Dicholoroacetate exerts anti-cancer activity on human renal cell carcinoma cells

Aim: Impaired mitochondrial function is a consequence of HIF1-induced overexpression of pyruvate dehydrogenase kinase (PDK) which phosphorylates and inactivates pyruvate dehydrogenase multi-enzyme complex (PDC), which converts pyruvate to acetyl-CoA for entry into the TCA cycle. Shifting cancer cells from glycolysis to - oxidative phosphorylation induces apoptosis, which is a new therapeutic strategy by utilizing PDK inhibitors. In this work, the effect of PDK inhibitor, dichloroacetate (DCA) has been investigated in Human renal carcinoma cell line. Methods: Adherent epithelium renal cell adenocarcinoma (ACHN) cells were treated with different concentrations of DCA at different time periods. Cell viability was measured by WST assay, cell-cycle profile and apoptosis were assessed by using flow cytometry. Metabolites of the cell extracts were analyzed by LC-MS/MS. Results: DCA reduced cell viability in a concentration-and time-dependent manner. Treatment with DCA induced G1 arrest and apoptosis in ACHN cells. Additionally, metabolite changes of ACHN cell line upon DCA treatments showed that lactate, citrate, N-acetylaspartate and 5-oxoproline levels, which were high in untreated cells, significantly reduced upon DCA treatment. Conclusion: Potential anti-carcinogenic effects of DCA, including inhibition of cell proliferation and growth, and induction of apoptosis, as well as the ability of markedly reducing lactate levels make this agent a promising drug candidate in renal adenocarcinomas.