Abstract 2123: A combinatorial approach using gemcitabine and bitter melon juice overcomes drug resistance impacting gemcitabine uptake and metabolism

Abstract

Abstract Pancreatic cancer (PanC) has the lowest 5-year survival rate (<3%) of all cancer types and is projected to be the second leading cause of cancer-associated mortalities by the year 2030 in the United States. Surgery alone fails to suffice in a majority of cases; the disease relapses in 70-80% of patients and is fatal without additional therapy. Currently, of all the available treatment modalities for PanC, gemcitabine (GEM) is the standard of care frontline drug, with a moderate success rate in improving the median overall PanC patient survival by about 5.7-6.8 months. Although a modest improvement is achieved using a combination therapy approach, the patient survival still remains less than 12 months, and includes a poor quality of life due to the extensive side effects. Moreover, chemoresistance to GEM is a major contributing factor for PanC patient’ morbidity and mortality resulting from dysfunctional uptake and metabolism of GEM in cancer cells. Therefore, there is an urgent need for agents that could reverse GEM resistance and allow continued chemosensitivity in PanC. Here, we employed natural agent bitter melon juice (BMJ) and GEM to examine their anticancer potential alone and in combination in PanC patient derived xenograft (PDX) - pancreatic ductal adenocarcinomas explants in nude mice. Comparing single agents versus combination in three explants PDX272, PDX261, and PDX266, both at the end of the active dosing regimen as well as following a post treatment-washout period (no drug administration) revealed enhanced efficacy of the combination treatment over failed GEM-in the post treatment termination cohort. Extensive mechanistic assessments revealed that overcoming GEM resistance was possibly due to modulation of GEM metabolism pathway molecules by the BMJ administration. While all drug exposures led to a decreased RRM1 expression during treatments in PanC-explants, at the end of treatment washout period explants displayed increased RRM1 levels in GEM-only group but a sustained decrease in BMJ and Combo groups. Investigation into hENT1 (human equilibrative nucleoside transporter 1) expression, responsible for bidirectional GEM trafficking, revealed that at the end of washout period, combination therapy was the only group that continued to express high levels of hENT1 for all three explants, whereas GEM only group showed poor hENT1 expression. Furthermore, analysis for deoxycytidine kinase (dCK), the enzyme responsible for GEM metabolism, revealed that the combination group had the most augmented dCK expression levels by study end. Taken together, the study outcomes highlight the efficacy of BMJ in combination with GEM in modifying and regulating multiple key players in GEM uptake and metabolism. These conclusions make a compelling case for future clinical investigations in PanC patients wherein BMJ is combined with GEM to target and overcome GEM resistance. Citation Format: Deepanshi Dhar, Dileep Kumar, Komal Raina, David J. Orlicky, Chapla Agarwal, Rajesh Agarwal. A combinatorial approach using gemcitabine and bitter melon juice overcomes drug resistance impacting gemcitabine uptake and metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2123.