Recent interests in the “Warburg effect” stimulated a variety of studies that have demonstrated many aggressive cancers have adapted to hypoxia and shifted to a glycolytic phenotype depending on their micro-environment. However, the mechanisms underlying their adaptive behavior have not been delineated. To further investigate our hypothesis that glycolytic enzymes are targets for new anti-cancer drug discovery, we have examined the effects of iodoacetate (IAA), an inhibitor of glyceraldehyde-3-phosphate dehydrogenase, and 3-bromopyruvate (3-BP), an inhibitor of hexokinase II, on human neuroblastoma SK-N-SH and astrocytoma U-87 cells. Our results from survival assays showed that both IAA and 3-BP induced concentration- and time-dependent lowering of survival of both cell types, with the effects of IAA being more potent than those of 3-BP in both cell types while SK-N-SH cells being more susceptible than U-87 cells to 3-BP-induced cytotoxicity. Employing lactate dehydrogenase release from cells to medium as a marker for necrosis, we also found IAA was more potent than 3-BP in inducing necrosis in both cells types. Further investigation employing flow cytometric analysis revealed that at 1-10 µM, IAA induced more apoptosis in SK-N-SH than in U-87 cells while at the higher levels in this range, IAA induced more necrosis relative to apoptosis in both cell types. However, at 10-40 µM, 3-BP induced mainly apoptosis but little necrosis in both cell types. Our results are therefore consistent with the notion that IAA and 3-BP exert differential effects in inducing apoptosis and necrosis in SK-K-SH and U-87 cells. Studies are ongoing to further elucidate the signaling mechanisms mediating these effects induced by IAA and 3-BP. Thus, our findings may have pathophysiological and therapeutic implications in employing glycolysis as a target for discovering new drugs for treating aggressive brain tumors.

Citation Format: Alok Bhushan, Tanushree Chatterji, Wendy Wong, Nisha Rizvi, Anurag K. Balaraju, Aishwarya Neti, James C.K. Lai. Iodoacetate and 3-bromopyruvate exert differential effects on human neuronal tumor SK-N-SH and U-87 cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3371. doi:10.1158/1538-7445.AM2014-3371