Abstract 1094: 3-Bromopyruvate reduces pancreatic tumor growth by damaging mitochondria and inhibiting glucose metabolism in both cell culture and mouse model

Abstract

Abstract Pancreatic cancer (PC) is the deadly cancer in both men and women, with a one-year relative survival rate of 20%, and a five-year relative survival rate of only 8%. Pancreatic cancer is characterized by dense fibrotic stroma that constitutes up to 90% of the total tumor volume and contains extracellular matrix (ECM), immune cells, vasculature, and cancer-associated fibroblasts which are hallmark of immunosuppressive tumor microenvironment. In present investigation we have tested anti-cancer effect of 3-BromoPyruvate (3-BP), an inhibitor of aerobic glycolysis employing Panc-2 cancer cells, and syngeneic pancreatic cancer mouse model. Panc-2 cancer cells treated with 40 uM of 3-BP showed significant inhibition in cell proliferation and ATP production. Cells treated with 60 uM dose level, showed drastic phenotypic changes (membrane blebbing) within 2 hours of treatment. The qRT PCR data showed 3BP inhibited hexokinase II (HK2) expression at 40uM, suggesting 3-BP regulate HK2 expression at transcriptional level. We also observed that 3-BP in combination with low doses of irradiation was more effective in killing cancer cells than 3-BP alone in both 2D and 3D culture model. Treatment of C57BL/6 subcutaneous pancreatic tumor model with 10 and 20 mg/kg of 3BP also showed significant reduction of tumor growth. The Transmission Electron Microscopy of tumor tissues treated with 3-BP revealed severely damaged mitochondrial structure which might have severely affected ATP generation in cancer cell. Altogether, the results in this study demonstrated that 3-BP could be a promising anti-tumor drug against pancreatic cancer and its efficacy could be improved in combination with radiation therapy. Citation Format: Sanjit Roy, Tijana Dukic, Binny Bhandary, Jason Molitoris, Young H Ko, Hem D Shukla. 3-Bromopyruvate reduces pancreatic tumor growth by damaging mitochondria and inhibiting glucose metabolism in both cell culture and mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1094.