Inhibition of Glutamate Cysteine Ligase Activity Sensitizes Human Breast Cancer Cells to the Toxicity of 2-Deoxy-d-Glucose

Kelly K. Andringa, Mitchell C. Coleman, Nukhet Aykin-Burns, Michael J. Hitchler, Susan A. Walsh, Frederick E. Domann, Douglas R. Spitz
2006 Cancer Research  
It has been hypothesized that cancer cells increase glucose metabolism to protect against metabolic fluxes of hydroperoxides via glutathione-dependent peroxidases. 2-Deoxy-D-glucose, inhibits glucose metabolism and has been shown to cause cytotoxicity in cancer cells that is partially mediated by disruptions in thiol metabolism. In the current study, human breast cancer cells were continuously treated (24 hours) with 2-deoxy-D-glucose, and total glutathione content as well as the expression of
more » ... he first enzyme in the glutathione synthetic pathway [glutamate cysteine ligase (GCL)] were found to be induced 2.0-fold. Inhibiting GCL activity during 2-deoxy-Dglucose exposure using L-buthionine-[S ,R]-sulfoximine (BSO) significantly enhanced the cytotoxic effects of 2-deoxy-Dglucose and caused increases in endpoints indicative of oxidative stress, including % oxidized glutathione and steadystate levels of pro-oxidants as assayed using an oxidationsensitive fluorescent probe. These results show that treatment of human breast cancer cells with 2-deoxy-D-glucose causes metabolic oxidative stress that is accompanied by increases in steady-state levels of GCL mRNA, GCL activity, and glutathione content. Furthermore, inhibition of 2-deoxy-D-glucosemediated induction of GCL activity with BSO increases endpoints indicative of oxidative stress and sensitizes cancer cells to 2-deoxy-D-glucose-induced cytotoxicity. These results support the hypothesis that drug combinations capable of inhibiting both glucose and hydroperoxide metabolism may provide an effective biochemical strategy for sensitizing human cancer cells to metabolic oxidative stress. (Cancer Res 2006; 66(3): 1605-10)
doi:10.1158/0008-5472.can-05-3462 pmid:16452219 fatcat:abkqdpmnyfhwplbxdxugyunaeq