Carolinas Research Day 2021

Biomedical Studies

04 A Novel Bipyridone Cisplatin Analog Exhibits Enhanced Anticancer Activity in Preclinical Models of Upper Gastrointestinal Cancers

Samhita Bapat, PhD, Vikas Sehdev, PhD, B. Pharm, Noah Kosnik, OMSII, Hannah Fischer, OMSII, Patrick D. Ellis Fisher, PhD, and Byron Bennett, PhD

Edward Via College of Osteopathic Medicine-Carolinas, Long Island University, Idaho State University

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. Hypothesis/Goal of Study: 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 (P53 WT) and mutant (P53 MT) models of UGCs.

Methods and Results: For this study, we evaluated the effect of CDDP or its derivative (DCTF- CDDP) on AGS (P53 WT) and FLO-1 (P53 MT) UGC cell lines. After treatment with CDDP or DCTF-CDDP; MTT cell viability, clonogenic cell survival, cell cycle, Annexin V staining, and western blot analyses were carried out to measure cell viability, cell survival, cell cycle progression, cell death, and expression of apoptotic proteins, respectively, in AGS and FLO-1 UGC cell lines. Our in vitro data indicate that DCTF-CDDP is significantly more potent at inhibiting cell viability and cell survival of P53 wild type and mutant UGC cells. The cell cycle, cell death, and pro-apoptotic protein expression analyses further indicate that DCTF-CDDP is much more effective in suppressing cell cycle

progression and inducing apoptotic markers in P53 wild type and mutant UGC cells. Conclusions: Overall, 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. Future studies characterizing the anticancer and toxicological effects in vivo are warranted to further develop this promising analogue.

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