Authors: James C.K. Lai¹, Vikas Bhardwaj¹, Tanushree Chatterji¹, Nisha Rizvi¹, Alfred O. Isaac¹, Maria B. Lai¹, Tara Johnson¹, Solomon W. Leung², Christopher K. Daniels¹, and Alok Bhushan¹

Affiliation: (1) Biomedical & Pharmaceutical Sciences Department, College of Pharmacy, and Biomedical Research Institute, Idaho State University, Pocatello, ID 83209 and (2) Civil & Environmental Engineering Department, College of Engineering, Biomedical Research Institute, Idaho State University, Pocatello, ID 83209

Title: Inhibitors of Glycolytic Enzymes: Induction of Cancer Cell Death & Alteration in Cell Signaling

Abstract: One version of the Warburg hypothesis states that, for their survival and proliferation, tumor cells depend critically on energy production derived from aerobic glycolysis rather than mitochondrial glucose oxidative metabolism. To test facets of this hypothesis further and determine the mechanistic possibility of employing glycolysis as the drug target for developing new chemotherapy, we have systematically investigated the effects of two glycolytic enzyme inhibitors (namely, 3-bromopyruvate (3BP), an inhibitor of hexokinase II, and iodoacetate (IAA), an inhibitor of glyceraldehyde-3-phosphate dehydrogenase) on survival of several different cancer cell types, including glioblastoma, pancreatic, and oral cancer cells. The results of our ongoing studies reveal that both 3BP and IAA induced cell death in all cancer cell types studied in a concentration- and time-related manner. We have further elucidated the modes of cell death induced by these inhibitors on various types of cancer cells as well as some of the signaling pathways underlying the effects of the inhibitors. Thus, the results of our ongoing studies prompted us to hypothesize that we can employ glycolytic enzyme inhibitors, such as IAA and 3BP, as "proof-of-concept" test drugs to derive a novel approach to inhibit cancer cell proliferation and invasion. Clearly, this area has emerged as being highly relevant as a novel approach to further elucidate cancer cell target as well as generating new ideas for anti-cancer drug development.