Combination of Metformin and Dichloroacetate Inhibits Proliferation and Induce Intrinsic Pathway of Apoptosis in PC-3 Human Prostate Cancer Cells

Objective: Prostate cancer is one of the most common cancers in men and is the second leading cause of male cancer deaths after lung cancer. Activation of apoptosis is an important process to overcome prostate cancer. In this study, we investigated the synergistic anti-proliferative and apoptotic effects of metformin and dichloroacetate (DCA) in human prostate cancer cell line PC-3. Methods: PC-3 cells were cultured in plate before being exposed to different concentrations of unaccompanied metformin and DCA as well as metformin and DCA combination. Cell proliferation and viability were investigated with WST-1 assay. After the protein isolation from control and treated cells, whole cell lysate was used for determining caspase-3, -8 and -9 activation by western blotting method. Results: Our results demonstrated that both drugs were found effective for inhibiting cell proliferation. This inhibition effect was markedly enhanced with a low-dose 30mM DCA plus metformin (2.5mM) combination treatment. Our western blot results showed that caspase-3 and -9 were activated after the combination treatment, but caspase-8 was not activated, which suggests that intrinsic apoptosis pathway was activated by DCA and metformin in PC-3 cells. Conclusion: Metformin and DCA combinations demonstrated growth inhibiting effects on PC-3 prostate cancer cells with inhibition of cell proliferation and increased apoptosis by caspase activation. By the application of combined doses of these drugs, inhibition of viability and proliferation occurred at lower doses in cells. Further research work should be performed in order to further investigate these promising agents as therapeutics and adjuvant substances for prostate cancer.