Abstract 4068: A novel antiglycolytic small compound inhibits cancer growth in vitro and in vivo by inhibiting glut1

Abstract

Abstract This is an anticancer mechanism and an in vivo anticancer efficacy studies of a novel antiglycolytic inhibitor. Increased aerobic glycolysis in cancer cells, known as the Warburg effect, is an important biological hallmark in tumorigenesis. However, the real mechanisms and functional significance of the effect, the switch from oxidative phosphorylation to aerobic glycolysis in cancer cells have just begun to be understood. As a result, glycolysis and cancer metabolism have become new cancer research focuses and anticancer targets. Using the glucose uptake and cell viability as well as clonogenic assays, we recently reported the identification of a group of novel small compounds that inhibit basal glucose transport and reduce cancer cell growth by inducing apoptosis and cell cycle arrest using a glucose deprivation-like mechanism. Additional analysis revealed that these two activities were correlated. Furthermore, these compounds inhibit basal glucose transport in various the cancer cell lines tested. Based on these and other results, we hypothesized that the compounds inhibit cancer growth by inhibiting Glut1 and they are efficacious in vivo as anticancer agents. To test the hypotheses, the representative compound WZB117, human red blood cells (RBC) as well as their derived plasma membrane vesicles were used in the protein target study. The results of the study showed that, at 10-30 μμ range, WZB117 inhibited glucose uptake in both RBC and the vesicles in a similar manner as the anti-Glut1 antibody, indicating that the inhibiting target of the compound is Glut1, as Glut1 is the only glucose transporter expressed in RBC. When treated with the compound, a reduced intracellular NADH concentration was observed in cancer cells, suggesting that glycolysis in the treated cancer cells was inhibited. Tested in nude mice grafted with human A549 non-small cell lung cancer, a more than 70% reduction in the tumor growth rate was observed when the tumor-bearing mice were treated with daily ip injection of WZB117 at 10 mg/kg body weight for 10 weeks and compared to the mock-treated control mice. Over the treatment period, these tumor-bearing mice demonstrated an average food intake similar to that of the control mice. Small but significant changes in body weight and in complete blood counts (CBC) were also observed, although various types of blood cells were all in the normal ranges. All these results indicate that WZB117 is both efficacious and safe in treating cancers in the nude mice. This is the first in vivo report on the anticancer efficacy of a Glut1and glucose transport inhibitor, which shows the potential as a prototypic compound for developing anticancer therapeutics targeting Glut1 and glycolysis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4068. doi:10.1158/1538-7445.AM2011-4068