Abstract 698A: Bitter melon juice targets molecular mechanisms underlying gemcitabine resistance in pancreatic cancer cells

Abstract

Abstract Pancreatic cancer is an aggressive disease and is usually advanced at the time of diagnosis. Median life of pancreatic cancer patients post-diagnosis is <6 months and an overall 5-year survival rate is 3-5%. In 2013, ∼44,980 new cases of pancreatic cancer are expected in United States with ∼38,460 deaths. In most cases, disease relapse occurs due to development of resistance towards gemcitabine (the frontline therapy for pancreatic cancer) and is the main cause for dismal rate of survival in pancreatic cancer patients. Therefore, overcoming gemcitabine resistance remains a major challenge towards effectively treating this deadly malignancy. Several molecular mechanisms are known to contribute to gemcitabine-resistance in pancreatic cancer; however, metabolism and bioenergetic alterations in gemcitabine-resistant pancreatic cancer cells have not yet been characterized. Here, we analyzed and compared the metabolic and bioenergetic functions between gemcitabine-resistance and sensitive pancreatic cancer cells along with underlying molecular mechanisms. Furthermore, we also assessed the anticancer efficacy of a natural agent bitter melon (Momordica charantia, Family: Cucurbitaceae) juice (BMJ) against gemcitabine-resistant pancreatic cancer cells. Results showed that gemcitabine-resistant human pancreatic adenocarcinoma AsPC-1 and MiaPaCa-2 cells have distinct morphological features including spindle-shaped morphology and a decrease in E-cadherin expression. Interestingly, gemcitabine-resistant cells showed higher ATP production along with an increase in oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) confirming an increase in both cellular oxidative phosphorylation and glycolysis. Molecular studies showed a higher expression of glucose transporters GLUT1 and GLUT4 suggesting an increase in glucose uptake by gemcitabine-resistant cells. Importantly, gemcitabine-resistant cells exhibited a significant increase in Akt and ERK1/2 phosphorylation, and Akt and/or ERK1/2 inhibition by specific chemical inhibitors significantly decreased the gemcitabine-resistant cells viability, suggesting the critical role of these molecules in the survival and drug resistance of these cells. Recently, BMJ has shown strong efficacy in a panel of gemcitabine-sensitive cells in culture and nude mice, which we expanded here and found that BMJ was also effective in strongly decreasing both Akt and ERK1/2 phosphorylation and viability of gemcitabine-resistant pancreatic cancer cells. Overall, we have identified novel mechanisms of gemcitabine-resistance in pancreatic cancer cells that are targeted by BMJ. Considering a short survival-rate in pancreatic cancer patient, our findings could have high translational potential in controlling this deadly malignancy. Citation Format: Ranganatha Somasagara, Gagan Deep, Sangeeta Shrotriya, Manisha Patel, Chapla Agarwal, Rajesh Agarwal. Bitter melon juice targets molecular mechanisms underlying gemcitabine resistance in pancreatic cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 698A. doi:10.1158/1538-7445.AM2014-698A