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Author (up) Kap, E.J.; Seibold, P.; Scherer, D.; Habermann, N.; Balavarca, Y.; Jansen, L.; Zucknick, M.; Becker, N.; Hoffmeister, M.; Ulrich, A.; Benner, A.; Ulrich, C.M.; Burwinkel, B.; Brenner, H.; Chang-Claude, J. file  url
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  Title SNPs in transporter and metabolizing genes as predictive markers for oxaliplatin treatment in colorectal cancer patients Type Journal Article
  Year 2016 Publication International Journal of Cancer Abbreviated Journal Int J Cancer  
  Volume 138 Issue 12 Pages 2993-3001  
  Keywords colorectal cancer; metabolism; oxaliplatin; predictive markers; transport  
  Abstract Oxaliplatin is frequently used as part of a chemotherapeutic regimen with 5-fluorouracil in the treatment of colorectal cancer (CRC). The cellular availability of oxaliplatin is dependent on metabolic and transporter enzymes. Variants in genes encoding these enzymes may cause variation in response to oxaliplatin and could be potential predictive markers. Therefore, we used a two-step procedure to comprehensively investigate 1,444 single nucleotide polymorphisms (SNPs) from these pathways for their potential as predictive markers for oxaliplatin treatment, using 623 stage II-IV CRC patients (of whom 201 patients received oxaliplatin) from a German prospective patient cohort treated with adjuvant or palliative chemotherapy. First, all genes were screened using the global test that evaluated SNP*oxaliplatin interaction terms per gene. Second, one model was created by backward elimination on all SNP*oxaliplatin interactions of the selected genes. The statistical procedure was evaluated using bootstrap analyses. Nine genes differentially associated with overall survival according to oxaliplatin treatment (unadjusted p values < 0.05) were selected. Model selection resulted in the inclusion of 14 SNPs from eight genes (six transporter genes, ABCA9, ABCB11, ABCC10, ATP1A1, ATP1B2, ATP8B3, and two metabolism genes GSTM5, GRHPR), which significantly improved model fit. Using bootstrap analysis we show an improvement of the prediction error of 3.7% in patients treated with oxaliplatin. Several variants in genes involved in metabolism and transport could thus be potential predictive markers for oxaliplatin treatment in CRC patients. If confirmed, inclusion of these variants in a predictive test could identify patients who are more likely to benefit from treatment with oxaliplatin.  
  Call Number Serial 1540  
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Author (up) Prabhu, V.V.; Hong, B.; Allen, J.E.; Zhang, S.; Lulla, A.R.; Dicker, D.T.; El-Deiry, W.S. file  url
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  Title Small-Molecule Prodigiosin Restores p53 Tumor Suppressor Activity in Chemoresistant Colorectal Cancer Stem Cells via c-Jun-Mediated DeltaNp73 Inhibition and p73 Activation Type Journal Article
  Year 2016 Publication Cancer Research Abbreviated Journal Cancer Res  
  Volume 76 Issue 7 Pages 1989-1999  
  Keywords p53; Tumor suppression; p73; Colorectal cancer; Stem cells  
  Abstract Tumor suppressor p53 is frequently mutated or inactivated in colorectal cancer. In contrast, p53 family member p73 is rarely mutated in colorectal cancer and p73 activation elicits p53-like tumor suppression. Colorectal cancer stem cells (CRCSC) comprise a rare self-renewing subpopulation that contributes to tumor maintenance and chemoresistance. p53 restoration is known to target CRCSCs, but p73 restoration in CRCSCs has not been examined. In this study, we investigated the effects of the small-molecule prodigiosin, which restores the p53 pathway in tumor cells via p73 activation, on CRCSCs in vitro and in vivo Prodigiosin prevented colonosphere formation independent of p53 status and reduced the viability of self-renewing, 5-fluorouracil-resistant Aldefluor positive [Aldefluor(+)] CRCSCs in vitro Furthermore, prodigiosin inhibited the growth of xenograft tumors initiated with Aldefluor+ cells without toxic effects and limited the tumorigenic potential of these cells. Consistently, prodigiosin induced activation of a p53-responsive luciferase reporter in colonospheres, Aldefluor(+) cells, and tumor xenografts. Mechanistic studies revealed that prodigiosin increased the levels of p73 and reduced levels of the oncogenic N-terminally truncated isoform DeltaNp73 in Aldefluor(+) cells. Accordingly, p73 knockdown or DeltaNp73 overexpression suppressed prodigiosin-mediated inhibition of colonosphere formation. Moreover, prodigiosin increased levels of the transcription factor c-Jun, a regulator of p73 and DeltaNp73, in both the cytoplasm and nucleus. c-Jun knockdown attenuated prodigiosin-mediated p53-reporter activation, DeltaNp73 downregulation, p73 activation, and cell death. Collectively, our findings highlight the previously uncharacterized use of p73-activating therapeutics to target CRCSCs.  
  Call Number Serial 1518  
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