Dichloro (4, 4'-bis (4, 4, 4-trifluorobutyl)-2, 2'-bipyridine1 platinum, a novel cisplatin analog, exhibits enhanced anticancer activity in preclinical models of Upper Gastrointestinal Cancers.

摘要

Introduction: Upper Gastrointestinal Cancers (UGCs) respond poorly to conventional chemotherapy due to variable Tumor protein-53 (TP53) status and overactive mechanisms that mediate drug resistance. Platinum based compounds like Cisplatin (CDDP) are frequently used for treatment of UGCs. However, clinical use of CDDP is limited due to development of drug resistance and dose limiting side-effects resulting in nausea, vomiting, neutropenia, thrombocytopenia and renal toxicity. In this study we investigated the anticancer potency of a novel CDDP derivative (dichloro [4, 4'-bis (4, 4, 4-trifluorobutyl)-2, 2'-bipyridine] platinum) (DCTF-CDDP) and compared it to CDDP in P53 wild type and mutant models of UGCs.;Methods: In this study, we investigated the effect of CDDP or its derivative (DCTF-CDDP) on AGS (P53 wild type) and FLO-1 (P53 mutant) UGC cell viability, survival, expression of apoptotic markers and progression of cell cycle.;Results: The cell viability data indicated that DCTF-CDDP treatment was comparatively more potent and effective than CDDP at inhibiting AGS (CDDP IC50: 6.3 +/- 0.2 microM; DCTF-CDDP IC 50. 1.7 +/- 0.5pM) and FLO-1 (CDDP IC50: 1.8 +/- 0.60 microM; DCTF-CDDP IC50: 0.5 +/- 0.12microM) UGC cancer cell viability. The clonogenic cell survival assay data also showed that DCTF-CDDP was significantly (p<0.05) more effective at suppressing long term UGC cell survival when compared to CDDP. The western blot data showed that the treatment with 5muM of CDDP and DCTF-CDDP for 8 hours induced higher levels of P53/P73, PUMA, P21, Cleaved PARP and Cleaved Caspase-3 with DCTF-CDDP treatment in UGC cells. The cell cycle analyses further indicate that compared to CDDP, DCTF-CDDP treatment of 5muM for 24 hours mediates higher induction of SubG1 phase and suppression of G1 and G2-M phases respectively in UGC cells.;Conclusions: Our in vitro data indicate that DCTF-CDDP is significantly more potent and effective at inhibiting cellular progression and inducing apoptosis in both P53 wild type and mutant UGC cell models. Our study suggests that DCTF-CDDP could be an effective CDDP derivative that can be used to achieve better therapeutic outcome at reduced doses. This work warrants further studies to investigate the anticancer and toxic effects of DCTF-CDDP in vivo.