Characterization Of A Novel Anti-Glucose Transporter Inhibitor As A Pan-Anticancer Therapeutic In Vitro And In Vivo

Cancer has surpassed cardiovascular diseases as the top killer in many US counties. Opportunistic uptake of extracellular nutrients has recently been named as an emerging hallmark of cancer metabolism. Glucose is a key nutrient taken in by cancer cells for satisfying their high energy and biosynthesis needs. Drastic upregulation of glucose uptake and metabolism, a phenomenon called the Warburg effect, is prevalent among cancers. Cancer cells overexpress specific glucose transporters (GLUTS), particularly GLUT1, on their cell surface for uptaking glucose via facilitated diffusion. Considering the addiction of cancer cells to glucose and their sensitivity and vulnerability to changes in glucose supply, Gluts, have been recognized as an attractive anticancer target. Previously, our first-generation GLUT-inhibitor, WZB117, had been characterized in vitro and in vivo as an anticancer therapeutic. In this study, DRB18, a novel and proprietary lead inhibitor of glucose transporters, is characterized in vitro and in vivo by bioassays. DRB18 inhibits growth and proliferation in about 90% of the 60 different cancer cell lines in 9 major cancer types. It shows IC50 values in high nM range in some cell lines in several different cancer types. DRB18 treatment leads to significant changes in glucose-based metabolism in A549 lung cancer cells, including cell death via ER/oxidative stress and necrosis. The docking and Seahorse studies reveal the surprising contributions of macropinocytosis in DRB18 internalization, ultimately leading to better GLUT1 binding and increase in potency in killing cancer cells. DRB18 (10mg/kg) treatment thrice a week significantly reduces growth in Xenograft A549 tumors. Comprehensive in vitro and in vivo metabolomics analysis would be presented to better describe anti-glucose metabolism of activity of DRB18. Further, GLUT1-KO A549 (A549glut1ko) cell lines, in which Glut1 gene has been knocked out, were generated using CRISPR-Cas9 system for further studying GLUT19s roles in A549 cells. Immunoblotting analysis revealed the upregulation of other GLUTs after GLUT1 is knocked out, strongly suggesting the need for a pan-GLUT inhibitor for better inhibition of tumor growth. Citation Format: Pratik Shriwas, Stephen Bergmeier, Xiaozhuo Chen. Characterization of a novel anti-glucose transporter inhibitor as a pan-anticancer therapeutic in vitro and in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4191.