Abstract 1268: Bitter melon efficacy against human pancreatic cancer cells: possible involvement of cellular stemness and metabolome targets

Abstract

Abstract Pancreatic cancer (PanC) has a dismal 5-year survival rate of < 5%. Symptomless progression, late diagnosis and rising drug resistance to leading chemotherapeutic agents like gemcitabine, add to PanC severity. Hence, there is a critical requirement for identifying alternative novel non-toxic agents (dietary/non-dietary) aimed at effective management of PanC with minimal patient distress. Bitter melon (Momordica charantia), a dietary agent, is actively being investigated for its anti-cancer potential against a variety of malignancies, including our work in PanC. Recent studies by us have shown bitter melon juice (BMJ) efficacy against a panel of human PanC cell lines in culture and tumor xenografts. For mechanistic studies, here we evaluated the efficacy of BMJ against cancer stem cells (CSCs) pool in PanC cells. Results indicated that BMJ treatment (0.25-2% v/v) significantly decreased CSC enriched (CD44+CD24+EpCAMhigh) PanC cell population. Successive immunofluorescence/ immunohistochemical analysis of BMJ exposed cells, spheroids and MiaPaCa2 xenograft tumors showed a significant reduction in CSC markers/ regulatory molecules. Since cancer cell metabolism is an important component to be targeted to control cancer growth and progression, we next assessed BMJ efficacy in that direction. Indeed, BMJ mediated its anti-PanC effect via activating the key metabolic regulator AMPK. Concomitantly, to determine whether BMJ-effects were nutrient/energy stress dependent, we next sought to determine the cellular energy profile and major metabolic changes induced by BMJ. PanC cell metabolome analysis was done, as a function of time, to determine the shift in PanC cell metabolism on BMJ exposure. 1H-, 13C- and 31P-NMR spectra of PanC cell monolayers treated with BMJ (2% v/v) at early ( 4h) and late (72h) time points showed significantly altered energy status and modulation of major metabolic pathways involved in PanC cell growth and proliferation. A significant reduction in glucose uptake and cellular energy levels (ATP/ADP) ratio was observed, but lactate export was increased. BMJ also modulated nucleotides and aromatic amino acids involved in protein precursors/synthesis for PanC growth and proliferation. Total fatty acids and phosphatidylcholine levels (a precursor of membrane lipids) were also downregulated by BMJ. Glutamine and glutamate levels were constrained by BMJ, indicating that it could potentially limit PanC cell ability for targeting an alternative energy source. Furthermore, the cellular levels and membrane localization of GLUT1 (major glucose transporter overexpressed in PanC) were also suppressed after BMJ treatment. Collectively, these results suggest that BMJ targets PanC CSCs and cellular metabolism in its efficacy against this deadly malignancy (supported by CA195708). Citation Format: Deepanshi Dhar, Gagan Deep, Sushil Kumar, Chapla Agarwal, Natalie Serkova, Michael Wempe, Komal Raina, Rajesh Agarwal. Bitter melon efficacy against human pancreatic cancer cells: possible involvement of cellular stemness and metabolome targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1268. doi:10.1158/1538-7445.AM2017-1268