Abstract 4776: Dichloro [4,40-bis(4,4,4-trifluorobutyl)-2,20-bipyridine] platinum, a novel Cisplatin analog, exhibits enhanced anticancer activity in preclinical models of upper gastrointestinal cancers

Abstract

Abstract Background: Upper Gastrointestinal Cancers (UGCs) respond poorly to conventional chemotherapy due to variable P53 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 [4,40-bis(4,4,4-trifluorobutyl)-2,20-bipyridine] platinum) (DCTF-CDDP) and compared it to CDDP in P53 wild type and mutant models of UGCs. Methods: For this study, we evaluated the effect of CDDP or its derivative (DCTF-CDDP) on AGS (P53 wild type) and FLO-1 (P53 mutant) UGC cell viability, survival, and expression of apoptotic markers. Results: The cell viability data indicated that DCTF-CDDP treatment was comparatively more effective than CDDP at inhibiting AGS (CDDP IC50: 6.3 ± 0.2 μM; DCTF IC50: 1.7 ± 0.5μM) and FLO-1 (CDDP IC50: 2.5 ± 0.68 μM; DCTF IC50: 0.5 ± 0.6μM) UGC cancer cell viability. The clonogenic cell survival assay data also showed that DCTF-CDDP was significantly (p<0.05) more potent at suppressing UGC cell survival when compared to CDDP. Similarly, the western blot data also showed that treatment with increasing concentrations (1, 2.5, and 5 μM) of CDDP and DCTF-CDDP for 24h induced higher levels of P53/P73 and cleaved PARP with DCTF-CDDP treatment in UGC cells. Conclusions: Our in vitro data indicate that DCTF-CDDP is significantly more potent at inhibiting cell viability and inducing apoptosis in P53 wild type and mutant UGC cells. Our study suggests that DCTF-CDDP could be an effective CDDP derivative that can be used to achieve better therapeutic outcome at lower doses and toxic side effects. Citation Format: Samhita Bapat, Tanmay Dichwalkar, Priya Pancholi, Byron L. Bennett, Vikas Sehdev. Dichloro [4,40-bis(4,4,4-trifluorobutyl)-2,20-bipyridine] platinum, a novel Cisplatin analog, exhibits enhanced anticancer activity in preclinical models of upper gastrointestinal cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4776.