Wednesday, June 20, 2007 - 2:30 PM Douglas Firs (Boise Centre on the Grove) 467
Glycolytic enzyme inhibitors as novel anti-cancer drugs
James C.K. Lai1, Vikas Bhardwaj2, Nisha Rizvi2, Tanushree Chatterji2, Alfred O. Isaac2, Maria B. Lai2, Tara Johnson2, Solomon W. Leung3, Christopher K. Daniels2, and Alok Bhushan1. (1) Idaho State University, Pocatello, ID, (2) Idaho State University College of Pharmacy and Biomedical Research Institute, Idaho State University, Pocatello, ID, (3) College of Engineering and Biomedical Research Institute, Idaho State University, Pocatello, ID
According to the Warburg hypothesis, tumor cell survival and proliferation critically depend on aerobic glycolysis rather than mitochondrial glucose oxidative metabolism as energy source. To further test the generality of the Warburg hypothesis, 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 the survival of several different types of cancer cells, including glioblastoma, pancreatic, and oral cancer cells. Our results demonstrate that both 3BP and IAA induced decreases in cell survival in all cancer cell types studied in a concentration- and time-related manner. Moreover, we found that one mechanism by which IAA induced cell death was necrosis, as determined by lactate dehydrogenase release into the medium, a marker of necrotic cell damage/death. Moreover, IAA was more potent than 3BP in inducing cell death in all the cancer cell types investigated. Thus, the results of our ongoing systematic 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. We are currently conducting additional mechanistic and signaling studies to systematically test this hypothesis further.