New Tricks for an Old Drug: Inhibition of Glyceraldehyde‐3‐Phosphate Dehydrogenase by Dithiolethiones to Suppress Cancer Cell Proliferation

Abstract

Dithiolethione compounds, such as the well‐characterized chemotherapeutic oltipraz, possess chemopreventive, cytoprotective, anti‐angiogenic, and chemotherapeutic properties. The chemopreventive effects of these compounds are mediated in part by the activation of antioxidant response elements and the increased expression of the tumor repressor PP2a and other cancer‐preventive proteins. Much of the transcriptional control of this response occurs via modification of thiol residues in the Keap1‐Nrf2 transcription factor complex. The 1,2‐dithiole‐3‐thione compound, ACS‐1, has also been shown to inhibit NF‐kB and downstream inflammatory molecules that promote tumor progression. As a result, these compounds can potentially be considered as promising multi‐targeting anticancer drugs.In addition to these established roles for dithiolethione compounds, we show here that ACS‐1 plays a novel role in inhibiting glycolysis, important for survival and proliferation of cancer cells. Here we show that ACS‐1 inhibits glycolysis in human tumor cell lines by targeting the glycolytic enzyme glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH). To understand the mechanism of action of ACS‐1, we have combined cell‐based assays, mutational analysis, kinetic assays, mass spectrometry, and x‐ray crystallography. We propose a mechanism whereby ACS‐1 inhibits glycolysis via covalent modification of GAPDH. Our results suggest that inhibition of GAPDH glycolytic function can be exploited in synergy with other cytotoxic chemotherapies to treat cancer. Cancer cells usually exhibit increased glycolysis (Warburg effect) in order to meet cellular energy requirements. Increasing evidence suggests that inhibition of glycolysis may be an effective strategy in chemoprevention. As such, these studies may provide new avenues for the treatment of cancer with the dithiolethione class of molecules.Support or Funding InformationNational Institutes of Health Grant T32 GM066706 (MRW)