Hyperglycemia Regulates MDR-1, Drug Accumulation and ROS Levels Causing Increased Toxicity of Carboplatin and 5-Fluorouracil in MCF-7 Cells

There is constant increase in number of diabetic cases thereby giving it status of a serious epidemic. Diabetes increases the risk of occurrence of several cancers including breast cancer and may also have a serious impact on the outcome of cancer treatment. In the present study we investigated effect of hyperglycemia on cytotoxic efficacy of carboplatin and 5-fluorouracil in MCF-7 cells. MCF-7 cells were grown in 5.5 or 25 mM glucose chronically. We show that hyperglycemia favors proliferation of MCF-7 cells and increases expression of cell cycle regulatory proteins cyclin E and cdk-2. Hyperglycemia enhances cytotoxicity of carboplatin and 5-fluorouracil in MCF-7 cells by approximately 30% and decreases their IC50 by 1.5- and 1.3-folds, respectively. Hyperglycemia reduces expression of P-glycoprotein and promotes cell killing by increasing drug accumulation. Treatment with 40 mu M verapamil, an inhibitor of P-gp activity specifically increases killing of MCF-7 cells cultured in 5.5 mM glucose. Further, this effect is synergized by elevated reactive oxygen species and treatment with N-Acetylcysteine, an inhibitor of ROS, increases survival by 30 and 18% in carboplatin-and 5-fluorouracil-treated cells cultured in high glucose, respectively. Cytotoxicity of these drugs is associated with reduced activation of Akt and decreased transcriptional activation of NF-kappa B. In conclusion, hyperglycemia potentiates cytotoxicity of drugs by reducing P-gp expression and, increased ROS levels may partially or completely contribute to enhanced toxicity. J. Cell. Biochem. 112: 2942-2952, 2011. (C) 2011 Wiley-Liss, Inc.