. _:b529130548 . _:b529130080 "3"^^ . . _:b529130551 . _:b529130083 "3"^^ . . _:b529130550 . _:b529130082 "3"^^ . _:b529130251 . _:b24205804 "Both events eventually lead to activation of caspase cascades known as \u2018executioner caspases\u2019 such as caspase-3, -6 and -7 [>>20<<,21]. The active executioner caspases cleave cellular substrates, which leads to characteristic biochemical and morphological changes observed in dying cells [22]. Cleavage of nuclear lamins is followed by chromatin condensation and" . _:b529130545 . _:b529130093 "3"^^ . _:b529130470 . . _:b529130544 . . _:b529130092 "3"^^ . _:b529130114 . _:b529130547 . _:b529130095 "3"^^ . . _:b529130401 . _:b529130546 . _:b529130094 "3"^^ . _:b24205792 . _:b529130557 . _:b529130586 . _:b529130089 "3"^^ . _:b529130113 . _:b529130490 . _:b529130556 . _:b529130088 "3"^^ . _:b529130589 . _:b529130215 . . _:b529130387 . _:b529130559 . _:b529130091 "3"^^ . _:b529130111 . . _:b529130558 . _:b529130090 "3"^^ . _:b529129957 . _:b529130273 . _:b529129983 . _:b529130553 . _:b529130101 "3"^^ . _:b529130432 . _:b529130445 . _:b529130552 . _:b529130100 "3"^^ . _:b529130555 . _:b529130103 "3"^^ . _:b529130112 . . _:b529130554 . _:b529130102 "3"^^ . _:b24205873 "The three well known MAPK families are: the extracellular signal-regulated kinases (ERKs), the c-Jun N-terminal kinases/stress-activated protein kinases (JNKs/SAPKs), and the p38 MAPK [>>88<<]. Each of these enzymes is a target for phosphorylation cascades in which the sequential activation of three kinases constitutes a common signaling pathway. The best characterized MAPK pathway is the Ras/Raf/MEK cascade leading to the" . . . _:b529129898 . _:b529130565 . _:b529130097 "3"^^ . _:b529130564 . _:b529130096 "3"^^ . . _:b529130567 . _:b529130099 "3"^^ . _:b529130297 . _:b529130566 . _:b529130098 "3"^^ . . _:b529130109 "2"^^ . _:b529130561 . _:b529129940 . . _:b529130108 "2"^^ . _:b529130560 . _:b24205801 _:b24205824 . . _:b24205801 _:b24205825 . _:b24205801 _:b24205826 . _:b529130563 . _:b529130111 "2"^^ . _:b24205801 _:b24205827 . _:b529130544 . . . . _:b24205801 _:b24205828 . _:b24205801 _:b24205829 . _:b24205801 _:b24205830 . _:b529130562 . . _:b529130110 "2"^^ . _:b24205801 _:b24205831 . _:b24205801 _:b24205832 . _:b24205801 _:b24205833 . _:b24205801 _:b24205834 . _:b24205914 "The IP3 protein, a regulator of the autophagic process associated with the ER [>>123<<,124] is affected by phthalocyanine photosensitizer Pc 4 [125]." . _:b529130573 . _:b24205801 _:b24205835 . _:b529130105 "3"^^ . _:b24205801 _:b24205836 . _:b24205801 _:b24205837 . . _:b24205801 _:b24205838 . _:b529130572 . _:b24205801 _:b24205839 . _:b24205809 . _:b529130104 "3"^^ . _:b24205801 _:b24205840 . _:b24205801 _:b24205841 . _:b24205801 _:b24205842 . _:b529130575 . _:b529130267 . . _:b24205801 _:b24205843 . _:b529130107 "3"^^ . . _:b24205801 _:b24205844 . _:b24205801 _:b24205845 . _:b24205801 _:b24205846 . _:b529130574 . _:b24205801 _:b24205847 . _:b529130106 "3"^^ . _:b24205801 _:b24205848 . _:b529130417 . _:b529130117 "2"^^ . _:b529130569 . _:b529130004 . . _:b529130235 . _:b529130116 "2"^^ . _:b529130568 . . _:b529130119 "2"^^ . _:b529130571 . . _:b529130118 "2"^^ . _:b529130570 . . . _:b529130581 . _:b529130113 "2"^^ . _:b529129893 . _:b24205829 "In the study by He et al. [>>45<<], employing a pair of Chinese hamster ovary cell lines that differed from one another by a transfected Bcl-2 gene, the ability of this gene to modulate PDT- induced apoptosis was investigated." . . _:b529130112 "2"^^ . _:b529130580 . . _:b529130464 . _:b529130115 "2"^^ . _:b529130583 . _:b529130449 . _:b529130114 "2"^^ . _:b529130582 . . . _:b529130125 "2"^^ . _:b529130577 . _:b529130124 "2"^^ . _:b529130576 . _:b529130505 . . _:b529130127 "2"^^ . _:b529130579 . _:b529130126 "2"^^ . _:b529130578 . . _:b529130121 "2"^^ . _:b529130589 . _:b529130120 "2"^^ . _:b529130588 . _:b529130002 . _:b529130123 "2"^^ . _:b529130591 . . _:b529130396 . . _:b529130590 . _:b529130122 "2"^^ . _:b529129899 . _:b529130133 "2"^^ . _:b529130585 . . _:b529129967 . . _:b529130132 "2"^^ . _:b529130584 . _:b529130135 "2"^^ . _:b529130587 . . _:b529130134 "2"^^ . _:b529130586 . _:b529130262 . _:b529130129 "2"^^ . _:b529130597 . _:b529130128 "2"^^ . _:b529130596 . _:b529130131 "2"^^ . _:b529130599 . _:b24205838 "When unleashed by death signals, they switch off survival function by inserting their BH3 domain into a groove on their pro-survival relatives [>>55<<]. During apoptosis, Bax and Bak oligomerize in the mitochondria outer membrane and probably break its integrity, freeing pro-apoptotic proteins like cytochrome c, which allows the activation of caspase 9 [29]." . _:b529130130 "2"^^ . _:b529130598 . . _:b24205904 . _:b529130141 "2"^^ . _:b529130593 . _:b24205891 "Nagata and colleagues [>>104<<] used the amphiphilic PS ATX-S10 (Na) and human malignant melanoma cells and found that light doses that led to less than 70% cytotoxicity induced mainly apoptosis; by contrast, most cells appeared necrotic with doses that induced 99%" . _:b529130140 "2"^^ . _:b529130592 . _:b529130143 "2"^^ . _:b24205921 "The released, but not neutralized proteases can cause induction of apoptosis by cathepsin-mediated cleavage of Bid [>>129<<]. The lysosomes, autophagosomes, endosomes, and autolysosomes of the cells treated with this amphiphilic photosensitizer will have it in their membranes. Upon irradiation, the membranes will break and release their contents into the" . _:b529130595 . _:b529130142 "2"^^ . _:b529130594 . . . _:b24205802 "Apoptosis is a very complex, multi-step, multi-pathway cell-death program that is genetically encoded in every cell of the body [>>18<<]. It can be initiated either through the activation of death receptors or the mitochondrial release of cytochrome c [19]." . . . _:b529130605 . _:b529130494 . . _:b529130137 "2"^^ . . _:b529130136 "2"^^ . _:b529130604 . _:b529130542 . . _:b529130247 . _:b529130139 "2"^^ . _:b529130607 . _:b529130276 . _:b529130138 "2"^^ . _:b529130606 . . _:b529130149 "2"^^ . _:b529130601 . . _:b529129973 . _:b529130148 "2"^^ . _:b529130600 . _:b529130151 "2"^^ . _:b529130603 . _:b529130034 . . _:b529130150 "2"^^ . _:b24205809 "The apoptotic process is tightly controlled by various proteins [24,>>25<<]. It is well known that resistance of tumor cells to apoptosis might be an essential feature of cancer development thus, modulation of the key elements of apoptosis signaling may directly influence therapy-induced tumor-cell death [26,27]." . _:b529130602 . _:b529130145 "2"^^ . _:b529130613 . . _:b529130144 "2"^^ . _:b24205892 . _:b529130612 . . . _:b529130147 "2"^^ . _:b24205800 "In the present review we aim to describe and summarize different cell death pathways activated by PDT [16,>>17<<] and describe the key players controlling cell death related to PDT (Table 1)." . _:b529130146 "2"^^ . _:b529130157 "2"^^ . _:b529130609 . _:b529130555 . _:b529130156 "2"^^ . _:b529130608 . . . _:b529130159 "2"^^ . _:b529130611 . _:b529130611 . . . _:b529130158 "2"^^ . _:b529130610 . _:b529130153 "2"^^ . . _:b529130581 . _:b529130222 . _:b529130152 "2"^^ . . _:b529130155 "2"^^ . _:b529130433 . . _:b529130154 "2"^^ . _:b529130521 . . _:b529130165 "2"^^ . _:b529130049 . . _:b529130164 "2"^^ . _:b529130167 "2"^^ . _:b24205886 _:b24205887 . . . _:b529130166 "2"^^ . _:b529130042 . _:b24205923 . . . . . _:b529130161 "2"^^ . . . _:b529130550 . _:b529130160 "2"^^ . _:b529130163 "2"^^ . . _:b529130162 "2"^^ . _:b529130142 . _:b24205881 _:b24205882 . _:b529130173 "2"^^ . _:b24205881 _:b24205883 . _:b529130063 . _:b24205881 _:b24205884 . _:b24205881 _:b24205885 . _:b529130224 . _:b529130075 . _:b529130172 "2"^^ . _:b529130175 "2"^^ . . _:b529130174 "2"^^ . _:b529130169 "2"^^ . _:b529130168 "2"^^ . _:b529130171 "2"^^ . . . . _:b529130170 "2"^^ . _:b24205886 _:b24205892 . _:b24205886 _:b24205893 . _:b529130232 . _:b24205886 _:b24205894 . . _:b529130181 "2"^^ . _:b24205886 _:b24205895 . _:b24205886 _:b24205888 . _:b24205886 _:b24205889 . . _:b529130180 "2"^^ . _:b24205886 _:b24205890 . _:b24205886 _:b24205891 . _:b529130320 . _:b24205871 _:b24205880 . _:b529130183 "2"^^ . _:b24205824 . _:b529130182 "2"^^ . _:b24205871 _:b24205872 . _:b24205871 _:b24205873 . . _:b24205871 _:b24205874 . _:b529130177 "2"^^ . _:b24205871 _:b24205875 . _:b24205871 _:b24205876 . _:b24205859 . _:b24205871 _:b24205877 . _:b529130442 . _:b529129920 . _:b24205871 _:b24205878 . _:b529130176 "2"^^ . _:b24205871 _:b24205879 . _:b529130179 "2"^^ . _:b529130178 "2"^^ . _:b529130155 . . _:b529130189 "2"^^ . _:b529130188 "2"^^ . . _:b24205859 "The other group use TNFR-associated factor to link these receptors to serine/threonine protein kinase cascades that regulate gene transcription [>>75<<]." . _:b529130191 "2"^^ . _:b529130190 "2"^^ . . _:b529130443 . _:b529130185 "2"^^ . . _:b529130184 "2"^^ . _:b24205833 . _:b529130187 "2"^^ . _:b529130556 . _:b529130186 "2"^^ . . _:b24205849 _:b24205850 . _:b529130197 "2"^^ . _:b24205849 _:b24205851 . _:b24205849 _:b24205852 . _:b24205849 _:b24205853 . _:b24205849 _:b24205854 . _:b529130196 "2"^^ . _:b24205913 "In these cells, PDT induced autophagy stimulates a necrotic, caspase independent cell death [>>64<<]. Suppression of autophagy in apoptosis-deficient cells resulted in the inhibition of cell death during PDT. In general, the induction of autophagy in PDT treated cells occurs independently of an apoptotic outcome. While autophagy seems" . . _:b529130199 "2"^^ . _:b529130198 "2"^^ . _:b529130193 "2"^^ . _:b529130192 "2"^^ . _:b529130397 . . _:b529130330 . _:b24205855 _:b24205864 . _:b24205797 "States Food and Drug Administration for use in endo-bronchial and endo-esophageal cancer [13,14] and also as a treatment of premalignant and early malignant lesions of skin (actinic keratosis), bladder, breast, stomach and oral cavity [>>4<<,15]." . _:b24205855 _:b24205865 . _:b529129980 . _:b24205855 _:b24205866 . _:b529130195 "2"^^ . _:b24205855 _:b24205867 . _:b24205855 _:b24205868 . _:b24205855 _:b24205869 . _:b24205855 _:b24205870 . _:b529130194 "2"^^ . _:b24205855 _:b24205856 . _:b24205855 _:b24205857 . _:b24205855 _:b24205858 . _:b529130205 "2"^^ . _:b24205855 _:b24205859 . _:b24205803 . _:b24205855 _:b24205860 . _:b529130553 . _:b24205855 _:b24205861 . _:b529129887 . _:b24205855 _:b24205862 . _:b529130204 "2"^^ . _:b24205855 _:b24205863 . . _:b529130180 . _:b24205811 "It is well known that resistance of tumor cells to apoptosis might be an essential feature of cancer development thus, modulation of the key elements of apoptosis signaling may directly influence therapy-induced tumor-cell death [26,>>27<<]." . _:b529129972 . _:b529130207 "2"^^ . _:b529130206 "2"^^ . . . _:b529130201 "2"^^ . _:b529130200 "2"^^ . _:b529130203 "2"^^ . . _:b529130202 "2"^^ . _:b24205848 . _:b529130213 "2"^^ . . _:b24205909 . _:b529129962 . _:b529130212 "2"^^ . . . _:b529130215 "2"^^ . _:b529130214 "2"^^ . . . _:b529130209 "2"^^ . _:b529130562 . _:b529130208 "2"^^ . _:b529130099 . _:b24205828 . _:b529130211 "2"^^ . . _:b24205829 . _:b529130210 "2"^^ . _:b24205830 . _:b529130221 "2"^^ . _:b24205831 . . _:b529130220 "2"^^ . _:b24205824 . _:b529130223 "2"^^ . _:b529130174 . . . _:b24205825 . _:b529130222 "2"^^ . _:b24205826 . _:b24205878 . _:b529130217 "2"^^ . . . _:b24205825 . _:b24205827 . _:b529130216 "2"^^ . _:b24205836 . . _:b529130219 "2"^^ . _:b529129981 . _:b24205837 . _:b529130218 "2"^^ . _:b24205793 . _:b24205895 . _:b529130568 . _:b24205838 . . _:b529130229 "2"^^ . _:b24205839 . _:b529130126 . _:b529130228 "2"^^ . _:b529130410 . _:b24205832 . . _:b529130231 "2"^^ . . _:b529130592 . _:b24205833 . _:b529130230 "2"^^ . _:b24205834 . _:b529130225 "2"^^ . . _:b24205835 . _:b529130224 "2"^^ . _:b24205844 . _:b529130227 "2"^^ . _:b24205910 . _:b529130096 . . _:b529129931 . _:b24205845 . _:b529130098 . _:b529130226 "2"^^ . . _:b24205846 . _:b529130237 "2"^^ . _:b24205847 . _:b529129930 . _:b529130236 "2"^^ . _:b24205840 . _:b529130574 . _:b529130239 "2"^^ . . _:b24205841 . _:b529130238 "2"^^ . _:b24205842 . _:b529130233 "2"^^ . _:b24205843 . _:b529130548 . . _:b529130232 "2"^^ . . _:b529130469 . _:b24205852 . . _:b24205918 . _:b529130235 "2"^^ . _:b529129974 . _:b24205853 . . _:b529130234 "2"^^ . _:b24205854 . _:b529130245 "2"^^ . . _:b24205855 . _:b529130316 . _:b529130244 "2"^^ . . _:b24205848 . . _:b529130247 "2"^^ . . . _:b24205905 . _:b24205849 . _:b529130246 "2"^^ . _:b529130349 . _:b24205850 . _:b529130241 "2"^^ . _:b24205851 . . . _:b529130240 "2"^^ . . _:b24205860 . _:b529130156 . _:b529130243 "2"^^ . _:b24205861 . _:b529130275 . _:b529130242 "2"^^ . _:b24205862 . . _:b529130253 "2"^^ . _:b24205863 . _:b529130252 "2"^^ . _:b529130438 . . _:b24205856 . _:b529130172 . . _:b529130216 . _:b529130255 "2"^^ . _:b24205828 . _:b24205857 . _:b529130510 . _:b529130254 "2"^^ . . _:b529130512 . _:b24205896 _:b24205900 . _:b24205858 . _:b529130327 . _:b24205896 _:b24205901 . _:b24205896 _:b24205902 . _:b529130599 . _:b529130249 "2"^^ . _:b24205896 _:b24205903 . . _:b24205859 . . _:b24205896 _:b24205897 . _:b24205788 "PDT is a two-step procedure that involves the administration of a photosensitizing agent [1-3], followed by activation of the drug with non-thermal light of a specific wavelength [>>4<<,5] (Figure 1)." . _:b24205896 _:b24205898 . _:b529130248 "2"^^ . _:b24205896 _:b24205899 . _:b24205896 _:b24205908 . _:b24205868 . _:b24205896 _:b24205909 . _:b24205896 _:b24205910 . _:b529130251 "2"^^ . _:b24205896 _:b24205911 . _:b24205896 _:b24205904 . _:b24205869 . _:b24205896 _:b24205905 . _:b24205896 _:b24205906 . . . _:b529130250 "2"^^ . _:b529129994 . _:b24205795 "The PDT effectiveness is therefore determined by oxygen supply and may be decreased in conditions where there is tissue hypoxia [>>12<<]." . _:b24205896 _:b24205907 . _:b24205896 _:b24205916 . _:b24205870 . _:b529130080 . _:b24205896 _:b24205917 . _:b24205896 _:b24205918 . _:b529130261 "2"^^ . _:b24205896 _:b24205919 . _:b24205896 _:b24205912 . _:b24205871 . _:b24205896 _:b24205913 . _:b24205896 _:b24205914 . _:b529130260 "2"^^ . _:b24205896 _:b24205915 . . _:b24205864 . _:b24205827 . _:b529130263 "2"^^ . . _:b24205865 . . _:b24205896 _:b24205920 . _:b24205896 _:b24205921 . _:b24205896 _:b24205922 . _:b24205790 . _:b529130262 "2"^^ . _:b24205896 _:b24205923 . _:b24205866 . _:b529130257 "2"^^ . . _:b24205867 . . _:b24205869 . _:b529130256 "2"^^ . . _:b24205876 . _:b529130520 . _:b529130259 "2"^^ . _:b24205877 . . _:b529130258 "2"^^ . _:b529130488 . . . . _:b24205878 . . _:b529130269 "2"^^ . . _:b24205879 . _:b529130268 "2"^^ . . _:b24205872 . _:b529130271 "2"^^ . . _:b24205873 . _:b529130270 "2"^^ . _:b24205874 . _:b529130265 "2"^^ . _:b24205875 . _:b529130264 "2"^^ . . _:b24205884 . . _:b529130267 "2"^^ . . _:b24205885 . _:b529130266 "2"^^ . . _:b24205886 . . _:b529130277 "2"^^ . . _:b529129909 . _:b24205887 . . . _:b529130276 "2"^^ . _:b529130100 . _:b24205880 . _:b24205920 . _:b529130279 "2"^^ . . _:b24205822 . _:b24205881 . . _:b529130278 "2"^^ . . . _:b529130188 . _:b24205882 . _:b529130273 "2"^^ . . _:b24205883 . _:b24205922 "In those cells that received PDT, AO staining was completely lost within an hour, and within two hours autophagosome accumulation was observed [>>130<<]. This indicates that autophagosomes can be formed in the absence of lysosomes, but autophagy cannot be completed due to the lack of these organelles." . . . _:b529130272 "2"^^ . _:b529130192 . _:b24205892 . _:b529130275 "2"^^ . . . _:b24205893 . _:b529130299 . . _:b529130274 "2"^^ . _:b529130210 . _:b24205894 . . _:b529130285 "2"^^ . _:b24205883 "Other modes of ceramide-mediated cell death involve the activation of stress-activated protein/JUN kinase (SAPK/JNK) [>>97<<], dephosphorylation of the retinoblastoma protein and upregulation of transcription factors." . _:b24205895 . _:b529130448 . . _:b529130284 "2"^^ . _:b24205888 . _:b529130287 "2"^^ . _:b24205889 . . _:b529130286 "2"^^ . _:b529130077 . _:b24205890 . . . _:b529130281 "2"^^ . . _:b24205891 . _:b529130280 "2"^^ . _:b24205900 . _:b529130283 "2"^^ . _:b529130115 . _:b24205901 . . _:b24205807 "Cleavage of cytoskeletal proteins leads to cell fragmentation and formation of apoptotic bodies [>>23<<]. The apoptotic process is tightly controlled by various proteins [24,25]. It is well known that resistance of tumor cells to apoptosis might be an essential feature of cancer development thus, modulation of the key elements of apoptosis" . _:b529130282 "2"^^ . _:b24205902 . _:b529130293 "2"^^ . _:b24205903 . . _:b529130292 "2"^^ . _:b24205896 . _:b529130295 "2"^^ . _:b529130025 . _:b24205897 . _:b529130294 "2"^^ . _:b24205898 . _:b529130014 . _:b529130289 "2"^^ . _:b529130245 . _:b24205907 "In general, mammalian cells use autophagy as a defense against ROS mediated damage by clearing the cell of damaged organelles [>>117<<]. Depending on the type of ROS and degree of oxidative injury, PDT may stimulate autophagy [118] that either acts in a cytoprotective manner or induces autophagic cell death [119]. Autophagy may play a role in PDT induced apoptosis, but" . . _:b24205899 . _:b529130244 . _:b529130288 "2"^^ . . . . _:b24205908 . _:b529130348 . . _:b529130291 "2"^^ . _:b529130247 . _:b24205909 . _:b529130162 . _:b529130591 . _:b529130290 "2"^^ . _:b529130246 . _:b529129937 . _:b24205910 . _:b529130241 . _:b529130301 "2"^^ . _:b529130351 . _:b24205911 . _:b529130240 . _:b24205789 "PDT is a two-step procedure that involves the administration of a photosensitizing agent [1-3], followed by activation of the drug with non-thermal light of a specific wavelength [4,>>5<<] (Figure 1)." . _:b529130385 . _:b529130300 "2"^^ . . _:b24205904 . _:b529130161 . _:b529130243 . _:b529130303 "2"^^ . . _:b24205905 . . _:b529130302 "2"^^ . _:b529130242 . _:b24205906 . _:b529129964 . _:b529130185 . _:b529130477 . _:b529130297 "2"^^ . _:b529130253 . _:b24205907 . _:b529130252 . _:b529130370 . _:b529130296 "2"^^ . _:b529130225 . _:b24205916 . _:b529130567 . . _:b529130299 "2"^^ . _:b529130255 . _:b529130527 . . _:b24205917 . . _:b529130254 . _:b529130298 "2"^^ . _:b24205918 . . _:b529130309 "2"^^ . _:b529130249 . _:b24205919 . . _:b529130248 . _:b529130308 "2"^^ . _:b24205912 . . . _:b529130311 "2"^^ . _:b529130251 . _:b24205913 . . _:b529130460 . _:b529130250 . _:b529130310 "2"^^ . _:b529130577 . _:b24205796 "PDT as a treatment procedure has been accepted by the United States Food and Drug Administration for use in endo-bronchial and endo-esophageal cancer [>>13<<,14] and also as a treatment of premalignant and early malignant lesions of skin (actinic keratosis), bladder, breast, stomach and oral cavity [4,15]." . _:b24205914 . _:b529130368 . _:b529130261 . _:b529130305 "2"^^ . . _:b24205915 . _:b529129986 . _:b529130260 . _:b529130304 "2"^^ . _:b529130263 . _:b529130307 "2"^^ . _:b24205857 . _:b529130400 . _:b24205841 "The research performed by Usuda et al. [>>57<<] further supported the role of Bax in PDT-mediated cell death. The results indicated that Pc4-PDT caused the release of the Bax protein from the mitochondria of MCF7c3 cells but not from those of Bax-negative DU-145 cells." . _:b529130262 . _:b529130306 "2"^^ . . _:b529130257 . _:b529130408 . _:b529130317 "2"^^ . _:b24205894 . _:b529130256 . _:b529130316 "2"^^ . _:b24205920 . . _:b529130121 . _:b529130319 "2"^^ . _:b529130259 . _:b529129916 . _:b24205921 . _:b529130258 . _:b529130318 "2"^^ . _:b24205922 . _:b529130269 . _:b529130313 "2"^^ . . . _:b24205923 . _:b529130268 . _:b529130312 "2"^^ . . _:b529130271 . _:b529130315 "2"^^ . . . _:b529130270 . _:b529130314 "2"^^ . _:b529130265 . _:b529130325 "2"^^ . _:b529130264 . _:b529130324 "2"^^ . . _:b529130027 . _:b529130327 "2"^^ . _:b529130267 . _:b24205821 "The PDT resistant HT29 human colon adenocarcinoma cell line showed variation in numerous genes and proteins including upregulation of Bcl-2 levels and downregulation of Bax [>>37<<]. Apoptotic death induced by 5-aminolevulinic (5-ALA) mediated PDT involved suppression of bcl-2 mRNA levels and elevation of Bax mRNA in cervical cancer cell line [38] and esophageal cancer cell [39]. This regimen also let to increase in" . _:b529130266 . _:b529130334 . _:b529130326 "2"^^ . . . _:b24205848 . _:b529129942 . _:b529130321 "2"^^ . _:b529130277 . . _:b529130588 . _:b529130320 "2"^^ . _:b529130276 . _:b529130279 . _:b529130323 "2"^^ . . _:b529130278 . _:b529130322 "2"^^ . _:b24205904 "It is still unclear exactly how autophagy affects the outcome of PDT [>>66<<,115,116]. In general, mammalian cells use autophagy as a defense against ROS mediated damage by clearing the cell of damaged organelles [117]." . . _:b529130333 "2"^^ . _:b529130273 . . _:b529130272 . _:b529130332 "2"^^ . _:b529130242 . . _:b529129890 . _:b529130552 . _:b529130275 . _:b529130335 "2"^^ . . _:b529130427 . . _:b529130334 "2"^^ . _:b529130274 . _:b529130285 . _:b529130329 "2"^^ . "PMC0" . _:b529130328 "2"^^ . _:b529130284 . _:b529130009 . _:b529130331 "2"^^ . _:b529130287 . . _:b24205825 "This regimen also let to increase in Bax/Bcl-2 ratio in human malignant glioblastoma U87MG cells [40] while in U937 cells increase in Bak and Bax/Bcl-xL but decrease in Bid was observed [>>41<<]. 5ALA-PDT also caused a significant decrease in mRNA expression of Bcl-2 and increased the levels of Bax and Bad mRNA in cervical cancer in BALB/c nude mice [42]. Hypericin (HY) mediated PDT in human breast adenocarcinoma cell line" . _:b529130330 "2"^^ . _:b529130286 . . _:b24205793 "After the absorption of photons the PS is transformed from its ground state to its triplet excited state via a short-lived excited singlet state (Figure 2) [>>11<<]. The triplet state can undergo two different reactions:" . _:b529130486 . _:b529130281 . _:b529130341 "2"^^ . _:b529130118 . _:b529130340 "2"^^ . _:b529130280 . . _:b529130283 . _:b529130343 "2"^^ . . . _:b24205846 . _:b529130282 . _:b529130342 "2"^^ . _:b24205841 . . _:b529130337 "2"^^ . _:b529130293 . . . _:b24205905 "It is still unclear exactly how autophagy affects the outcome of PDT [66,>>115<<,116]. In general, mammalian cells use autophagy as a defense against ROS mediated damage by clearing the cell of damaged organelles [117]." . _:b529130292 . _:b529130336 "2"^^ . . _:b24205821 . _:b529130570 . _:b529130295 . _:b529130339 "2"^^ . _:b529130064 . _:b529130294 . _:b529130338 "2"^^ . _:b529130137 . _:b529130289 . _:b529130349 "2"^^ . _:b24205835 "A study performed by Kim et al. [>>51<<] showed that Bcl-2 transfection of MCF10A adhering human breast epithelial cell line resulted in a decrease in the light dose required for 90% loss of viability." . . _:b529130565 . _:b529130050 . _:b529130288 . _:b529130536 . _:b529130499 . _:b529130348 "2"^^ . _:b529130178 . _:b529130291 . _:b529130351 "2"^^ . _:b529130205 . _:b529130290 . _:b529130350 "2"^^ . _:b529130301 . _:b529130532 . _:b529130345 "2"^^ . _:b529130300 . _:b529130344 "2"^^ . . _:b529130347 "2"^^ . _:b529130303 . _:b529130045 . _:b529130302 . _:b529130346 "2"^^ . . _:b529130357 "2"^^ . _:b529130297 . _:b24205849 "cytochrome c release after pdt" . . _:b529130116 . _:b529130356 "2"^^ . _:b529130296 . . _:b529130501 . _:b529130299 . _:b529130359 "2"^^ . . _:b529130220 . _:b529130358 "2"^^ . _:b529130298 . . _:b529130309 . _:b24205888 "Necrosis has been referred to as accidental cell death, caused by physical or chemical damage and has generally been considered an unprogrammed process [>>101<<]. It is characterized by a pyknotic nucleus, cytoplasmic swelling, and progressive disintegration of cytoplasmic membranes, all of which lead to cellular fragmentation and release of material into the extracellular compartment." . _:b529130353 "2"^^ . . _:b529130308 . _:b529130352 "2"^^ . _:b529130109 . . _:b529130311 . _:b529130452 . _:b529130355 "2"^^ . . _:b529130310 . _:b529130354 "2"^^ . _:b24205843 "Moreover the decreases in the expression of Bcl-2 after PDT in LLC and LLC-IL-6 cells were similar thereby eliminating modulation of Bcl-2 expression levels by PDT as an explanation in this case [>>59<<]. The dependence of Pc4-PDT induced apoptosis on Bax remains under active investigation and reports from Chiu et al. [60,61] indicated that commitment to cell death after PDT occurs prior to Bax activation while Usuada et al. [62]" . _:b529129984 . _:b529130365 "2"^^ . _:b529130305 . _:b529130244 . _:b529130364 "2"^^ . _:b529130304 . _:b529130307 . _:b529130367 "2"^^ . _:b529130254 . _:b529130358 . _:b529130306 . _:b529130366 "2"^^ . _:b529130117 . . _:b529130317 . _:b529130361 "2"^^ . . _:b529130316 . _:b529130360 "2"^^ . _:b24205832 "Similar results were obtained in a study by Srivastava et al. [>>48<<]. The two employed cell lines (RIF1 and A431) differed in their response to Pc4-PDT-induced apoptosis in antisense treatment and overexpression approaches." . _:b529130342 . _:b529130319 . _:b529130363 "2"^^ . . _:b529129965 . _:b529130362 "2"^^ . _:b529130318 . _:b529130571 . _:b529130313 . _:b24205848 "In the absence of Bax/Bak, autophagy appears to be predominantly responsible for cell death following PDT with different photosensitizers [>>64<<-66]." . _:b529130373 "2"^^ . . _:b529130312 . _:b529130372 "2"^^ . . . . _:b529130315 . _:b529130375 "2"^^ . _:b529130392 . _:b529130314 . _:b529130374 "2"^^ . . _:b529130157 . _:b529130030 . . _:b529130325 . _:b529130369 "2"^^ . _:b529130607 . _:b529129977 . _:b529130324 . _:b529130368 "2"^^ . _:b529130376 . _:b529130327 . _:b529130371 "2"^^ . . . _:b529130326 . _:b529130370 "2"^^ . . _:b529130321 . _:b529130381 "2"^^ . _:b529130336 . . _:b529130143 . . _:b529130380 "2"^^ . _:b529130320 . _:b529130323 . _:b529130383 "2"^^ . . _:b529130083 . _:b529130340 . . _:b529130382 "2"^^ . _:b529130322 . . _:b529130333 . _:b529130377 "2"^^ . . _:b529130332 . _:b529130376 "2"^^ . _:b24205877 "A link between SAPK and p38 pathways and apoptosis has been suggested in several studies [91,>>92<<]. The evidence of the involvement of JNK1 and p38 was provided by Assefa et al. [93]." . _:b24205881 "involvement of other factors in pdt mediated apoptosis" . _:b24205814 . _:b24205799 "In the present review we aim to describe and summarize different cell death pathways activated by PDT [>>16<<,17] and describe the key players controlling cell death related to PDT (Table 1)." . _:b529130335 . _:b529130379 "2"^^ . _:b529130131 . _:b529130378 "2"^^ . _:b529130334 . . _:b529130329 . _:b529130389 "2"^^ . _:b24205845 . _:b529130328 . _:b529130388 "2"^^ . . _:b529130313 . . _:b529130391 "2"^^ . _:b529130331 . _:b529130053 . _:b529130330 . _:b529130390 "2"^^ . _:b529130209 . _:b529130341 . _:b529130385 "2"^^ . . _:b529130340 . _:b529130384 "2"^^ . _:b529130578 . _:b529130315 . . _:b529130343 . _:b529130387 "2"^^ . _:b529130149 . _:b529130342 . _:b529130386 "2"^^ . _:b529130337 . _:b529130397 "2"^^ . _:b24205917 "The photosensitizer AlPcS causes damage to the mammalian target of rapamycin, mTOR, a cell growth regulator that takes part in the autophagic signaling pathway [>>126<<]. Other proteins, like Beclin1, Atg5, and Atg7, appear to be unaffected by PDT. Although many proteins involved in the autophagic process are photodamaged by PDT, it appears that those involved in the formation of autophagosomes remain" . _:b529130582 . _:b529130336 . _:b529130396 "2"^^ . _:b24205903 . _:b529130339 . _:b529130399 "2"^^ . _:b24205902 . _:b529129954 . _:b529130398 "2"^^ . _:b529130338 . . _:b529130349 . _:b529130393 "2"^^ . . _:b24205901 . . _:b529130392 "2"^^ . _:b529130348 . . _:b529130351 . _:b529130395 "2"^^ . . . _:b529130350 . _:b529130394 "2"^^ . . _:b529130563 . _:b529130405 "2"^^ . _:b529130345 . _:b529130344 . _:b529130404 "2"^^ . . _:b529130347 . _:b529130407 "2"^^ . _:b529130346 . _:b529130406 "2"^^ . _:b529130357 . _:b529130401 "2"^^ . _:b529130356 . _:b529130400 "2"^^ . . _:b529130153 . _:b529130359 . _:b529130403 "2"^^ . . _:b529130543 . _:b529130402 "2"^^ . _:b529130358 . _:b529130355 . _:b529130353 . _:b529130413 "2"^^ . _:b24205893 "For instance, Lavie and coworkers [>>106<<] used the perylenequinones (hypericin and dimethyl tetrahydroxyhelianthrone) and found high dose PDT inhibited apoptosis by interfering with lamin phosphorylation, or by photodynamic cross-linking of lamins." . _:b529130352 . _:b529130412 "2"^^ . . _:b529130194 . _:b529130355 . _:b529130415 "2"^^ . _:b529130354 . _:b529130414 "2"^^ . _:b529130365 . _:b529130409 "2"^^ . _:b529130575 . . _:b24205910 "Autophagy may play a role in PDT induced apoptosis, but the two processes can also occur independently of one another [>>120<<]. A study done on murine leukemia L1210 cells found that a wave of autophagy occurs right before apoptosis [121]. It was also found that prevention of autophagy by silencing the Agt7 gene allowed photo-killing to occur at lower light" . _:b24205842 "Bax was found to translocate to mitochondria during apoptosis in HeLa cells after PDT with zinc (II) phthalocyanine [>>58<<]. Npe6 mediated PDT involved Bax protein as indicated by a study in Lewis lung carcinoma cells transfected with IL-6 that have higher Bax protein levels than the parent cells." . _:b529130408 "2"^^ . _:b529130364 . . . _:b529129921 . _:b529130367 . _:b529130411 "2"^^ . _:b529130366 . _:b529130410 "2"^^ . . . . _:b529130182 . _:b529130361 . _:b529130421 "2"^^ . . _:b529130360 . _:b529130420 "2"^^ . . . . _:b529130363 . _:b529130423 "2"^^ . . _:b529130059 . _:b529130467 . _:b529130422 "2"^^ . _:b529130362 . _:b529130373 . _:b529130417 "2"^^ . _:b24205836 "Another work indicating possible role of Bcl-2 in PDT response was reported by Xue et al. [>>52<<]. In this study it was shown that the anti-apoptotic protein Bcl-2 was highly sensitive to PDT mediated damage." . _:b529130372 . _:b529130416 "2"^^ . . _:b529130375 . _:b529130419 "2"^^ . _:b529130300 . _:b24205837 . _:b529130374 . _:b529130418 "2"^^ . _:b529130369 . _:b529130429 "2"^^ . . _:b529130428 "2"^^ . _:b529130368 . _:b24205831 "A higher ratio is known to promote initiation of apoptosis [>>47<<], thus explaining the contradictory results." . _:b24205865 . _:b529130371 . _:b529130431 "2"^^ . _:b529130370 . _:b529130430 "2"^^ . _:b529130144 . _:b529130381 . _:b529130425 "2"^^ . _:b24205865 "IkB members undergo rapid ubiquitin-dependent degradation after exposure to a variety of agonists, which activate the I\u03BAB kinase complex (IKK) [>>82<<]. This complex induces the phosphorylation-dependent removal of the IKB-like C-terminal domain of NF-\u03BAB, which allows dimers to translocate to the nucleus. Once in the nucleus the dimers target genes that belong to four broad categories:" . _:b529130380 . _:b529130424 "2"^^ . _:b24205806 "The active executioner caspases cleave cellular substrates, which leads to characteristic biochemical and morphological changes observed in dying cells [>>22<<]. Cleavage of nuclear lamins is followed by chromatin condensation and nuclear shrinkage; cleavage of the inhibitor of the DNase CAD (caspase activated deoxyribonuclease) causes DNA fragmentation. Cleavage of cytoskeletal proteins leads" . _:b529130383 . _:b529130427 "2"^^ . _:b529130199 . _:b529130382 . _:b529130426 "2"^^ . . _:b529130377 . _:b529130437 "2"^^ . _:b529129970 . _:b24205877 . _:b529130341 . _:b529130547 . _:b529130376 . _:b529130436 "2"^^ . _:b529129996 . . _:b529130381 . _:b529130379 . _:b529130439 "2"^^ . . . _:b529130378 . _:b529130438 "2"^^ . . . . . _:b529130433 "2"^^ . _:b529130389 . _:b529130388 . _:b529130432 "2"^^ . _:b529130055 . . _:b529130258 . _:b529130391 . _:b529130435 "2"^^ . _:b24205787 . _:b529130390 . _:b529130434 "2"^^ . . . _:b529130344 . _:b24205919 "When tetra(4-sulphonatophenyl)-porphine (TPPS4) photosensitizer is used photo-oxidation of the organelle matrix occurs [>>127<<]. In this type of PDT, lysosomal enzymes are inactivated before the membrane ruptures, which allows for specific targeting of this organelle without causing damage to the rest of the cell. This treatment can be used to selectively enrich" . _:b529130385 . _:b529130445 "2"^^ . _:b529130435 . _:b529130253 . _:b529130384 . _:b529130444 "2"^^ . _:b529130020 . _:b529130387 . _:b24205895 "Dahle, Steele and Moan reported [>>108<<] that the mode of cell death induced by PDT depended on cell density." . _:b529130447 "2"^^ . . . _:b529130446 "2"^^ . _:b529130386 . _:b529130101 . _:b529130434 . . _:b529130397 . _:b529130441 "2"^^ . . _:b24205898 . _:b529130440 "2"^^ . _:b529130396 . _:b529130399 . _:b529130443 "2"^^ . . _:b529130580 . _:b529130398 . _:b529130442 "2"^^ . . _:b529130362 . _:b529130393 . _:b529130453 "2"^^ . . _:b529130286 . _:b529130392 . _:b529130452 "2"^^ . . _:b529130395 . _:b529130455 "2"^^ . . . . _:b529130394 . _:b529130454 "2"^^ . . _:b529130405 . _:b529130449 "2"^^ . . _:b529130448 "2"^^ . _:b529130404 . _:b529130407 . _:b529130451 "2"^^ . _:b529130465 . _:b529130441 . _:b529130406 . _:b529130450 "2"^^ . _:b24205802 . . _:b529130461 "2"^^ . _:b529130401 . _:b529130482 . _:b529130400 . _:b529130460 "2"^^ . _:b529130403 . _:b529130463 "2"^^ . . _:b529130402 . _:b529130462 "2"^^ . . _:b529130331 . _:b529130457 "2"^^ . _:b529130413 . _:b529130306 . . _:b529130456 "2"^^ . _:b529130412 . . _:b529130198 . _:b24205885 . _:b24205823 "Apoptotic death induced by 5-aminolevulinic (5-ALA) mediated PDT involved suppression of bcl-2 mRNA levels and elevation of Bax mRNA in cervical cancer cell line [38] and esophageal cancer cell [>>39<<]. This regimen also let to increase in Bax/Bcl-2 ratio in human malignant glioblastoma U87MG cells [40] while in U937 cells increase in Bak and Bax/Bcl-xL but decrease in Bid was observed [41]. 5ALA-PDT also caused a significant decrease" . _:b529130459 "2"^^ . _:b529130415 . _:b529130414 . _:b529130458 "2"^^ . . . _:b529130469 "2"^^ . _:b529130409 . _:b529130048 . _:b529130411 . _:b529130408 . _:b529130468 "2"^^ . _:b529130411 . _:b24205787 "PDT is a two-step procedure that involves the administration of a photosensitizing agent [>>1<<-3], followed by activation of the drug with non-thermal light of a specific wavelength [4,5] (Figure 1)." . _:b529130471 "2"^^ . . _:b529130410 . _:b529130470 "2"^^ . _:b529130421 . _:b529130465 "2"^^ . _:b529130160 . _:b529129993 . _:b529130420 . _:b529130464 "2"^^ . _:b529130423 . _:b529130467 "2"^^ . _:b529130583 . . _:b529130422 . _:b529130466 "2"^^ . . . _:b529130477 "2"^^ . _:b529130417 . . . _:b529130476 "2"^^ . _:b529130416 . _:b24205871 "mitogen-activated protein kinases (mapk) involvement in pdt-mediated apoptosis" . _:b529130479 "2"^^ . _:b529130419 . . _:b529130219 . _:b529130478 "2"^^ . _:b529130418 . . _:b529130429 . _:b529130473 "2"^^ . _:b529130183 . _:b529130196 . _:b529129975 . _:b529130472 "2"^^ . _:b529130428 . _:b529130602 . _:b529130431 . _:b529130475 "2"^^ . . _:b529130011 . _:b529130474 "2"^^ . _:b529130430 . _:b529130425 . _:b529130485 "2"^^ . . . _:b529130424 . _:b529130484 "2"^^ . _:b529130427 . _:b529130487 "2"^^ . . _:b529130426 . _:b529130486 "2"^^ . _:b24205863 . . . _:b529130437 . _:b529130481 "2"^^ . _:b529130332 . _:b529130480 "2"^^ . _:b529130436 . _:b529130439 . _:b529130483 "2"^^ . _:b529130379 . . _:b529130482 "2"^^ . _:b529130438 . . . . _:b529130433 . _:b529130493 "2"^^ . _:b529130394 . _:b529129882 . _:b24205798 . . _:b529130241 . _:b24205912 . _:b529130492 "2"^^ . _:b529130432 . _:b529129912 . . _:b529130435 . _:b529130495 "2"^^ . _:b529130579 . _:b529130434 . _:b529130494 "2"^^ . _:b529129917 . _:b529130489 "2"^^ . _:b529130445 . _:b529130019 . . _:b24205916 . _:b24205817 . _:b529130444 . _:b529130488 "2"^^ . _:b529130447 . _:b529130594 . _:b529130491 "2"^^ . _:b529130446 . _:b24205894 "Xue and Oleinick [>>107<<] compared Pc4-mediated PDT of MCF7 cells that lack caspase 3 with the same cell line with caspase 3 transfected back in." . _:b529130490 "2"^^ . . . . _:b529130441 . _:b529130440 . _:b529130373 . . _:b529130443 . . . _:b529130463 . _:b529130442 . . . _:b529130453 . _:b529130208 . _:b24205880 "Xue et al. [>>95<<] investigated the involvement of Etk/Bmx kinase in PDT mediated apoptosis. Etk/Bmx is a newly discovered tyrosine kinase, commonly expressed in prostate epithelial and carcinoma cells." . . _:b529129896 . _:b529130452 . _:b529130455 . _:b529130454 . _:b529130085 . _:b529130449 . . _:b529129885 . _:b529130448 . _:b529130298 . _:b529130451 . . _:b529130450 . _:b529130461 . _:b529130296 . _:b529130460 . _:b529130463 . . _:b529130097 . _:b529130462 . _:b529130457 . . . _:b529130444 . _:b529130456 . . _:b529130459 . . . _:b529130458 . _:b529130469 . . . _:b529130468 . _:b24205897 . _:b24205830 "Kim et al. [>>46<<], however, reported a contradictory finding wherein overexpression of Bcl-2 in a subline of human breast epithelial cell MCF10A made them more sensitive to photodamage mediated by aluminum phthalocyanine." . _:b529130181 . _:b529130471 . _:b529130470 . _:b529130465 . _:b24205848 . _:b529130464 . _:b529130193 . _:b529130309 . . _:b529130467 . _:b529130466 . _:b24205839 . . . _:b529130477 . _:b24205817 "Bcl-2 and several other pro-survival molecules associate with the mitochondria outer membrane and the endoplasmic reticulum/nuclear membrane and maintain their integrity [>>33<<]. They can prevent cytochrome c release and subsequent caspase 9 activation. They probably also regulate the activation of several other caspases, independently of mitochondrial damage [34]." . _:b529130476 . _:b529130479 . . _:b24205791 "of a low-to-moderately selective degree of photosensitizer (PS) uptake by proliferating malignant cells, direct cytotoxicity of reactive oxygen species (ROS) and a severe vascular damage that impairs blood supply to the treated area [6,>>7<<]. Those biological effects of PDT are limited to the particular areas of tissues exposed to light." . _:b529130478 . _:b529130473 . . _:b24205834 . _:b529130130 . _:b529130472 . _:b529129888 . _:b529130369 . . _:b529129956 . _:b529129957 . _:b24205831 . _:b529130475 . _:b529129958 . _:b529129959 . _:b529129952 . _:b529129953 . _:b529130474 . _:b529129954 . _:b529129955 . _:b529129951 . _:b529129964 . _:b529130127 . _:b529130485 . _:b529129965 . _:b529129966 . _:b529130559 . _:b529129967 . _:b529130421 . _:b529129960 . _:b24205882 "Ceramide is implicated in the cell-signaling pathway involved in apoptosis as it acts as a second messenger to permeabilize the outer mitochondrial membrane and facilitate the release of cytochrome c from the mitochondria [>>96<<]. Other modes of ceramide-mediated cell death involve the activation of stress-activated protein/JUN kinase (SAPK/JNK) [97], dephosphorylation of the retinoblastoma protein and upregulation of transcription factors." . _:b529130509 . _:b529129961 . _:b529130484 . _:b529129948 . _:b529129962 . . _:b529129963 . _:b529129972 . _:b529129973 . _:b529130487 . _:b529129974 . _:b529129975 . _:b529129968 . _:b529130414 . _:b529130277 . _:b529130201 . _:b24205872 . _:b529130486 . _:b529130407 . _:b529129969 . _:b529129970 . _:b529130529 . _:b529129971 . _:b529129980 . _:b529129981 . _:b529130481 . _:b529129982 . _:b529129983 . _:b529129976 . _:b529129977 . _:b529130480 . _:b529129978 . _:b529129979 . _:b529129924 . _:b529129925 . _:b529130483 . _:b529129926 . _:b529129927 . _:b529130406 . _:b529129920 . _:b529129921 . _:b529130482 . _:b529130062 . _:b529129922 . _:b529129923 . _:b529129932 . _:b529129933 . _:b529130493 . . _:b529129934 . _:b529129935 . . _:b529129928 . _:b529129929 . _:b529130492 . _:b529129930 . _:b529129931 . . _:b529129940 . _:b529129941 . _:b529130495 . _:b529129942 . _:b529129943 . _:b529129936 . . _:b529130494 . _:b529129937 . _:b529129938 . . _:b529129939 . _:b529129948 . _:b529129949 . _:b529130489 . _:b529129950 . _:b529129951 . _:b529129944 . _:b529129945 . _:b529130488 . _:b529129946 . _:b529129947 . _:b529129892 . _:b529129893 . _:b529130491 . _:b529130324 . _:b529129894 . _:b529129895 . _:b529129888 . . _:b529130490 . _:b529129889 . . _:b529129890 . . _:b529129891 . . _:b529129900 . . _:b529129901 . . _:b529129989 . _:b529129902 . _:b529129903 . _:b529130102 . _:b529129896 . . _:b529129988 . _:b529129897 . . _:b529130175 . _:b529129898 . _:b529129899 . _:b24205803 "It can be initiated either through the activation of death receptors or the mitochondrial release of cytochrome c [>>19<<]. Both events eventually lead to activation of caspase cascades known as \u2018executioner caspases\u2019 such as caspase-3, -6 and -7 [20,21]. The active executioner caspases cleave cellular substrates, which leads to characteristic biochemical" . . _:b529129908 . _:b529130088 . _:b529129991 . _:b529129909 . _:b529130169 . . _:b529129910 . _:b529129911 . _:b529129904 . _:b529129990 . _:b529129905 . _:b529129906 . _:b529129907 . _:b529129916 . _:b529129985 . _:b529129917 . . _:b529129918 . _:b529130069 . _:b529129919 . _:b529129912 . _:b529129984 . _:b529129913 . _:b529129914 . _:b529129915 . _:b24205851 "by proteins of the Bcl-2 family. In the cytosol, cytochrome c activates the caspases\u2014a family of killer proteases\u2014through formation of a complex with Apaf-1 (for apoptotic-protease activating factor-1), procaspase-9 and ATP or dATP. [>>68<<]. The opening of the mitochondrial membrane permeability transition pores, which results in the dissipation of the mitochondrial membrane potential (\u0394\u03C8m), has been proposed as the main mechanism for release of cytochrome c." . _:b529129987 . _:b24205834 "Granvile et al. [>>50<<] in his overexpression model using benzoporphyrin derivative monoacid ring A (BPD-MA) and human acute myelogenous leukemia HL-60 cells observed that Bcl-2 overexpression may influence caspase 3 and caspase 6 activation and prevent the" . _:b529129986 . _:b529130609 . _:b529130295 . . . . _:b529129868 . _:b529129997 . _:b529129869 . . _:b529129870 . _:b529129871 . _:b529129996 . _:b24205858 . _:b529129907 . . _:b529129876 . . _:b529129999 . _:b529129877 . . _:b529129878 . _:b529129879 . _:b529129872 . _:b529129998 . _:b529129873 . . _:b529129874 . _:b529129875 . _:b529129884 . _:b529129993 . _:b529129885 . _:b529129886 . . _:b529129887 . _:b529129880 . _:b529129992 . _:b529130409 . _:b529129881 . . . _:b529129882 . _:b529129883 . . _:b529130084 . _:b529129995 . _:b529130085 . _:b529130086 . _:b529130087 . _:b529130080 . _:b529129994 . _:b529130081 . _:b529130082 . _:b529130083 . _:b529130537 . _:b529130092 . _:b529130005 . _:b529130093 . _:b529130094 . _:b529130095 . _:b529130088 . _:b529130004 . _:b529130089 . _:b529130090 . _:b529130091 . _:b529130100 . _:b529130007 . _:b529130101 . . . _:b529130102 . _:b529130103 . _:b529130096 . _:b529130006 . _:b529130097 . _:b529130260 . _:b529130098 . _:b529130099 . _:b529130108 . _:b529130001 . _:b24205892 "With PS localized in the plasma membrane the photosensitization process can rapidly switch the balance towards necrotic cell death likely due to loss of plasma membrane integrity and rapid depletion of intracellular ATP [>>105<<]. It is also possible that high doses of PDT can photochemically inactivate essential enzymes and other components of the apoptotic cascade such as caspases. For instance, Lavie and coworkers [106] used the perylenequinones (hypericin and" . _:b529130109 . _:b529130110 . _:b529130111 . . _:b529130104 . _:b529130000 . _:b529130105 . _:b529130106 . _:b529130302 . _:b529130107 . _:b529130366 . _:b529130052 . _:b529130003 . _:b24205885 "p21/WAF1 involvement in PDT was investigated by Ahmad et al. [>>99<<]. They found that cells subjected to PDT resulted in a growth arrest particularly observed in G0-G1 phase." . _:b529130608 . _:b529130053 . . _:b529130054 . _:b529130055 . _:b529130048 . _:b529130002 . _:b529130049 . _:b529130050 . _:b529130051 . _:b529130060 . _:b529130013 . _:b529130061 . _:b529130152 . . _:b529130062 . . _:b529130063 . _:b529130056 . _:b529130012 . _:b529130057 . _:b529130058 . _:b529130059 . _:b529130068 . _:b529130015 . _:b529130069 . _:b529130070 . _:b529130071 . _:b529130064 . . _:b529130065 . _:b529130014 . _:b529130066 . _:b529130067 . . _:b529130076 . _:b529130009 . _:b529130077 . _:b529130078 . _:b529130079 . _:b24205890 "e.g., apoptosis or necrosis following PDT are: the cell type, the presence of an intact set of apoptosis machinery, the subcellular localization of the PS, the light dose applied to activate it locally, and the oxygen partial pressure [>>103<<]. One factor that can be agreed upon by all commentators is that high dose PDT (either a high photosensitizer concentration or a high light fluence or both) tends to cause cell death by necrosis, while PDT administered at lower doses tend" . _:b529129929 . _:b529130072 . _:b529130073 . _:b529130008 . _:b529130074 . _:b529130075 . _:b529130020 . _:b529130021 . _:b529130011 . . _:b529130022 . _:b24205870 . _:b529130023 . _:b529130016 . _:b529130017 . _:b529130605 . _:b529130010 . _:b529130018 . . _:b529130019 . _:b529130028 . _:b529130029 . _:b529130021 . _:b529130030 . _:b529130031 . _:b529130024 . _:b529130025 . _:b529130020 . _:b529130026 . . _:b529130027 . . _:b529130036 . _:b529130037 . _:b529130374 . _:b529130023 . _:b529130038 . _:b529130039 . _:b529130032 . _:b529130033 . _:b24205795 . . _:b529130022 . _:b529130034 . _:b24205913 . . _:b529130035 . . _:b529130044 . _:b529130045 . _:b24205844 "The dependence of Pc4-PDT induced apoptosis on Bax remains under active investigation and reports from Chiu et al. [>>60<<,61] indicated that commitment to cell death after PDT occurs prior to Bax activation while Usuada et al. [62] reported that Smac/DIABLO promotes apoptosis after Pc4-PDT in a Bax dependent manner." . . _:b529130017 . _:b529130046 . _:b24205901 "One of the first diseases associated with autophagy was cancer [>>113<<]. It was discovered that Beclin1, an essential protein for autophagy, is also a tumor suppressor [114]." . _:b529130047 . _:b529130040 . _:b529130041 . _:b529130498 . _:b529130016 . _:b529130042 . _:b529130043 . _:b529130517 . _:b529130285 . _:b529129988 . . _:b529129989 . _:b529130019 . _:b529129990 . _:b529129991 . _:b529129984 . _:b529129985 . _:b529130018 . _:b529129986 . _:b529129987 . _:b529129996 . _:b529129997 . _:b529130029 . _:b529129998 . _:b529129999 . _:b529129992 . _:b529129993 . _:b529129952 . _:b529130028 . _:b529129994 . _:b529130293 . _:b529129995 . _:b529130004 . . _:b529130005 . _:b529130031 . _:b529130006 . _:b529130007 . _:b529130000 . _:b529130001 . _:b529130030 . _:b529130002 . _:b529130003 . _:b529130012 . _:b529130013 . _:b529130025 . _:b529130014 . _:b529130015 . _:b529130008 . _:b24205816 "Bcl-2 itself is required for the survival of kidney and melanocyte stem cells and mature lymphocytes [30], BclXL for neuronal and erythroid cells [31], and Bcl-w for sperm progenitors [>>32<<]. Bcl-2 and several other pro-survival molecules associate with the mitochondria outer membrane and the endoplasmic reticulum/nuclear membrane and maintain their integrity [33]. They can prevent cytochrome c release and subsequent caspase" . _:b529130009 . _:b529130024 . _:b529130010 . . _:b529130011 . _:b529130212 . _:b529130213 . _:b529130027 . _:b529130214 . _:b529130122 . _:b529130215 . _:b529129891 . . _:b529130208 . _:b529130209 . . _:b529129990 . _:b529130026 . _:b529130210 . _:b529130060 . _:b529130211 . _:b529130220 . _:b24205810 "It is well known that resistance of tumor cells to apoptosis might be an essential feature of cancer development thus, modulation of the key elements of apoptosis signaling may directly influence therapy-induced tumor-cell death [>>26<<,27]." . . _:b529130221 . _:b529130037 . _:b529130222 . _:b529130223 . _:b529130216 . _:b529130217 . _:b529130036 . _:b529130218 . _:b529130219 . _:b529130228 . _:b529130229 . _:b529130256 . _:b529130039 . _:b529130230 . _:b529130231 . _:b529130224 . _:b529130225 . _:b529130038 . _:b529130226 . _:b529130227 . _:b529130236 . _:b529130237 . . _:b529130033 . _:b529130238 . _:b529130239 . _:b529130232 . _:b529130233 . _:b529130032 . _:b529130234 . _:b529130235 . _:b529130180 . _:b529130066 . . _:b529130181 . _:b529130035 . _:b529130182 . _:b529130183 . _:b529130176 . _:b529130177 . _:b529130034 . _:b529130178 . _:b529130179 . _:b529130188 . _:b529130189 . _:b529130119 . _:b529130045 . _:b529130190 . _:b529130191 . . _:b529130184 . _:b529130185 . _:b529130044 . . _:b529129992 . _:b529130150 . _:b529130186 . _:b529130187 . . _:b529130196 . _:b24205886 "pdt and necrosis" . _:b529130217 . _:b529130197 . _:b529130047 . _:b529130198 . _:b529130199 . _:b529130192 . _:b529130193 . _:b529130046 . _:b529130194 . _:b529130195 . _:b529130204 . _:b529130205 . _:b529130041 . _:b529130206 . _:b529130207 . _:b529130200 . _:b529130522 . . _:b529130201 . _:b529130040 . _:b529130202 . _:b529130203 . _:b529130148 . _:b24205799 . _:b529130149 . _:b529130043 . _:b529130150 . _:b529130151 . . _:b529130144 . _:b529130145 . _:b529130042 . _:b529130146 . _:b529130147 . _:b529129892 . _:b529130156 . . _:b529130157 . _:b529130053 . _:b529130158 . _:b529130159 . _:b529130152 . _:b529130153 . _:b529130052 . _:b529130154 . _:b529130155 . . _:b529130164 . _:b529130165 . _:b529130480 . _:b529130055 . _:b529130166 . . _:b529130167 . _:b529130160 . _:b529129991 . _:b529130161 . _:b529130054 . _:b529130162 . _:b529130430 . _:b529130255 . _:b529130163 . _:b529129879 . . _:b529130172 . . _:b529130173 . _:b529130049 . _:b529130174 . _:b529130175 . _:b529130168 . _:b529130169 . _:b24205787 . _:b529130048 . _:b529130170 . _:b529130171 . _:b529130116 . _:b529130117 . _:b24205891 . _:b529130051 . _:b529130118 . _:b24205862 . _:b529130119 . _:b529130112 . _:b529130113 . _:b529130204 . _:b529130051 . _:b529130050 . _:b529130114 . _:b529130115 . . _:b529130124 . _:b529130125 . _:b529130061 . _:b529130126 . . _:b529130127 . _:b529130184 . _:b529130120 . _:b529130121 . _:b529130060 . _:b529130122 . _:b24205920 "This treatment can be used to selectively enrich autophagosomes [>>128<<]. On the other hand, NPe6 and TPPS2 photosensitizers bind to the lysosomal membrane, causing it to rupture upon irradiation." . _:b529130123 . _:b24205861 . _:b529130038 . _:b529130132 . _:b24205800 . _:b529130133 . _:b529130063 . . _:b529130134 . _:b529130135 . _:b529130471 . _:b529130128 . _:b529130129 . _:b529130062 . _:b529130130 . _:b529130131 . _:b529130140 . _:b529130141 . _:b529129915 . _:b529130057 . _:b529130142 . _:b529129959 . _:b529130143 . . _:b529130136 . _:b529130137 . _:b529130056 . _:b529130138 . . _:b529130139 . _:b529130340 . _:b529130341 . _:b529130059 . _:b529130342 . . _:b529130343 . . _:b529130336 . _:b529130337 . _:b529130506 . _:b529130412 . . _:b529130058 . _:b529130338 . _:b529130339 . _:b529130348 . _:b529130349 . _:b529130069 . _:b529130350 . _:b529130351 . _:b529130344 . _:b529130345 . _:b529130068 . _:b529130346 . _:b529130347 . _:b529130356 . _:b529130357 . _:b529130388 . _:b529130071 . _:b529130358 . _:b529130359 . _:b529130352 . _:b529130353 . _:b529130070 . . _:b529130354 . _:b529130355 . _:b529130364 . . _:b529130365 . _:b529130065 . _:b529130366 . _:b529130367 . _:b529130360 . . _:b529130361 . . _:b529130064 . _:b529130362 . _:b529130363 . . _:b529130308 . . _:b529130309 . _:b529130067 . _:b529130310 . _:b529130311 . _:b529129939 . _:b529130304 . _:b529130305 . _:b529130066 . _:b529130306 . _:b529130307 . _:b529130284 . _:b529130316 . _:b529130317 . _:b24205845 "The dependence of Pc4-PDT induced apoptosis on Bax remains under active investigation and reports from Chiu et al. [60,>>61<<] indicated that commitment to cell death after PDT occurs prior to Bax activation while Usuada et al. [62] reported that Smac/DIABLO promotes apoptosis after Pc4-PDT in a Bax dependent manner." . _:b529130077 . . _:b529130318 . _:b529130319 . _:b529130312 . _:b529130313 . _:b529130076 . _:b529130314 . _:b529130315 . _:b529130324 . _:b529129936 . _:b529130325 . _:b529130079 . _:b529130326 . _:b529130327 . _:b529130320 . . _:b529130078 . _:b529130321 . _:b529130322 . _:b529130323 . _:b529130292 . . _:b529130332 . _:b529130333 . _:b529130073 . . _:b529130334 . . _:b529130335 . _:b529130328 . _:b529130329 . _:b529130072 . _:b529130330 . _:b529130331 . _:b529130276 . _:b529130277 . _:b529130075 . _:b529130278 . _:b529130279 . _:b529130283 . _:b529130272 . _:b529130273 . _:b529130074 . _:b529130274 . . _:b529130275 . _:b529130284 . _:b529130285 . _:b529130085 . _:b529130286 . _:b529130287 . _:b529130280 . _:b529130281 . _:b529130084 . _:b529130282 . _:b529129897 . _:b529130283 . _:b529130292 . _:b529130293 . _:b529130087 . . _:b529130294 . _:b529130295 . _:b529130288 . _:b529130462 . _:b529130289 . _:b529130086 . _:b529130290 . _:b529129902 . _:b529130291 . _:b529130300 . _:b529130301 . _:b24205878 "The evidence of the involvement of JNK1 and p38 was provided by Assefa et al. [>>93<<]. In hypericin-mediated PDT of A431, HaCaT, HeLa and L929 cell lines theye observed a rapid and persistent activation of JNK1 and severely inhibition of the basal levels of ERK2. It was also demonstrated that photo-activated hypericin" . _:b529130081 . _:b529130302 . _:b529130303 . _:b529130296 . _:b529130297 . _:b529130080 . _:b529130298 . . _:b529130299 . . _:b529130244 . _:b24205814 "Bcl-2 itself is required for the survival of kidney and melanocyte stem cells and mature lymphocytes [>>30<<], BclXL for neuronal and erythroid cells [31], and Bcl-w for sperm progenitors [32]." . _:b529130245 . _:b529130083 . _:b529130246 . _:b529130247 . _:b529130271 . _:b529130240 . _:b529130241 . _:b529130082 . _:b529130242 . _:b529130243 . _:b529130252 . _:b529130253 . _:b529130093 . _:b529130254 . _:b529130255 . _:b24205889 . _:b24205861 "To further evaluate the role of Fas in PDT mediated apoptosis, Ali et al. [>>77<<] used a model of Hypocrellin A (HA) and Hypocrellin B (HB) as photosensitizers in CNE2 and TW0-1 cells." . _:b529130248 . _:b529130395 . _:b529130249 . _:b529130092 . _:b529130250 . _:b529130251 . _:b529130260 . . _:b529130261 . _:b529130095 . _:b529130262 . _:b24205872 "Mitogen-activated protein kinases are proline-directed Ser/Thr protein kinases activated by dual phosphorylation on both tyrosine and threonine residues [>>87<<]. These enzymes are critical components of a complex cellular signaling network that ultimately regulates gene expression in response to variety extracellular stimuli." . _:b529130263 . . _:b529130256 . _:b529130257 . _:b529130094 . _:b529130258 . _:b529130259 . _:b529130268 . _:b529130269 . _:b529130089 . _:b529130270 . _:b529130271 . _:b529130264 . _:b529129894 . _:b529130265 . . _:b529130088 . _:b529130266 . _:b529130267 . _:b529130468 . _:b529130469 . . _:b529130091 . . _:b529129958 . _:b529130470 . _:b529130471 . _:b529130464 . _:b529130465 . . _:b529130090 . _:b529130466 . _:b529130467 . _:b529130476 . _:b529130477 . _:b529130101 . _:b529130478 . _:b529130479 . _:b529130472 . . _:b529130100 . _:b529130473 . _:b529130474 . _:b529130475 . . _:b529130484 . _:b529130513 . _:b529130485 . _:b529130103 . _:b529130486 . _:b24205880 . _:b529130371 . _:b529130487 . _:b529130480 . _:b529129976 . _:b529130102 . _:b529130481 . _:b529130482 . . _:b24205819 "PDT is thought to induce photodamage of Bcl-2 and related antiapoptotic proteins and activate the proapoptotic members of the family [>>35<<]. Alteration in expression of members of Bcl-2 family proteins following PDT has been reported in various cell lines and tumors." . _:b529130386 . _:b529130483 . _:b529130492 . _:b529130493 . _:b529130097 . _:b529130494 . . _:b529130495 . _:b529130488 . _:b529130489 . _:b529130096 . _:b529130490 . _:b529130491 . _:b529130436 . . _:b529130437 . _:b24205823 . _:b529130483 . _:b529130099 . _:b529130438 . _:b529130439 . . _:b529130432 . _:b529130433 . _:b529130098 . _:b529130434 . _:b529130585 . _:b529130564 . _:b529130435 . _:b529130444 . _:b529130445 . _:b529130419 . _:b529130109 . _:b529130446 . _:b529130447 . _:b529130007 . _:b529130440 . _:b529130441 . _:b529130108 . _:b529130442 . _:b529130443 . _:b529130452 . _:b529130453 . _:b529130111 . _:b529130454 . _:b24205857 "The most complex example is APO2/TRAIL, which binds five different receptors [>>73<<]." . _:b529130455 . _:b529130448 . _:b529130449 . . _:b529130110 . _:b529130450 . _:b529130451 . . _:b529130460 . _:b529130008 . _:b529130461 . _:b529130105 . _:b529130462 . _:b529130463 . _:b529130456 . _:b529130457 . _:b529130104 . _:b529130458 . _:b529130459 . _:b529130404 . _:b24205804 . . _:b529130405 . _:b529129949 . _:b529130107 . _:b529130406 . _:b529130407 . _:b529130526 . _:b529130400 . _:b529130401 . _:b529130106 . _:b529130402 . _:b529130403 . _:b24205807 . _:b529130412 . _:b529130413 . _:b529130117 . _:b529130414 . _:b529130415 . _:b529130408 . _:b529130409 . . _:b529130116 . _:b529130410 . _:b529130411 . _:b529130546 . _:b529130252 . _:b529130420 . _:b529130421 . _:b529130119 . _:b529130422 . _:b24205888 . . _:b529130423 . _:b529130422 . _:b529130403 . . _:b529130416 . _:b529130238 . _:b529130417 . _:b529130118 . _:b529130418 . _:b529130419 . _:b529130428 . _:b529130429 . _:b24205853 "Another work indicating an important role of cytochrome c in PDT-induced apoptosis was carried out by Vantieghem et al. [>>70<<]. In his approach, the overexpression of Bcl-2 in Pc60R1R2 cells revealed that mechanism of cytochrome c release after hypericin mediated PDT is caspase-dependent." . _:b529130301 . _:b529130113 . _:b529130430 . _:b529130431 . _:b24205828 "However, HY-PDT did not affect Bcl-2 levels in p53 null and wt-p53 expressing HCT 116 cells [>>44<<]. These studies indicated a possible involvement of the antiapoptotic Bcl-2 family members in PDT induced apoptotic cell death, but a more definite role for Bcl-2 comes from studies involving antisense treatment and overexpression" . . . _:b529130424 . _:b24205868 . _:b529130425 . _:b529130112 . _:b529130426 . _:b529130427 . _:b529130372 . _:b529130373 . _:b24205792 "Additionally, PDT leads to activation of tumor directed, systemic immune responses [>>8<<-10]." . _:b529130115 . _:b529130374 . _:b24205836 . _:b529130375 . _:b529130368 . _:b529130369 . _:b529130114 . _:b529130370 . _:b529130371 . . _:b529130380 . _:b529130381 . _:b529130125 . _:b529130382 . _:b529130383 . _:b529130376 . _:b529130377 . _:b529130124 . _:b529130378 . _:b529130379 . _:b24205788 . _:b529130388 . . _:b529130389 . _:b529130127 . _:b529130390 . . _:b529130391 . _:b24205789 . _:b529130384 . _:b529130385 . _:b529130126 . . _:b529130386 . _:b529130387 . _:b24205790 . _:b529130396 . _:b24205867 . _:b529130397 . _:b529130597 . _:b529130121 . _:b529130398 . _:b529130399 . _:b24205791 . _:b529130392 . _:b529130393 . _:b529130551 . _:b529130120 . . _:b529130394 . _:b529130395 . _:b529130596 . . _:b529130597 . _:b529130123 . _:b529130598 . _:b529130326 . _:b529130599 . . _:b529130592 . _:b529130593 . . _:b529130122 . _:b529130594 . _:b529130595 . . _:b529130604 . _:b529130595 . _:b24205786 . . _:b529130605 . _:b529130082 . _:b529130133 . _:b529130606 . _:b529130607 . _:b24205787 . _:b529130600 . . _:b529130601 . _:b529130132 . _:b529130602 . _:b529130603 . _:b24205796 . _:b529130612 . _:b529130613 . _:b529130135 . . . _:b529130125 . _:b24205797 . _:b529130608 . _:b529130609 . _:b529130134 . _:b529130610 . . _:b24205798 . _:b529130611 . _:b529130129 . _:b24205799 . _:b529130128 . _:b529130428 . _:b24205792 . _:b529130564 . _:b529130565 . _:b529130131 . _:b529130566 . _:b529130567 . _:b24205793 . _:b529130560 . _:b529129881 . _:b529130561 . _:b529130130 . _:b529130562 . _:b529130563 . _:b24205794 . _:b529130572 . . . _:b529130573 . _:b529130141 . _:b529130574 . _:b529130575 . _:b24205795 . _:b529130568 . _:b529130587 . _:b529130569 . _:b529130140 . _:b529130570 . _:b529130571 . _:b24205804 . _:b529130580 . _:b529130581 . _:b24205855 "involvement of death receptors in pdt response" . _:b529130143 . . _:b529130582 . _:b529130583 . _:b24205805 . _:b529130576 . . _:b529130142 . _:b529130577 . _:b529130578 . _:b24205869 "PDT produces an oxidative stress that can result in activation and translocation of NF-\u03BAB to the nucleus, as originally shown for treatment of L1210 murine leukemia cells with Photofrin and light. [>>85<<]. The claim that NF-\u03BAB may be a target for PDT has been convincingly demonstrated by Granville et al. [86]." . _:b529130579 . _:b24205806 . _:b529130588 . _:b529130589 . _:b529130000 . _:b529130137 . _:b529130590 . _:b529130591 . _:b24205807 . _:b529130584 . _:b529130585 . _:b529130136 . _:b529130586 . _:b529130587 . _:b24205800 . _:b529130012 . _:b529130532 . _:b24205840 . _:b529130533 . _:b529130139 . _:b529130534 . _:b529130535 . _:b529130528 . _:b24205801 . . _:b529130529 . _:b529130138 . _:b529130530 . _:b529130531 . _:b24205802 . _:b529130540 . _:b529130541 . _:b529130149 . _:b529130542 . _:b529129880 . _:b24205803 . _:b529130436 . _:b529130543 . _:b529130145 . _:b529130536 . _:b529130537 . _:b529130440 . _:b529130148 . _:b529130538 . _:b529130539 . _:b24205879 "The involvement of stress kinases in PDT mediated cell death was also investigated by Chan et al. [>>94<<]. They evaluated the role of JNK1 and involvement of singlet oxygen in triggering the JNK pathway." . _:b24205812 . _:b529130548 . _:b529130549 . _:b529130151 . _:b529130550 . _:b529130551 . _:b24205813 . _:b529130544 . _:b24205805 "Both events eventually lead to activation of caspase cascades known as \u2018executioner caspases\u2019 such as caspase-3, -6 and -7 [20,>>21<<]. The active executioner caspases cleave cellular substrates, which leads to characteristic biochemical and morphological changes observed in dying cells [22]. Cleavage of nuclear lamins is followed by chromatin condensation and nuclear" . _:b529130545 . _:b529130150 . _:b529130110 . _:b529130546 . _:b529130547 . _:b24205814 . _:b529130556 . _:b529130557 . _:b529130145 . _:b529130558 . _:b529130559 . _:b24205815 . _:b529130552 . _:b529130553 . _:b529130144 . _:b529130554 . _:b529130555 . _:b24205808 . _:b529130500 . _:b24205911 "A study done on murine leukemia L1210 cells found that a wave of autophagy occurs right before apoptosis [>>121<<]. It was also found that prevention of autophagy by silencing the Agt7 gene allowed photo-killing to occur at lower light doses. This observation is consistent with the theory that autophagy is a defense mechanism against PDT induced ROS" . _:b24205832 . . _:b529130501 . _:b529130147 . _:b529130502 . _:b529130503 . _:b24205813 "The family includes four other anti-apoptotic proteins: BclXL, Bcl-w, A1 and Mcll, and two groups of proteins that promote apoptosis: the Bax and the BH3-only families [28,>>29<<]." . _:b24205809 . . _:b529130496 . . _:b529130035 . _:b529130497 . _:b529130447 . _:b529130329 . _:b529130200 . _:b529130146 . _:b529130498 . _:b529130501 "2"^^ . _:b529130499 . _:b24205810 . _:b529130466 . _:b529130508 . _:b529130509 . _:b529130157 . _:b529130510 . _:b529130500 "2"^^ . _:b529130511 . _:b24205811 . _:b529130504 . _:b529130505 . _:b529130156 . _:b529130506 . _:b529130503 "2"^^ . _:b529130507 . _:b24205820 . _:b529130516 . _:b529129926 . . _:b529130517 . _:b529130159 . _:b529130518 . _:b24205876 "A link between SAPK and p38 pathways and apoptosis has been suggested in several studies [>>91<<,92]. The evidence of the involvement of JNK1 and p38 was provided by Assefa et al. [93]." . _:b529130502 "2"^^ . _:b529130519 . _:b24205821 . _:b529130512 . . _:b529130513 . _:b529130261 . _:b529130158 . . _:b529130497 "2"^^ . _:b529130514 . _:b529130515 . _:b24205899 . _:b24205822 . _:b529130524 . . _:b529130525 . _:b529130153 . _:b529130526 . _:b529130496 "2"^^ . _:b529130527 . _:b24205823 . _:b529130520 . _:b529130521 . _:b529130569 . _:b529130152 . _:b529130522 . _:b529130499 "2"^^ . _:b529130523 . _:b24205816 . _:b529130197 . _:b529130155 . _:b529130498 "2"^^ . _:b24205817 . _:b529130154 . _:b24205822 "Apoptotic death induced by 5-aminolevulinic (5-ALA) mediated PDT involved suppression of bcl-2 mRNA levels and elevation of Bax mRNA in cervical cancer cell line [>>38<<] and esophageal cancer cell [39]." . _:b529130509 "2"^^ . _:b24205818 . _:b529130165 . . _:b529130508 "2"^^ . _:b24205819 . _:b24205870 "The claim that NF-\u03BAB may be a target for PDT has been convincingly demonstrated by Granville et al. [>>86<<]. The photodynamic treatment of HL-60 cells with Verteporfin has no detectable effect on cellular I\u03BAB levels by 1 h. Furthermore, lysates prepared up to 3 h post PDT did not contain detectable I\u03BAB degradation products. However, the" . _:b529130352 . _:b529130164 . _:b529130511 "2"^^ . . _:b529130167 . . _:b529130510 "2"^^ . _:b529130166 . _:b529130505 "2"^^ . . . . _:b529130161 . _:b529130504 "2"^^ . _:b529130023 . _:b529130160 . _:b529130485 . _:b529130507 "2"^^ . _:b529130163 . _:b529130506 "2"^^ . _:b24205797 . _:b529129910 . _:b529130162 . _:b529130517 "2"^^ . _:b529130173 . . _:b529129900 . . _:b529130516 "2"^^ . _:b529130172 . . _:b529130519 "2"^^ . _:b529130612 . _:b24205794 . . _:b529130175 . _:b529130593 . _:b529130518 "2"^^ . _:b529130174 . . _:b529130513 "2"^^ . _:b529130169 . _:b529130512 "2"^^ . _:b529130094 . _:b529130168 . _:b529130515 "2"^^ . _:b529130534 . _:b529130171 . _:b529130514 "2"^^ . _:b24205826 "5ALA-PDT also caused a significant decrease in mRNA expression of Bcl-2 and increased the levels of Bax and Bad mRNA in cervical cancer in BALB/c nude mice [>>42<<]. Hypericin (HY) mediated PDT in human breast adenocarcinoma cell line involved downregulation of Bcl-xl and upregulation of Bax [43]. However, HY-PDT did not affect Bcl-2 levels in p53 null and wt-p53 expressing HCT 116 cells [44]. These" . _:b529130290 . . _:b529130170 . . _:b529130525 "2"^^ . . _:b529130181 . _:b529130524 "2"^^ . . _:b529130180 . _:b529129985 . _:b529130527 "2"^^ . _:b529130183 . _:b529130526 "2"^^ . . _:b529130182 . _:b529130211 . _:b529130521 "2"^^ . _:b529130177 . _:b529130520 "2"^^ . . _:b529130176 . _:b529130523 "2"^^ . . _:b529130179 . _:b529130522 "2"^^ . _:b529130178 . . _:b529130533 "2"^^ . _:b529130189 . . _:b529130532 "2"^^ . _:b529130033 . _:b529130188 . _:b529130535 "2"^^ . _:b24205792 . . _:b24205890 . _:b529130191 . _:b529130534 "2"^^ . . _:b529130190 . _:b529130529 "2"^^ . _:b529129877 . _:b529130185 . . _:b529130528 "2"^^ . _:b529130081 . . _:b529130184 . _:b529130531 "2"^^ . _:b529130187 . . _:b529130530 "2"^^ . . _:b529130186 . _:b529130541 "2"^^ . . _:b24205788 . . _:b529130197 . _:b529130540 "2"^^ . _:b529129919 . _:b24205850 . _:b529130196 . _:b529130543 "2"^^ . . _:b529130052 . . _:b529130393 . . _:b529130199 . . _:b529130542 "2"^^ . . _:b529130584 . _:b529130308 . _:b529130198 . . _:b529130537 "2"^^ . _:b529130193 . . _:b24205864 . _:b529130536 "2"^^ . _:b529130192 . _:b529130539 "2"^^ . . _:b24205796 . _:b529130195 . _:b529130538 "2"^^ . _:b529130093 . _:b529130573 . . _:b529130531 . _:b529130190 . _:b529130491 . _:b529130194 . _:b529130549 "2"^^ . _:b529130205 . _:b24205789 . _:b529130548 "2"^^ . _:b529130147 . _:b529130204 . . _:b529130551 "2"^^ . _:b529130207 . _:b529130550 "2"^^ . _:b24205899 "Signaling pathways governing this process became better understood after the identification of the target of rapamycin kinase (TOR), which controls cell growth and protein synthesis [>>111<<]. In 1997, Ohsumi's group showed that yeast autophagy is similar to that of mammals, which allowed them to analyze the process in the genetically tractable yeast system. This study led to the discovery of the first autophagy-related gene," . _:b24205862 "Schempp et al. [>>78<<] used Hypericin mediated PDT in Jurkat cells and by using neutralizing antibodies against Fas, FasL, TRAIL and TNFR1 discovered that post PDT apoptosis can be inhibited by polyclonal anti-TRAIL antibody." . _:b529130206 . _:b529130545 "2"^^ . _:b529130201 . _:b529130544 "2"^^ . _:b529130200 . _:b529130547 "2"^^ . _:b529130233 . _:b529130203 . . _:b529130546 "2"^^ . . . _:b529130202 . . _:b529130557 "2"^^ . _:b529129947 . _:b529130213 . _:b529130399 . _:b529130556 "2"^^ . . _:b529130212 . _:b529129872 . _:b529130559 "2"^^ . _:b529130493 . _:b529130215 . _:b529130558 "2"^^ . _:b529129961 . _:b529130214 . _:b529130553 "2"^^ . _:b529130209 . _:b529130552 "2"^^ . _:b529130338 . _:b529130208 . _:b529130555 "2"^^ . _:b529130211 . _:b529130554 "2"^^ . _:b529130210 . . _:b529130565 "2"^^ . _:b529130221 . _:b529130564 "2"^^ . . _:b529130220 . _:b529130567 "2"^^ . _:b529130223 . _:b529130566 "2"^^ . . _:b24205851 . _:b529130222 . _:b529130561 "2"^^ . _:b529130339 . . _:b529130217 . _:b529130560 "2"^^ . _:b529130216 . _:b529130186 . _:b529130563 "2"^^ . . _:b529130219 . . _:b529130562 "2"^^ . . _:b529130218 . _:b529130573 "2"^^ . _:b529130229 . _:b529130572 "2"^^ . _:b529130024 . _:b529130228 . _:b529130425 . _:b529130575 "2"^^ . . _:b529130079 . _:b529130231 . _:b529130574 "2"^^ . . _:b529130230 . _:b529130569 "2"^^ . . _:b529130225 . _:b529130568 "2"^^ . _:b529130224 . _:b529130571 "2"^^ . _:b529130378 . _:b529130227 . . _:b529130570 "2"^^ . _:b529130530 . _:b529130226 . _:b529130581 "2"^^ . _:b24205879 . _:b529130237 . _:b529130580 "2"^^ . _:b529130236 . _:b529130583 "2"^^ . _:b529130239 . . _:b529130582 "2"^^ . _:b24205896 "pdt and autophagy" . _:b529130238 . _:b529130577 "2"^^ . _:b529129895 . _:b529130233 . _:b529130576 "2"^^ . _:b529130232 . _:b529130579 "2"^^ . _:b529130235 . _:b529130578 "2"^^ . _:b529130234 . _:b529130214 . . _:b529130589 "2"^^ . _:b24205842 . _:b529130461 . . _:b529130588 "2"^^ . _:b529130591 "2"^^ . . _:b529130590 "2"^^ . _:b529130405 . _:b24205826 . _:b529130585 "2"^^ . . _:b529130584 "2"^^ . . _:b529130151 . _:b529130587 "2"^^ . _:b529130357 . _:b529130586 "2"^^ . _:b24205919 . _:b529130545 . _:b529130597 "2"^^ . _:b529130596 "2"^^ . _:b24205811 . . _:b529130599 "2"^^ . _:b529130598 "2"^^ . _:b529130593 "2"^^ . _:b529130592 "2"^^ . _:b529130595 "2"^^ . _:b24205847 . _:b529130594 "2"^^ . "10.3390%2Fcancers3022516" . _:b529130605 "2"^^ . _:b529130524 . _:b529130141 . _:b529130604 "2"^^ . _:b529130005 . _:b529130607 "2"^^ . . _:b529130606 "2"^^ . . _:b529129923 . _:b24205854 . . _:b529130601 "2"^^ . _:b529130600 "2"^^ . _:b24205798 "Food and Drug Administration for use in endo-bronchial and endo-esophageal cancer [13,14] and also as a treatment of premalignant and early malignant lesions of skin (actinic keratosis), bladder, breast, stomach and oral cavity [4,>>15<<]." . _:b529129995 . _:b529129945 . . _:b529130603 "2"^^ . . _:b529130070 . _:b529130602 "2"^^ . _:b529130195 . . _:b529130613 "2"^^ . _:b529130105 . . _:b529130612 "2"^^ . _:b24205812 "The family includes four other anti-apoptotic proteins: BclXL, Bcl-w, A1 and Mcll, and two groups of proteins that promote apoptosis: the Bax and the BH3-only families [>>28<<,29]." . . _:b529129874 . _:b529130377 . _:b529130402 . _:b529130609 "2"^^ . _:b529130078 . _:b529130608 "2"^^ . . _:b529130611 "2"^^ . _:b24205818 "They probably also regulate the activation of several other caspases, independently of mitochondrial damage [>>34<<]." . . _:b529130610 "2"^^ . _:b24205900 "This study led to the discovery of the first autophagy-related gene, ATG1. Shortly thereafter, the first mammalian autophagy genes were identified [>>112<<]." . _:b529129941 . _:b24205909 "Depending on the type of ROS and degree of oxidative injury, PDT may stimulate autophagy [118] that either acts in a cytoprotective manner or induces autophagic cell death [>>119<<]. Autophagy may play a role in PDT induced apoptosis, but the two processes can also occur independently of one another [120]. A study done on murine leukemia L1210 cells found that a wave of autophagy occurs right before apoptosis [121]." . _:b529130364 . _:b529130108 . _:b529129889 . _:b529130431 . _:b529130248 . _:b529130179 . _:b529130223 . . . . . . . . _:b529130203 . . . _:b24205902 "It was discovered that Beclin1, an essential protein for autophagy, is also a tumor suppressor [>>114<<]. Further studies on the role of autophagy in cancer revealed some interesting properties of the disease. Initially, autophagy suppresses tumor growth through its production of Beclin1. This changes as the tumor becomes more advanced;" . _:b529130317 . _:b24205922 . _:b529130289 . . . . . _:b529130265 . _:b529130496 . . . . _:b529130047 . . _:b529129878 . _:b24205820 "mediated PDT induced apoptosis in bovine retinal capillary endothelial (BRCE) cells involved changes in Bcl-2 and Bax levels while in human retinal pigment epithelial (RPE) cells changes in Bcl-xL and Bak proteins were observed [>>36<<]. The PDT resistant HT29 human colon adenocarcinoma cell line showed variation in numerous genes and proteins including upregulation of Bcl-2 levels and downregulation of Bax [37]." . _:b529130032 . _:b529130507 . . . . _:b529130148 . _:b529130391 . _:b529129982 . _:b529130087 . _:b24205918 "Although many proteins involved in the autophagic process are photodamaged by PDT, it appears that those involved in the formation of autophagosomes remain active [>>120<<]." . . _:b529130227 . _:b529129886 . _:b529130322 . . . . . . . _:b24205860 . _:b24205863 "Nuclear factor kappa B (NF-\u03BAB) is a term referring to a group of dimeric transcription factors that belong to the Rel family and are regulated via shutting from the cytoplasm to the nucleus in response to cell stimulation [>>80<<]. The Rel proteins belong to two classes. The first class includes RelA, RelB and c-Rel, proteins that are synthesized as mature products and do not require proteolytic processing." . . . _:b529130158 . _:b529130353 . _:b529130269 . _:b529130404 . _:b529130515 . . _:b529130246 . . _:b529129971 . . _:b529130525 . _:b529130347 . _:b529130010 . . _:b24205805 . _:b529129932 . _:b24205873 . . _:b529130213 . _:b529130307 . _:b24205794 "The first process is called a type I reaction and the second a type II reaction [>>4<<]. The PDT effectiveness is therefore determined by oxygen supply and may be decreased in conditions where there is tissue hypoxia [12]." . . _:b529130287 . _:b24205792 . _:b529129950 . _:b24205818 . _:b529130389 . . _:b529130497 . _:b529129869 "21"^^ . _:b529130170 . _:b24205867 "This factor activates transcription of several genes that are known to block the induction of apoptosis by TNF superfamily members [>>84<<]. The anti-apoptotic factors that are induced by NF-\u03BAB include cellular inhibitors of apoptosis (cIAPs), FLICE and members of Bcl-2 family. NF-\u03BAB can also attenuate the apoptotic response to genotoxic anticancer drugs and radiation" . _:b529130044 . _:b529129871 "18"^^ . _:b24205916 "The IP3 protein, a regulator of the autophagic process associated with the ER [123,124] is affected by phthalocyanine photosensitizer Pc 4 [>>125<<]. The photosensitizer AlPcS causes damage to the mammalian target of rapamycin, mTOR, a cell growth regulator that takes part in the autophagic signaling pathway [126]. Other proteins, like Beclin1, Atg5, and Atg7, appear to be unaffected" . _:b529130132 . _:b529129870 "20"^^ . _:b529130539 . _:b529129868 "32"^^ . _:b529129878 "9"^^ . _:b529129879 "9"^^ . . . _:b529129876 "10"^^ . . . _:b529129877 "9"^^ . _:b529129875 "10"^^ . _:b529129927 . . _:b24205819 . _:b529129874 "11"^^ . _:b529129873 "12"^^ . . _:b529129998 . _:b529129872 "13"^^ . _:b529129886 "7"^^ . . _:b529130068 . _:b529129887 "7"^^ . _:b529129884 "7"^^ . . _:b529129885 "7"^^ . _:b529130487 . . _:b529129882 "8"^^ . _:b24205866 "NF-\u03BAB is also known as an inhibitor of programmed cell death [>>83<<]. This factor activates transcription of several genes that are known to block the induction of apoptosis by TNF superfamily members [84]." . _:b529129883 "8"^^ . _:b529130046 . _:b529129880 "9"^^ . _:b529129881 "8"^^ . _:b529129894 "6"^^ . . _:b529129955 . _:b529129895 "6"^^ . _:b24205824 "This regimen also let to increase in Bax/Bcl-2 ratio in human malignant glioblastoma U87MG cells [>>40<<] while in U937 cells increase in Bak and Bax/Bcl-xL but decrease in Bid was observed [41]." . _:b529129892 "7"^^ . _:b529129893 "7"^^ . _:b529130107 . _:b529130279 . _:b529129890 "7"^^ . . _:b529130398 . _:b529129891 "7"^^ . . _:b529129888 "7"^^ . _:b529129889 "7"^^ . . _:b529129902 "6"^^ . _:b529130346 . . _:b529129903 "6"^^ . . . _:b529129900 "6"^^ . _:b24205906 "It is still unclear exactly how autophagy affects the outcome of PDT [66,115,>>116<<]. In general, mammalian cells use autophagy as a defense against ROS mediated damage by clearing the cell of damaged organelles [117]." . . _:b24205808 "Cleavage of cytoskeletal proteins leads to cell fragmentation and formation of apoptotic bodies [23]. The apoptotic process is tightly controlled by various proteins [>>24<<,25]. It is well known that resistance of tumor cells to apoptosis might be an essential feature of cancer development thus, modulation of the key elements of apoptosis signaling may directly influence therapy-induced tumor-cell death" . _:b529130039 . _:b529129901 "6"^^ . . _:b529129898 "6"^^ . _:b529130458 . _:b529129911 . _:b529129899 "6"^^ . _:b529129896 "6"^^ . _:b529130138 . _:b529129968 . _:b529129897 "6"^^ . _:b529129978 . _:b529129909 "5"^^ . . . . _:b529129908 "6"^^ . . . _:b529129911 "5"^^ . . . _:b529129910 "5"^^ . _:b529129906 "6"^^ . _:b529130065 . _:b529129907 "6"^^ . _:b529129904 "6"^^ . . _:b529130475 . _:b529129905 "6"^^ . . . _:b24205833 "A similar approach was used in human gastric adenocarcinoma MGC803 cell line which was infected with antisense bcl-2 RNA retrovirus vector to study effect of 2-butylamino-2-demethoxy-hypocrellin A (2-BA-2-DMHA) photosensitization [>>49<<]. A significant reduction in Bcl-2 protein expression accompanied by an increased phototoxicity and susceptibility to apoptosis was observed." . _:b529129917 "5"^^ . . _:b529130166 . _:b529130133 . . _:b529129916 "5"^^ . . _:b529129919 "5"^^ . _:b529129918 "5"^^ . . _:b529129869 . _:b529129913 "5"^^ . _:b529129868 . _:b529129912 "5"^^ . _:b529129871 . . _:b529129915 "5"^^ . _:b529129870 . _:b529129914 "5"^^ . . _:b529129925 "5"^^ . . _:b529129924 "5"^^ . _:b24205787 . _:b529129927 "5"^^ . _:b529130076 . _:b529130446 . _:b529129884 . . _:b529129926 "5"^^ . _:b529129877 . _:b529129921 "5"^^ . _:b529129876 . . . _:b529129871 . . . _:b529129920 "5"^^ . _:b529129879 . _:b529130159 . _:b529129923 "5"^^ . _:b529129878 . _:b529129922 "5"^^ . _:b529129873 . _:b529129933 "5"^^ . _:b529129872 . _:b529129932 "5"^^ . . _:b529129875 . . _:b529129935 "4"^^ . _:b529129874 . _:b529129934 "4"^^ . _:b529129885 . . _:b529129929 "5"^^ . _:b529129884 . _:b529130206 . . _:b529129928 "5"^^ . _:b529129887 . _:b529129931 "5"^^ . _:b529129886 . _:b529130314 . . _:b529129930 "5"^^ . _:b529129881 . _:b529129941 "4"^^ . _:b529129880 . _:b529130226 . _:b529129940 "4"^^ . _:b529129883 . _:b529130167 . _:b24205908 "Depending on the type of ROS and degree of oxidative injury, PDT may stimulate autophagy [>>118<<] that either acts in a cytoprotective manner or induces autophagic cell death [119]." . _:b529129943 "4"^^ . _:b529129882 . _:b529129942 "4"^^ . _:b529129893 . . _:b529129937 "4"^^ . . _:b529129892 . . . _:b529129875 . _:b529129936 "4"^^ . . _:b529129895 . . _:b529129939 "4"^^ . . _:b529129894 . _:b529130453 . _:b529130325 . _:b529129934 . _:b529129938 "4"^^ . _:b529130523 . _:b529129889 . _:b529130303 . _:b529130028 . . _:b529129949 "4"^^ . _:b529129888 . _:b529130367 . _:b529129948 "4"^^ . _:b529129891 . _:b529129951 "4"^^ . _:b529129890 . _:b529129906 . _:b529129950 "4"^^ . _:b529129901 . _:b529129945 "4"^^ . _:b529129900 . _:b529129944 "4"^^ . _:b529130600 . _:b24205882 . _:b529129933 . _:b529129903 . _:b529129947 "4"^^ . _:b529130120 . _:b529129902 . _:b529130272 . _:b529129946 "4"^^ . _:b529129897 . _:b529130031 . _:b529129957 "4"^^ . _:b529129896 . _:b529129956 "4"^^ . _:b529130001 . _:b529129899 . _:b529129959 "4"^^ . _:b529129898 . _:b529130090 . . _:b529129958 "4"^^ . _:b24205852 "Chiu and Olenick [>>69<<], showed that treatment of LY-R cells with Pc4 based PDT resulted in release of cytochrome c to the cytoplasm after 15 min, as estimated by an immunohistochemical method, and the loss of \u0394\u03C8m depended on PDT dose and the post treatment" . _:b529129909 . . _:b529130603 . _:b529129953 "4"^^ . _:b529129908 . _:b529129952 "4"^^ . _:b529129911 . _:b529129955 "4"^^ . _:b529129910 . _:b24205893 . _:b529129954 "4"^^ . _:b529130413 . . . _:b529129905 . _:b24205900 . _:b529129965 "4"^^ . _:b529129904 . _:b529130129 . _:b529129964 "4"^^ . _:b24205887 . . _:b529129907 . . _:b529129967 "4"^^ . _:b529129906 . _:b529129966 "4"^^ . . _:b529129960 . _:b529129917 . _:b529129961 "4"^^ . _:b529130382 . _:b529129916 . _:b529130356 . _:b529129960 "4"^^ . _:b529130022 . _:b529129919 . _:b529129963 "4"^^ . _:b529130274 . _:b24205897 "Autophagy is a catabolic cellular mechanism that allows the cell to maintain a balance between the synthesis, degradation, and recycling of cellular products [>>109<<]. A variety of autophagic processes exist, all of which involve the lysosomal degradation of the cellular organelles and proteins." . _:b529129918 . _:b529129962 "4"^^ . _:b529130229 . . _:b529129913 . _:b529129973 "4"^^ . _:b529129912 . . _:b529129972 "4"^^ . _:b529130021 . _:b529129915 . _:b529129975 "4"^^ . . . _:b529129914 . _:b529129974 "4"^^ . _:b529130343 . _:b529129925 . _:b529129969 "4"^^ . _:b529130015 . . _:b529129924 . _:b529129968 "4"^^ . _:b529129927 . . _:b529129971 "4"^^ . _:b529129926 . . _:b24205898 "This vesicle is then transported and fused to the lysosome, forming a structure called the autophagolysosome, the contents of which are subsequently degraded by lysosomal hydrolases [>>110<<]. Besides facilitating the disposal of unwanted proteins, organelles, and invading microorganisms, autophagy also allows a cell to reallocate its nutrients from unnecessary processes to life-essential ones in times of starvation or stress." . _:b529129970 "4"^^ . _:b529129921 . _:b529129981 "3"^^ . _:b529130228 . _:b24205854 "Another support for the hypothesis that cytochrome c plays a vital role in PDT-induced apoptosis was provided by Varnes et al. [>>71<<]. In this study, an LD99.9 dose of Pc4 PDT induced loss of cytochrome c from the mitochondria of LY-R cells, but also inhibited respiration and caused activation of caspase 3-like proteases." . _:b529130383 . _:b529130321 . _:b529129920 . _:b529129980 "3"^^ . _:b529130249 . . _:b529130218 . _:b529129923 . _:b529130006 . _:b529129983 "3"^^ . _:b529129922 . _:b529129982 "3"^^ . _:b529129933 . _:b529129977 "4"^^ . _:b529129932 . _:b529129976 "4"^^ . _:b529129935 . . _:b529129979 "4"^^ . _:b529129934 . . . _:b529129978 "4"^^ . _:b529129929 . _:b529129928 . _:b529130318 . _:b529129931 . . _:b529129883 . _:b529130071 . _:b529130266 . _:b529129930 . _:b529129941 . _:b529130163 . . _:b529129940 . _:b529130420 . _:b24205815 "Bcl-2 itself is required for the survival of kidney and melanocyte stem cells and mature lymphocytes [30], BclXL for neuronal and erythroid cells [>>31<<], and Bcl-w for sperm progenitors [32]." . _:b529129943 . _:b529129942 . . _:b529129870 . . _:b529129937 . _:b529130495 . _:b529129936 . _:b529129939 . . _:b529129938 . _:b24205829 . _:b529130479 . _:b529129949 . _:b529130504 . _:b529130333 . . _:b529129948 . _:b529130610 . . _:b529129951 . . _:b529129950 . _:b529129945 . _:b529129944 . _:b24205874 . _:b529129947 . _:b529130136 . _:b529129946 . _:b529130311 . _:b529129957 . _:b529130061 . _:b529129956 . _:b24205838 . _:b529130067 . _:b529130139 . _:b529129959 . _:b529129958 . _:b529129953 . . _:b24205786 "introduction" . _:b529130171 . _:b529129952 . . _:b529129955 . . _:b529130601 . _:b529129954 . _:b529130359 . _:b24205790 "of a low-to-moderately selective degree of photosensitizer (PS) uptake by proliferating malignant cells, direct cytotoxicity of reactive oxygen species (ROS) and a severe vascular damage that impairs blood supply to the treated area [>>6<<,7]. Those biological effects of PDT are limited to the particular areas of tissues exposed to light." . _:b529129965 . _:b529130177 . _:b529129964 . _:b529130323 . . _:b529130095 . _:b529129967 . _:b529129966 . _:b529130478 . _:b529129961 . _:b529129960 . _:b529130558 . _:b529130560 . _:b529129963 . _:b529129873 . _:b529129962 . _:b529129973 . _:b529129972 . . . _:b529129975 . . _:b529130016 . . . _:b529129974 . _:b24205866 . . _:b529130040 . _:b529129969 . . _:b529129968 . _:b24205907 . _:b24205875 . _:b529129971 . _:b529129970 . _:b24205923 "In cells that are able to undergo apoptosis autophagy alleviates the destructive effects of PDT by recycling damaged organelles [>>131<<]. This opens up a possibility that PDT of these cancer cells can be enhanced by suppressing pro-autophagic proteins. Autophagy has the opposite effect on cells that are apoptosis-deficient, promoting cell death through necrosis. The last" . _:b529129981 . _:b24205884 "Evidence of ceramide involvement in PDT-mediated apoptosis was provided by Separovic et al. [>>98<<]. In phthalocyanine PDT model they demonstrated in the U937 cell line elevated levels of ceramide by 45, 37, 67, 118 and 134% at 1, 10, 30, 60 and 120 min, respectively, after PDT procedure. In CHO cells ceramide generation in response to" . _:b529130243 . _:b529130516 . _:b529129980 . _:b529130074 . _:b529129983 . . . _:b529130257 . _:b529129982 . . . _:b529129977 . _:b529129976 . . . _:b529129979 . _:b529130187 . _:b529130484 . . _:b529129978 . . _:b529130456 . _:b529130140 . . _:b529130514 . . . . _:b529130576 . _:b24205856 . . _:b529130328 . _:b529130104 . _:b529130057 . . . _:b529130489 . . . . _:b529130036 . _:b529130613 . _:b24205915 . _:b529129987 . _:b24205853 . _:b529130519 . _:b529130528 . _:b529129928 . _:b529130541 . . _:b529130124 . . _:b24205839 "During apoptosis, Bax and Bak oligomerize in the mitochondria outer membrane and probably break its integrity, freeing pro-apoptotic proteins like cytochrome c, which allows the activation of caspase 9 [>>29<<]." . . _:b529130245 . _:b529130013 . . . _:b24205844 . _:b529130037 . . _:b529130189 . _:b529130278 . _:b24205886 . _:b24205911 . _:b529130606 . _:b24205881 . _:b529130345 . _:b529129943 . _:b24205903 "It was also found that autophagy blocks apoptotic pathways, thereby protecting cancer cells from treatment [>>114<<]. On the other hand, some cancer therapies induce autophagic cell death of tumor cells. This two-sided effect of autophagy on tumors can be exploited by anticancer therapy to provide better treatment for cancer patients." . _:b529130518 . _:b24205871 . . . _:b529130337 . _:b24205855 . . . _:b24205849 . . _:b24205876 . . . _:b529130457 . . . _:b529130281 . _:b24205908 . . . . _:b24205912 "This observation is consistent with the theory that autophagy is a defense mechanism against PDT induced ROS [>>122<<]. The situation is different for tumor cells that do not have the ability to undergo apoptosis through a deficiency in Bax and Bac, which regulate the apoptotic pathway. In these cells, PDT induced autophagy stimulates a necrotic, caspase" . . _:b529129938 . . _:b529130237 . _:b529129997 . _:b529130473 . . _:b529130468 . . . . _:b529129925 . _:b529130310 . . _:b24205837 "This team provided additional evidence to the hypothesis that Bcl-2 photodamage can be a target for some photosensitizing agents by showing that the effects of the photosensitizer CPO can be mimicked by the Bcl-2 antagonist HA14-1 [>>54<<]." . _:b529130426 . _:b529130372 . . _:b529129935 . . _:b529130280 . . . . . . _:b24205860 "The early evidence comes from the study designed by Ahmad et al. [>>76<<] where the involvement of the cell surface receptor Fas (CD95) pathway in A431 cells in Pc4 mediated PDT was investigated." . . . _:b24205896 . _:b529129979 . . . . _:b529130450 . _:b529130250 . . _:b529129989 . . _:b24205840 "The possible role of Bax in PDT-mediated apoptosis was showed by Srivastava et al. [>>56<<], when assessing the impact of PDT on the status of Bax protein in Bcl-2-overexpressing A431 cells." . _:b529130176 . _:b529129966 . . _:b529129904 . . . . _:b529130598 . _:b24205791 . _:b529130459 . _:b529130089 . . _:b529130596 . . _:b529130056 . . . . _:b529130455 . _:b529130212 . . _:b24205858 "Death domain containing receptors activate the apoptotic pathway by caspase-8 mediated cleavage of the pro-apoptotic Bcl-2 superfamily member BID [>>74<<]. This protein interacts with other molecules like Bax and Bak, which cause release of mitochondrial cytochrome c and SMAC/DIABLO, activating caspase-9 and eventually caspase-3. The other group use TNFR-associated factor to link these" . _:b529130288 . . . . . _:b529129963 . . _:b529130041 . _:b529130086 . . _:b529129876 . . _:b529130239 . . . . _:b529130017 . _:b529130123 . . . . . _:b24205835 . . _:b529130264 . _:b24205830 . _:b529129922 . _:b24205843 . _:b529130003 . _:b529130415 . _:b24205786 _:b24205788 . _:b24205786 _:b24205789 . _:b24205786 _:b24205790 . _:b24205786 _:b24205791 . _:b24205786 _:b24205787 . _:b24205850 "It is generally recognized that mitochondria play a critical role in the apoptotic cascade by controlling the release of crucial factors involved in that process [>>67<<]. Among these factors cytochrome c plays an essential role. During the process of apoptosis, cytochrome c is released from mitochondria into the cytosol." . . _:b529130538 . . _:b24205847 "Furthermore, Bax was not found to be essential for Photofrin-PDT induced apoptosis in human lung adenocarcinoma cells (ASTC-a-1) [>>63<<]. In the absence of Bax/Bak, autophagy appears to be predominantly responsible for cell death following PDT with different photosensitizers [64-66]." . . _:b24205786 _:b24205800 . _:b529129999 . _:b24205786 _:b24205796 . _:b24205786 _:b24205797 . _:b24205786 _:b24205798 . _:b24205786 _:b24205799 . _:b529130361 . . _:b24205786 _:b24205792 . _:b529130029 . _:b529130282 . _:b24205786 _:b24205793 . _:b24205786 _:b24205794 . _:b24205786 _:b24205795 . . _:b529130168 . _:b529130360 . . . . _:b529130240 . . _:b529130476 . . . _:b529130072 . . . . . . . . . . . _:b529130165 . . _:b529130375 . _:b529130134 . _:b529130500 . _:b24205874 "The best characterized MAPK pathway is the Ras/Raf/MEK cascade leading to the activation of ERK1/2 in response to growth factors [>>89<<]. JNK and p38 are key mediators of stress signals and inflammatory response [90]." . . . _:b529129913 . _:b24205801 _:b24205802 . _:b24205801 _:b24205803 . _:b24205801 _:b24205804 . _:b24205801 _:b24205805 . . _:b24205801 _:b24205806 . _:b24205801 _:b24205807 . _:b24205801 _:b24205808 . . _:b24205801 _:b24205809 . _:b24205801 _:b24205810 . _:b529130103 . _:b24205801 _:b24205811 . _:b24205801 _:b24205812 . _:b24205801 _:b24205813 . _:b24205801 _:b24205814 . _:b529130259 . _:b24205801 _:b24205815 . _:b24205801 _:b24205816 . _:b24205801 _:b24205817 . _:b24205801 _:b24205818 . _:b24205801 _:b24205819 . _:b24205801 _:b24205820 . _:b24205801 _:b24205821 . . _:b24205801 _:b24205822 . . _:b24205801 _:b24205823 . _:b529130202 . _:b24205852 . . . . _:b529130451 . _:b529130549 . _:b24205815 . . _:b529129908 . _:b529130291 . _:b529130135 . . _:b529130191 . . _:b24205868 "NF-\u03BAB can also attenuate the apoptotic response to genotoxic anticancer drugs and radiation therapy [>>84<<]." . _:b529130423 . _:b529130058 . _:b529130492 . _:b529130416 . _:b24205921 . _:b529129901 . . . . . _:b24205914 . . _:b24205806 . _:b529130481 . _:b24205846 "The dependence of Pc4-PDT induced apoptosis on Bax remains under active investigation and reports from Chiu et al. [60,61] indicated that commitment to cell death after PDT occurs prior to Bax activation while Usuada et al. [>>62<<] reported that Smac/DIABLO promotes apoptosis after Pc4-PDT in a Bax dependent manner." . _:b529130294 . . _:b529130305 . _:b529130043 . _:b529130557 . _:b24205801 "pdt and apoptosis" . _:b24205883 . . . _:b529129988 . _:b529130236 . . . . . _:b529130026 . _:b529130350 . _:b529130390 . _:b529130270 . _:b24205816 . _:b529130418 . . . _:b24205812 . . _:b24205808 . . _:b529129869 . . _:b529130091 . _:b529130106 . _:b529129989 "3"^^ . _:b529130304 . _:b529130535 . _:b529129988 "3"^^ . . _:b529129991 "3"^^ . . _:b529129990 "3"^^ . _:b529129985 "3"^^ . _:b529129953 . _:b529129984 "3"^^ . . _:b529129987 "3"^^ . . . _:b529129986 "3"^^ . _:b529129905 . . _:b529129997 "3"^^ . _:b529130231 . _:b529129996 "3"^^ . . . . _:b529129999 "3"^^ . _:b529130566 . _:b529130429 . _:b529129998 "3"^^ . . _:b529129993 "3"^^ . _:b529129992 "3"^^ . _:b529130092 . _:b529129995 "3"^^ . . _:b529130454 . _:b529129994 "3"^^ . _:b529130005 "3"^^ . _:b529130234 . _:b529130004 "3"^^ . . _:b529130018 . _:b529130007 "3"^^ . _:b529129944 . _:b529130006 "3"^^ . _:b529130437 . _:b529130001 "3"^^ . _:b529130000 "3"^^ . _:b529130003 "3"^^ . _:b529130365 . _:b529130146 . . _:b529130002 "3"^^ . . _:b529130013 "3"^^ . . _:b529130012 "3"^^ . . _:b529130015 "3"^^ . _:b529130472 . _:b24205917 . . _:b529130014 "3"^^ . _:b529130009 "3"^^ . _:b529130008 "3"^^ . _:b24205864 "NF-\u03BAB dimers are held in the cytoplasm through specific inhibitors of kappa B, the I\u03BABs [>>81<<]. IkB members undergo rapid ubiquitin-dependent degradation after exposure to a variety of agonists, which activate the I\u03BAB kinase complex (IKK) [82]. This complex induces the phosphorylation-dependent removal of the IKB-like C-terminal" . _:b529130011 "3"^^ . _:b529130268 . _:b24205906 . _:b529130010 "3"^^ . _:b529130054 . _:b529130021 "3"^^ . . _:b529130173 . _:b529130020 "3"^^ . . _:b529130023 "3"^^ . _:b529129956 . _:b529130022 "3"^^ . _:b529130508 . . _:b529130319 . _:b529130221 . _:b529130017 "3"^^ . . _:b529130016 "3"^^ . _:b529130019 "3"^^ . . _:b529130018 "3"^^ . _:b529130029 "3"^^ . _:b24205801 . _:b529129969 . _:b529130028 "3"^^ . _:b529130031 "3"^^ . _:b529130384 . _:b24205875 "The best characterized MAPK pathway is the Ras/Raf/MEK cascade leading to the activation of ERK1/2 in response to growth factors [89]. JNK and p38 are key mediators of stress signals and inflammatory response [>>90<<]." . _:b529130030 "3"^^ . . _:b529129914 . . _:b529130025 "3"^^ . . . _:b529130604 . _:b529130572 . _:b529130024 "3"^^ . . _:b24205786 . _:b529130027 "3"^^ . _:b529130154 . . _:b529130026 "3"^^ . _:b529130380 . . _:b529130037 "3"^^ . _:b529130424 . . _:b529130036 "3"^^ . _:b529130039 "3"^^ . _:b529130503 . _:b529130038 "3"^^ . . _:b529130501 . _:b24205884 . _:b529130033 "3"^^ . _:b529130128 . . . _:b529130533 . _:b529130500 . _:b529130032 "3"^^ . _:b24205813 . _:b529130503 . _:b529130035 "3"^^ . _:b529130502 . _:b529130034 "3"^^ . _:b529130497 . _:b529130045 "3"^^ . . _:b529130496 . _:b529130044 "3"^^ . . _:b529130499 . _:b529130047 "3"^^ . _:b529130164 . _:b529130498 . _:b529130046 "3"^^ . _:b529130590 . _:b24205810 . _:b529130509 . _:b529130041 "3"^^ . _:b529129918 . . _:b529130508 . _:b529130040 "3"^^ . _:b529130230 . _:b529130511 . _:b529130043 "3"^^ . . . _:b529130073 . _:b529130510 . _:b529130042 "3"^^ . _:b529130505 . _:b529130053 "3"^^ . . _:b529130504 . _:b529130052 "3"^^ . . . . _:b529130507 . _:b529130055 "3"^^ . _:b529130506 . _:b529130054 "3"^^ . _:b529130517 . _:b529130049 "3"^^ . _:b529130516 . _:b529130048 "3"^^ . . . . _:b529130519 . _:b24205915 "The IP3 protein, a regulator of the autophagic process associated with the ER [123,>>124<<] is affected by phthalocyanine photosensitizer Pc 4 [125]." . _:b529130051 "3"^^ . _:b529130561 . . _:b529130518 . _:b529130050 "3"^^ . . _:b529130513 . _:b529130061 "3"^^ . . . _:b529130512 . _:b24205889 "In necrosis, decomposition is principally mediated by proteolytic activity, but the precise identities of proteases and their substrates are poorly defined [>>102<<]." . _:b529130060 "3"^^ . . _:b529129868 . _:b529130515 . _:b529130063 "3"^^ . . _:b529130514 . _:b529130062 "3"^^ . . _:b529130525 . _:b529130057 "3"^^ . . _:b529130524 . _:b529130354 . _:b529130056 "3"^^ . _:b529130527 . _:b24205820 . _:b529130059 "3"^^ . _:b529130084 . _:b529130439 . . _:b529130526 . _:b529130058 "3"^^ . _:b529129946 . _:b529130521 . _:b529130069 "3"^^ . _:b24205856 "All death receptors belong to TNFR superfamily (tumor necrosis factor receptor) [>>72<<]. Most of them act as transmembrane signal transducers that respond to ligand binding." . _:b529130520 . _:b529130068 "3"^^ . _:b529130312 . _:b529129924 . _:b529130523 . _:b529130263 . _:b529130071 "3"^^ . _:b529130522 . _:b529130070 "3"^^ . . _:b529130540 . _:b529130533 . _:b529130065 "3"^^ . . _:b529130532 . _:b529130064 "3"^^ . . _:b529130535 . _:b529130067 "3"^^ . _:b529130511 . . _:b529130534 . _:b529130066 "3"^^ . . . . _:b529130207 . _:b529130529 . _:b529130077 "3"^^ . _:b529130528 . _:b24205887 "affecting large fractions of cell populations, characterized by cytoplasmic swelling, destruction of organelles and disruption of the plasma membrane, leading to the release of intracellular contents and consequent inflammation [>>100<<]." . _:b529130076 "3"^^ . . _:b529130531 . _:b529130079 "3"^^ . . _:b529129903 . _:b529130530 . . _:b529130078 "3"^^ . _:b529130335 . _:b529130541 . _:b529130073 "3"^^ . . _:b529130540 . _:b529130072 "3"^^ . _:b529130474 . _:b529130543 . _:b529130075 "3"^^ . _:b24205827 "Hypericin (HY) mediated PDT in human breast adenocarcinoma cell line involved downregulation of Bcl-xl and upregulation of Bax [>>43<<]. However, HY-PDT did not affect Bcl-2 levels in p53 null and wt-p53 expressing HCT 116 cells [44]. These studies indicated a possible involvement of the antiapoptotic Bcl-2 family members in PDT induced apoptotic cell death, but a more" . _:b529130542 . _:b529130074 "3"^^ . _:b529130537 . _:b529130085 "3"^^ . . _:b529130536 . _:b529130084 "3"^^ . _:b529130539 . _:b529130087 "3"^^ . . . _:b529130538 . _:b529130502 . _:b529130086 "3"^^ . . _:b529130549 . _:b529130081 "3"^^ . _:b529130363 . . _:b529130554 .