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n2:pmcid: PMC0
bibo:doi: 10.1186%2F1476-4598-8-129
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Subject Item: _:vb6686811
rdf:type: n7:Section
dc:title: materials and methods
n7:contains: _:vb6686812 _:vb6686813 _:vb6686814

Subject Item: _:vb6686812
rdf:type: n2:Context
rdf:value: The nuclear translocation of p65 was examined by immunocytochemistry as described previously [30,>>31<<]. Briefly, cells were plated on SuperFrost glass slides for adherence and treated the next day with Curcumin.
n2:mentions: n3:11911253

Subject Item: _:vb6686813
rdf:type: n2:Context
rdf:value: Relative expression values with standard errors were obtained using Qgene software [>>33<<] and statistical comparisons (unpaired two-tailed t-test) were performed using Prism (GraphPad) software.
n2:mentions: n3:12074169

Subject Item: _:vb6686814
rdf:type: n2:Context
rdf:value: Micorarray gene expression dataset GSE7553 [>>35<<] were obtained form Gene Expression Omnibus http://www.ncbi.nlm.nih.gov/geo/. The expression values published by the authors were used without further processing.
n2:mentions: n3:18442402

Subject Item: _:vb6686815
rdf:type: n7:Section
dc:title: results
n7:contains: _:vb6686816 _:vb6686817 _:vb6686818 _:vb6686819 _:vb6686820 _:vb6686821

Subject Item: _:vb6686816
rdf:type: n2:Context
rdf:value: In contrast to the here presented data on melanoma cells, the human breast cancer cells MDA-MB-231 cells, who respond very well to Curcumin, undergo early and late apoptosis (published by us previously [>>3<<].
n2:mentions: n3:17310108

Subject Item: _:vb6686817
rdf:type: n2:Context
rdf:value: The direct correlation between NFκB and CXCL1 and -2 expressions implies that the two cytokines are NFκB targets [>>4<<]. CXCL1 is also present in several metastasis signatures [26,36,37]. We wished to understand whether CXCL1 may play a role in melanoma so we analyzed published microarray gene expression data [35]. CXCL1 is strongly and highly
n2:mentions: n3:17999991

Subject Item: _:vb6686818
rdf:type: n2:Context
rdf:value: CXCL1 is also present in several metastasis signatures [>>26<<,36,37]. We wished to understand whether CXCL1 may play a role in melanoma so we analyzed published microarray gene expression data [35].
n2:mentions: n3:16049480

Subject Item: _:vb6686819
rdf:type: n2:Context
rdf:value: CXCL1 is also present in several metastasis signatures [26,>>36<<,37]. We wished to understand whether CXCL1 may play a role in melanoma so we analyzed published microarray gene expression data [35].
n2:mentions: n3:12469122

Subject Item: _:vb6686820
rdf:type: n2:Context
rdf:value: CXCL1 is also present in several metastasis signatures [26,36,>>37<<]. We wished to understand whether CXCL1 may play a role in melanoma so we analyzed published microarray gene expression data [35].
n2:mentions: n3:18046511

Subject Item: _:vb6686821
rdf:type: n2:Context
rdf:value: We wished to understand whether CXCL1 may play a role in melanoma so we analyzed published microarray gene expression data [>>35<<]. CXCL1 is strongly and highly differentially expressed in primary and metastatic melanoma and in other skin cancers (figures 3a and 3b). During the progression from normal human melanocytes (n = 1) over melanoma in situ (n = 2) and
n2:mentions: n3:18442402

Subject Item: _:vb6686822
rdf:type: n7:Section
dc:title: discussion
n7:contains: _:vb6686836 _:vb6686837 _:vb6686838 _:vb6686839 _:vb6686832 _:vb6686833 _:vb6686834 _:vb6686835 _:vb6686828 _:vb6686829 _:vb6686830 _:vb6686831 _:vb6686824 _:vb6686825 _:vb6686826 _:vb6686827 _:vb6686823

Subject Item: _:vb6686823
rdf:type: n2:Context
rdf:value: We have recently shown that Curcumin inhibits the formation but not the growth of metastases in an in vivo model of immunodeficient mice [>>3<<]. However, the anti-metastatic activity of the natural polyphenol cannot be completely ascribed to its pro-apoptotic activity. Curcumin apparently also influences a network of pro-metastatic players that depend on NFκB and in this context
n2:mentions: n3:17310108

Subject Item: _:vb6686824
rdf:type: n2:Context
rdf:value: players that depend on NFκB and in this context the inflammatory cytokines CXCL1 and -2 (GROα and β) appear to play a crucial role inasmuch as they influence the expression of several other pro-metastatic genes including CXCR4 [>>4<<]. The importance of CXCL1 in the process of metastasis has recently been reported and is also reflected by its presence in several metastasis signatures [26,37].
n2:mentions: n3:17999991

Subject Item: _:vb6686825
rdf:type: n2:Context
rdf:value: The importance of CXCL1 in the process of metastasis has recently been reported and is also reflected by its presence in several metastasis signatures [>>26<<,37]. The lung metastasis signature presented by Minn and coworkers has been developed using a CXCL1 and -2 positive cell line, yet in human breast cancers, CXCL1 and -2 are not expressed at considerable levels, and in only a small
n2:mentions: n3:16049480

Subject Item: _:vb6686826
rdf:type: n2:Context
rdf:value: The importance of CXCL1 in the process of metastasis has recently been reported and is also reflected by its presence in several metastasis signatures [26,>>37<<]. The lung metastasis signature presented by Minn and coworkers has been developed using a CXCL1 and -2 positive cell line, yet in human breast cancers, CXCL1 and -2 are not expressed at considerable levels, and in only a small minority
n2:mentions: n3:18046511

Subject Item: _:vb6686827
rdf:type: n2:Context
rdf:value: metastasis signature presented by Minn and coworkers has been developed using a CXCL1 and -2 positive cell line, yet in human breast cancers, CXCL1 and -2 are not expressed at considerable levels, and in only a small minority of cases [>>37<<].
n2:mentions: n3:18046511

Subject Item: _:vb6686828
rdf:type: n2:Context
rdf:value: variably) expressed in human primary and metastatic melanomas as well as other skin cancers and several other groups have underlined the importance of CXCL1 in melanoma progression pointing to its tumorigenic and angiogenic effects [>>38<<] and to tumor-host interactions [39]. With this in mind we set out to test the potential of Curcumin as chemopreventive drug for melanoma.
n2:mentions: n3:10647998

Subject Item: _:vb6686829
rdf:type: n2:Context
rdf:value: and metastatic melanomas as well as other skin cancers and several other groups have underlined the importance of CXCL1 in melanoma progression pointing to its tumorigenic and angiogenic effects [38] and to tumor-host interactions [>>39<<]. With this in mind we set out to test the potential of Curcumin as chemopreventive drug for melanoma.
n2:mentions: n3:15899804

Subject Item: _:vb6686830
rdf:type: n2:Context
rdf:value: Our results demonstrate that the highly metastatic melanoma cell line M14 is, however, relatively resistant to the effects of Curcumin, in particular if compared to what we have observed for breast cancer cells [>>3<<,4]. Even after 48 hours only early apoptosis can be observed and very few cells are irreversibly committed to cell death.
n2:mentions: n3:17310108

Subject Item: _:vb6686831
rdf:type: n2:Context
rdf:value: Our results demonstrate that the highly metastatic melanoma cell line M14 is, however, relatively resistant to the effects of Curcumin, in particular if compared to what we have observed for breast cancer cells [3,>>4<<]. Even after 48 hours only early apoptosis can be observed and very few cells are irreversibly committed to cell death.
n2:mentions: n3:17999991

Subject Item: _:vb6686832
rdf:type: n2:Context
rdf:value: To our best knowledge, this is the first description of resistance to Curcumin, a drug that has itself been reported to be able to overcome drug resistance to classical chemotherapy [>>40<<-43]. Drug resistance is in most cases a result of over-expression of cellular transporters that are able to extrude the compound in a short time thereby avoiding the accumulation within the cell to active concentrations [28]. We therefore
n2:mentions: n3:18006147

Subject Item: _:vb6686833
rdf:type: n2:Context
rdf:value: Drug resistance is in most cases a result of over-expression of cellular transporters that are able to extrude the compound in a short time thereby avoiding the accumulation within the cell to active concentrations [>>28<<]. We therefore created and analyzed gene expression profiles of M14 cells in comparison to the highly sensitive cell line MDA-MB-231. Most of the gene expression differences between the two cell lines can be attributed to their different
n2:mentions: n3:16816140

Subject Item: _:vb6686834
rdf:type: n2:Context
rdf:value: Moreover its activity is essential for formation of high-density lipoprotein (HDL) particles in vivo and mutations of ABCA1 lead to Tangier disease, an autosomal recessive trait characterized by HDL deficiency [>>44<<,45]. Low plasma HDL is associated with type 2 diabetes and metabolic syndrome [46,47] suggesting that ABCA1 contributes to this complication. Metabolic syndrome and type 2 diabetes are strongly correlated with therapy resistance and
n2:mentions: n3:10431237

Subject Item: _:vb6686835
rdf:type: n2:Context
rdf:value: Moreover its activity is essential for formation of high-density lipoprotein (HDL) particles in vivo and mutations of ABCA1 lead to Tangier disease, an autosomal recessive trait characterized by HDL deficiency [44,>>45<<]. Low plasma HDL is associated with type 2 diabetes and metabolic syndrome [46,47] suggesting that ABCA1 contributes to this complication. Metabolic syndrome and type 2 diabetes are strongly correlated with therapy resistance and
n2:mentions: n3:10431236

Subject Item: _:vb6686836
rdf:type: n2:Context
rdf:value: Low plasma HDL is associated with type 2 diabetes and metabolic syndrome [>>46<<,47] suggesting that ABCA1 contributes to this complication.
n2:mentions: n3:1959476

Subject Item: _:vb6686837
rdf:type: n2:Context
rdf:value: Low plasma HDL is associated with type 2 diabetes and metabolic syndrome [46,>>47<<] suggesting that ABCA1 contributes to this complication.
n2:mentions: n3:16394610

Subject Item: _:vb6686838
rdf:type: n2:Context
rdf:value: Metabolic syndrome and type 2 diabetes are strongly correlated with therapy resistance and increased cancer risk [>>48<<]. We show here that the ability of Curcumin to induce apoptosis and to act on NFκB is restored by knocking down ABCA1 in treatment resistant M14 melanoma cells. Interestingly, silencing of the ABCA1 transporter alone, in the absence of
n2:mentions: n3:17261760

Subject Item: _:vb6686839
rdf:type: n2:Context
rdf:value: In the majority of primary and metastatic melanomas ABCA1 is highly expressed [>>35<<]. Melanoma is therefore most likely not a good target for Curcumin treatments unless patients are selected on the base of ABCA1 expression.
n2:mentions: n3:18442402

Subject Item: _:vb6686840
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dc:title: bachground
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Subject Item: _:vb6686841
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rdf:value: It has been used for centuries as a traditional medicine to treat various inflammatory disorders [>>1<<,2] and has revealed remarkable anti-tumor activity in various organs and cell models [3-11]).
n2:mentions: n3:2062949

Subject Item: _:vb6686842
rdf:type: n2:Context
rdf:value: It has been used for centuries as a traditional medicine to treat various inflammatory disorders [1,2] and has revealed remarkable anti-tumor activity in various organs and cell models [>>3<<-11]). offering a role as novel candidate for chemoprevention of cancer.
n2:mentions: n3:9771944 n3:9973206 n3:18479807 n3:17999991 n3:14657599 n3:10657978 n3:10625938 n3:17310108 n3:9215864

Subject Item: _:vb6686843
rdf:type: n2:Context
rdf:value: In a previous study we have shown that Curcumin significantly reduces the number of metastases formed from intracardially injected breast cancer cells [>>3<<]. The underlying molecular mechanism involves the inhibition of the survival related transcription factor nuclear factor κB (NFκB) and its down-stream targets, the pro-inflammatory cytokines CXCL1 and -2 [4].
n2:mentions: n3:17310108

Subject Item: _:vb6686844
rdf:type: n2:Context
rdf:value: The underlying molecular mechanism involves the inhibition of the survival related transcription factor nuclear factor κB (NFκB) and its down-stream targets, the pro-inflammatory cytokines CXCL1 and -2 [>>4<<]. CXCL1 and -2 are expressed at high levels in very few breast cancers but in many primary and metastatic melanomas (see results section). We therefore addressed the question whether Curcumin could be a possible candidate drug for the
n2:mentions: n3:17999991

Subject Item: _:vb6686845
rdf:type: n2:Context
rdf:value: The current treatment modalities for melanoma fail to prevent the spread of metastasis in nearly 50% of the patients [>>12<<]. The development of new therapies is therefore required.
n2:mentions: n3:14585164

Subject Item: _:vb6686846
rdf:type: n2:Context
rdf:value: models of melanoma has so far shown promising results, inasmuch as the melanoma cell lines responded well to the polyphenol in terms of diminished NFκB activity, which is associated with reduced proliferation and induction of apotosis [>>13<<,14].
n2:mentions: n3:17885582

Subject Item: _:vb6686847
rdf:type: n2:Context
rdf:value: of melanoma has so far shown promising results, inasmuch as the melanoma cell lines responded well to the polyphenol in terms of diminished NFκB activity, which is associated with reduced proliferation and induction of apotosis [13,>>14<<].
n2:mentions: n3:16007726

Subject Item: _:vb6686848
rdf:type: n2:Context
rdf:value: However, the cell lines used in these studies are less tumorigenic and have a lower metastatic potential than the highly metastatic human M14 melanoma cell line that we use here [>>15<<-17].
n2:mentions: n3:10842189 n3:17262079 n3:9303353

Subject Item: _:vb6686849
rdf:type: n2:Context
rdf:value: Curcumin acts at least in part through diminished translocation of the transcription factor NFκB [>>18<<] which is constitutively active in many tumor cells. Inhibition of NFκB activity is associated with anti-proliferative effects, as well as with the induction of apoptosis [19,20].
n2:mentions: n3:12393461

Subject Item: _:vb6686850
rdf:type: n2:Context
rdf:value: Inhibition of NFκB activity is associated with anti-proliferative effects, as well as with the induction of apoptosis [>>19<<,20]. Several signal transduction pathways converge on NFκB and its regulators to mediate the transcriptional control of apoptosis and cell-cycle control [21,22]. NFκB is required for prevention of cell death induced by tumor necrosis
n2:mentions: n3:15476283

Subject Item: _:vb6686851
rdf:type: n2:Context
rdf:value: NFκB is required for prevention of cell death induced by tumor necrosis factor alpha (TNF-alpha) and its ability to induce anti-apoptotic genes such as bcl2 and birc5/survivin protects cancer cells from apoptosis [>>23<<,24]. Activation of NFκB constitutes a crucial step in tumor promotion and progression, angiogenesis, inflammation, invasion, and metastasis [25].
n2:mentions: n3:8864119

Subject Item: _:vb6686852
rdf:type: n2:Context
rdf:value: NFκB is required for prevention of cell death induced by tumor necrosis factor alpha (TNF-alpha) and its ability to induce anti-apoptotic genes such as bcl2 and birc5/survivin protects cancer cells from apoptosis [23,>>24<<]. Activation of NFκB constitutes a crucial step in tumor promotion and progression, angiogenesis, inflammation, invasion, and metastasis [25].
n2:mentions: n3:8864118

Subject Item: _:vb6686853
rdf:type: n2:Context
rdf:value: Activation of NFκB constitutes a crucial step in tumor promotion and progression, angiogenesis, inflammation, invasion, and metastasis [>>25<<].
n2:mentions: n3:12040437

Subject Item: _:vb6686854
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rdf:value: As a consequence, the polyphenol does not reduce the expression of the metastasis-related pro-inflammatory cytokine CXCL1/GROα [>>26<<], which is known to be a NFκB target [27].
n2:mentions: n3:16049480

Subject Item: _:vb6686855
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rdf:value: of multidrug resistance genes, a superfamily of transmembrane proteins that act as ATP hydrolyzing cellular transporters and are able to export a wide variety of natural and synthetic compounds from the cells (for a review see [>>28<<]).
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