Abstract 3231: A small molecule inhibitor of glucose transporter 1 (Glut1) down-regulates glycolysis, induces cell cycle arrest, and inhibits cancer cell growth in vitro and in vivo

Abstract

Abstract Increased dependence on glycolysis and glucose metabolism, known as the Warburg effect, is a near-universal hallmark of cancer. The functional and therapeutic importance of the effect has been increasingly recognized and glycolysis has become a new target of anticancer strategies. We recently reported the identification of a group of novel small compounds that inhibit basal glucose transport and reduce cancer cell growth by using a glucose deprivation-like mechanism. Based on these and other results, we hypothesized that the compounds inhibit cancer growth by targeting Glut1 and they are efficacious in vivo as anticancer agents. Here we report that the representative and novel compound WZB117 not only inhibited cancer cell growth in multiple cancer cell lines but also inhibited cancer growth in a nude mouse model. Daily intraperitoneal (ip) injection of WZB117 at a dose of 10 mg/kg resulted in an over 70% reduction in the average size of xenografted tumor of human lung cancer A549 cell origin. Compound target study showed that WZB117 inhibited glucose transport in human red blood cells (RBC) and RBC-derived vesicles, both of which express Glut1 as their sole glucose transporter. Docking studies of WZB117-Glut1 interaction also demonstrate and support the binding of WZB117 to Glut1. Mechanism studies using multiple cancer cell lines revealed that treatment of WZB117 led to an induction of glycolytic enzymes, such as hexokinase, PKM2 and PGAM1; and then a decline of glycolysis as indicated by reduced lactate production with changes in Akt, AMPK and mTOR, protein factors in energy sensitive signaling pathways. These resulted in ER stress, followed by cell cycle arrest mediated through downregulation of cyclin E and Rb. Taken together, cell cycle arrest at G1/S phase plays major roles in the WZB117-induced inhibition of cancer cell growth while apoptosis is secondary. WZB117 can serve as a prototypic compound for further development of Glut1 inhibitors into novel anticancer therapeutics targeting glucose transport and glucose metabolism. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3231. doi:1538-7445.AM2012-3231