "Preclinical studies have shown greater efficacy when cells were pretreated with HDACi prior to exposure to DNA damaging agents (>>64<<, 68), similar to the decondensation of chromatin seen in cells from breast and other cancers (50, 69)." . _:b646523060 . _:b646524012 "2"^^ . _:b76341331 . _:b646523063 . _:b646524015 "2"^^ . . _:b646523230 . _:b76341340 . _:b76341235 "introduction" . _:b646523062 . _:b646524014 "2"^^ . _:b76341341 . _:b646523057 . _:b646524009 "2"^^ . _:b76341342 . _:b646523056 . _:b646524383 . _:b646524008 "2"^^ . _:b76341343 . _:b646523190 . _:b646523059 . _:b646524011 "2"^^ . _:b76341336 . _:b646523058 . _:b646524010 "2"^^ . . _:b76341337 . _:b646523449 . _:b646523069 . _:b646524055 . _:b646524021 "2"^^ . _:b76341338 . _:b646523068 . _:b646524020 "2"^^ . . _:b76341339 . . _:b646523071 . _:b646524023 "2"^^ . _:b76341348 . _:b646523070 . _:b646524022 "2"^^ . . _:b76341349 . . _:b646523065 . _:b646524017 "2"^^ . _:b76341350 . _:b646523064 . _:b646524016 "2"^^ . _:b76341351 . . _:b646523067 . _:b646524019 "2"^^ . _:b76341344 . _:b646524376 . _:b646523066 . _:b646524018 "2"^^ . _:b646523111 . _:b76341345 . _:b646523077 . _:b646524029 "2"^^ . _:b76341346 . _:b646523491 . _:b646523076 . _:b646524028 "2"^^ . . _:b76341347 . _:b646523295 . _:b646523900 . _:b646523079 . _:b646524031 "2"^^ . _:b646523173 . _:b76341356 . _:b646523078 . _:b646524030 "2"^^ . _:b76341357 . _:b646523073 . _:b646524025 "2"^^ . . _:b76341358 . _:b646523072 . _:b76341358 . _:b646524024 "2"^^ . _:b76341359 . . _:b646523075 . _:b646524027 "2"^^ . _:b646523801 . _:b76341352 . _:b646523074 . _:b646524026 "2"^^ . _:b76341353 . _:b646523085 . _:b646524037 "2"^^ . _:b76341354 . _:b646523084 . _:b646524036 "2"^^ . _:b76341355 . . _:b76341351 "gov identifier: NCT00589472) (>>117<<). The second clinical trial was a phase I/II clinical trial studying the safety and efficacy of panobinostat and bicalutamide in patients with recurrent prostate cancer after castration (ClinicalTrial." . _:b646523087 . _:b76341268 . _:b646524039 "2"^^ . _:b76341364 . _:b646523086 . _:b646524038 "2"^^ . _:b76341365 . _:b646523554 . . _:b646524033 "2"^^ . . _:b646523081 . . _:b76341366 . _:b646523080 . _:b646524032 "2"^^ . _:b76341367 . _:b646523083 . _:b646524035 "2"^^ . _:b76341360 . _:b646523082 . _:b646524034 "2"^^ . _:b646523594 . _:b76341361 . _:b646523093 . _:b646524045 "2"^^ . _:b76341362 . . _:b646523909 . _:b646523092 . _:b646524044 "2"^^ . _:b76341363 . . . _:b646523095 . _:b646524047 "2"^^ . . _:b76341372 . _:b646524074 . _:b646523094 . _:b646524046 "2"^^ . _:b76341373 . _:b646522983 . _:b646523089 . _:b646524041 "2"^^ . _:b646523915 . _:b76341374 . _:b646523088 . _:b646524040 "2"^^ . _:b76341375 . . _:b646523091 . _:b646524043 "2"^^ . _:b646524008 . . _:b76341368 . . _:b646523090 . _:b646524042 "2"^^ . _:b76341369 . . . _:b646523101 . _:b646524053 "2"^^ . _:b76341370 . _:b646523149 . _:b646523100 . _:b646524052 "2"^^ . _:b76341371 . _:b646523472 . _:b646523956 . _:b646523103 . _:b646524055 "2"^^ . _:b76341380 . _:b76341381 . _:b646523102 . _:b646524054 "2"^^ . _:b76341381 . _:b76341236 "The N-terminal tail of histones can be modified posttranslationally by acetylation, methylation, ubiquitination, phosphorylation, sumoylation, ADP ribosylation, deamination, and proline isomerization (>>1<<\u20133)." . _:b646523097 . _:b646524049 "2"^^ . _:b646523768 . _:b646523365 . _:b76341382 . _:b646523096 . _:b646524048 "2"^^ . _:b76341383 . . . _:b646523099 . _:b646524051 "2"^^ . _:b76341376 . _:b646523098 . _:b646524050 "2"^^ . . . _:b76341378 . _:b76341377 . _:b646523275 . _:b646523109 . _:b646524061 "2"^^ . _:b76341378 . _:b646523320 . _:b646523108 . _:b646524060 "2"^^ . _:b76341379 . _:b646523111 . _:b646524063 "2"^^ . _:b646523228 . _:b646523110 . _:b646524062 "2"^^ . _:b646523105 . _:b646524057 "2"^^ . _:b646524139 . _:b646523101 . _:b646523104 . _:b646524056 "2"^^ . _:b646523094 . . _:b646523107 . _:b646524059 "2"^^ . _:b76341384 . _:b646523106 . _:b646524058 "2"^^ . _:b76341385 . _:b646523117 . _:b646524069 "2"^^ . . . _:b76341386 . _:b646523116 . _:b646524068 "2"^^ . _:b646524330 . . _:b646523119 . _:b646524071 "2"^^ . . _:b646524109 . _:b646523118 . _:b76341302 "Preclinical studies have shown greater efficacy when cells were pretreated with HDACi prior to exposure to DNA damaging agents (64, >>68<<), similar to the decondensation of chromatin seen in cells from breast and other cancers (50, 69)." . _:b646524070 "2"^^ . . . _:b646523113 . _:b646524065 "2"^^ . . . _:b646523112 . _:b646524064 "2"^^ . _:b646523115 . _:b646524067 "2"^^ . _:b646523114 . _:b646524066 "2"^^ . _:b646523171 . _:b646524244 . _:b646523125 . _:b646524077 "2"^^ . . _:b76341308 "hdaci in combination with platinum-based chemotherapeutics" . _:b646523124 . _:b646524076 "2"^^ . _:b76341243 . _:b646523127 . _:b646524079 "2"^^ . . . _:b646523126 . _:b646524078 "2"^^ . _:b646523121 . _:b646524073 "2"^^ . . _:b646523908 . _:b646523202 . _:b646523120 . _:b646524072 "2"^^ . . _:b646523123 . _:b646524087 . _:b646524075 "2"^^ . _:b646523122 . _:b646524074 "2"^^ . _:b646523507 . . _:b646523453 . _:b646523133 . _:b646524085 "2"^^ . _:b646523132 . _:b646524084 "2"^^ . . _:b646523689 . . _:b646523135 . _:b646524087 "2"^^ . . _:b646523490 . _:b646523134 . _:b646524086 "2"^^ . . _:b646523187 . _:b646523129 . _:b646524081 "2"^^ . _:b646523128 . _:b646524080 "2"^^ . _:b646523457 . _:b646523131 . _:b646524083 "2"^^ . _:b646524100 . _:b646523130 . _:b646524082 "2"^^ . _:b646523907 . _:b646523905 . . . _:b646524093 "2"^^ . . _:b76341264 "hdaci resistance and rational for combination therapy" . . _:b646524092 "2"^^ . . _:b646523138 . _:b646524095 "2"^^ . _:b646524366 . _:b646524427 . _:b646524094 "2"^^ . _:b646524089 "2"^^ . _:b646524072 . _:b646524088 "2"^^ . _:b646523624 . _:b646522932 . _:b646524091 "2"^^ . _:b646524090 "2"^^ . . _:b646524101 "2"^^ . . _:b646524100 "2"^^ . . _:b646523557 . . _:b646524103 "2"^^ . _:b646523248 . _:b646524102 "2"^^ . _:b646523559 . _:b646523820 . _:b646523090 . _:b646524097 "2"^^ . _:b646523425 . _:b646524096 "2"^^ . _:b646524015 . _:b646524099 "2"^^ . _:b646523217 . _:b646523985 . _:b646524098 "2"^^ . _:b646524109 "2"^^ . . . _:b646524108 "2"^^ . _:b646524111 "2"^^ . . _:b646524110 "2"^^ . . _:b646524225 . _:b646524105 "2"^^ . . _:b646524104 "2"^^ . _:b646523742 . _:b646524107 "2"^^ . _:b646522997 . _:b646524267 . _:b646524106 "2"^^ . . _:b646524117 "2"^^ . _:b646524116 "2"^^ . _:b646524343 . . _:b646524119 "2"^^ . _:b646524118 "2"^^ . _:b646524429 . _:b646524113 "2"^^ . _:b646523596 . _:b646524112 "2"^^ . . _:b646524115 "2"^^ . . _:b646523092 . _:b646524114 "2"^^ . . _:b646523872 . _:b646524078 . _:b646524306 . _:b646523690 . _:b646524125 "2"^^ . _:b646523807 . _:b646524124 "2"^^ . . . _:b646524127 "2"^^ . . . _:b646524126 "2"^^ . _:b646523156 . _:b646524121 "2"^^ . _:b646523861 . . _:b646524205 . _:b646524120 "2"^^ . . _:b646524123 "2"^^ . _:b646523683 . _:b646524371 . _:b646524122 "2"^^ . . _:b646523606 . _:b646524133 "2"^^ . . . . _:b646524132 "2"^^ . _:b646523257 . _:b646523382 . _:b646524135 "2"^^ . _:b646523898 . _:b646523193 . _:b646524134 "2"^^ . _:b646523108 . _:b646524129 "2"^^ . _:b646523185 . . . _:b646524128 "2"^^ . _:b646522940 . _:b646523086 . . _:b76341265 . _:b646524131 "2"^^ . _:b646523639 . _:b646524130 "2"^^ . _:b646523593 . _:b646524141 "2"^^ . . _:b646524250 . _:b646524140 "2"^^ . _:b646524143 "2"^^ . _:b646523691 . . _:b646524142 "2"^^ . . _:b646524137 "2"^^ . . _:b646524136 "2"^^ . _:b646523535 . _:b76341366 "Two phase I clinical trials were carried out to assess the pharmacokinetics of 5-azacitidine administered with the HDACi, phenylbutyrate, for the treatment of refractory solid tumors or hematological malignancies (>>129<<). 5-azacitidine was administered once daily as a subcutaneous injection, while varying doses of phenylbutyrate were administered as a continuous intravenous infusion. This study showed that 5-azacitidine was rapidly absorbed and" . . _:b646524139 "2"^^ . . _:b646523357 . _:b646524138 "2"^^ . _:b646524104 . _:b646524149 "2"^^ . . .