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- W2602470679 abstract "e13546 Background: Inactivating TP53 mutations are common events in different types of cancers, including pancreatic adenocarcinoma, where it occurs in as much as 70% of cases. Accumulation of mutant p53 provides a molecular target that may be reactivated into a conformation capable of arresting tumor growth. The small molecule PRIMA-1 (p53 reactivation and induction of massive apoptosis) has been shown to selectively induce apoptosis in tumor cells by reactivating some p53 mutants, but no previous studies have investigated its effects in pancreatic cancer. Methods: PANC-1 (mutant TP53 R273H) and CAPAN-2 (wild-type TP53) pancreatic cell lines were used as in vitro models. We tested the effects of PRIMA-1 on cell viability (MTT assay), apoptosis (morphology, AnnexinV/FITC-FACS), cell cycle (BrdU incorporation) and expression of p53 regulated proteins by western blotting. As control of p53-dependent effects, PANC-1 cell lines were transfected with siRNA against TP53 (sip53). Results: PRIMA-1 selectively induced apoptosis in PANC-1 cells compared to CAPAN-2 cells and this effect was concomitant with an increase in the levels of MDM2, Bax and cleaved caspase-3 as detected by western blot analysis. Treatment with PRIMA-1 for 24h induced a 50% reduction in DNA synthesis whereas G2/M arrest was detected after 12h of treatment. p53 silencing in PANC-1 decreased the cytotoxicity of PRIMA-1, characterizing a p53-dependent effect. Finally, N-acetylcysteine completely blocked PRIMA-1-induced growth suppression and apoptosis, suggesting that PRIMA-1 exerts its effect at least in part via restoring redox-dependent effects to mutant p53. Conclusions: Our data indicate that PRIMA-1 induces apoptosis in TP53 mutant pancreatic cancer cells by promoting the re-activation of p53 and subsequent of proapoptotic signaling pathways, suggesting a possible mechanism for effective targeting of pancreatic cancer." @default.
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- W2602470679 date "2012-05-20" @default.
- W2602470679 modified "2023-09-26" @default.
- W2602470679 title "Reactivation of p53 mutant protein by PRIMA-1 and induction of apoptosis in pancreatic cancer cells." @default.
- W2602470679 doi "https://doi.org/10.1200/jco.2012.30.15_suppl.e13546" @default.
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