Combination of Metformin and Dichloroacetate Inhibits Proliferation and Induce Intrinsic Pathway of Apoptosis in PC-3 Human Prostate Cancer Cells
AbstractObjective: 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.
Rider JR, Sandin F, Andrén O, et al. Long-term outcomes among noncuratively treated men according to prostate cancer risk category in a nationwide, population-based study. Eur Urol. 2013; 63: 88-96.
Graham GG, Punt J, Arora M et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011; 50: 81-98.
Quinn BJ, Kitagawa H, Memmott RM, et al. Repositioning metformin for cancer prevention and treatment. Trends Endocrinol Metab. 2013; 24: 469–80.
Würth R, Pattarozzi A, Gatti M et al. Metformin selectively affects human glioblastoma tumor-initiating cell viability: A role for metformin-induced inhibition of Akt. Cell Cycle. 2013; 12: 145–56.
Jones NP, Schulze A. Targeting cancer metabolism -aiming at a tumour's sweet-spot. Drug Discov Today. 2012; 17: 232–41.
Riedmaier AE, Fisel P, Nies AT, et al. Metformin and cancer: from the old medicine cabinet to pharmacological pitfalls and prospects. Trends Pharmacol Sci. 2013; 34: 126–35.
Rattan R, Rouba AF, Munkarah A. Metformin: An Emerging New Therapeutic Option for Targeting Cancer Stem Cells and Metastasis. J Oncol. 2012; 2012:928127.
Kumar A, Kant S, Singh SM. Novel molecular mechanisms of antitumor action of dichloroacetate against T cell lymphoma: Implication of altered glucose metabolism, pH homeostasis and cell survival regulation. Chem Biol Interact. 2012; 199: 29-37.
Michelakis ED, Webster L, Mackey JR, Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br. J. Cancer 2008; 99: 989–94.
Haugrud AB, Zhuang Y, Coppock JD, Miskimins MK. Dichloroacetate enhances apoptotic cell death via oxidative damage and attenuates lactate production in metformin-treated breast cancer cells. Breast Cancer Res Treat. 2014; 147: 539-50.
Stockwin LH, Yu SX, Borgel S, et al. Sodium dichloroacetate selectively targets cells with defects in the mitochondrial ETC. Int J Cancer. 2010; 127: 2510-9.
Kasznicki J, Sliwinska A, Drzewoski J. Metformin in cancer prevention and therapy. Ann Transl Med. 2014; 2(6): 57.
Zakikhani M, Dowling R, Fantus IG, et al. Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res 2006; 66: 10269–73.
Isakovic A, Harhaji L, Stevanovic D, et al. Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis. Cell Mol Life Sci 2007; 64: 1290–302.
Buzzai M, Jones RG, Amaravadi RK, et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 2007; 67: 6745–52.
Wigfield SM, Winter SC, Giatromanolaki A, et al. PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer. Br J Cancer 2008; 98: 1975–84.
Andersen LW, Mackenhauer J, Roberts JC, et al. Etiology and therapeutic approach to elevated lactate levels. Mayo Clin Proc. 2013; 88: 1127-40.
Bonnet S, Archer SL, Allalunis-Turner J, et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007; 11: 37-51.
McIlwain DR, Berger T, Mak TW. Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol. 2013; 5: a008656.
Hyman BT, Yuan J. Apoptotic and non apoptotic roles of caspases in neuronal physiology and pathophysiology. Nat Rev Neurosci 2012; 13: 395 406.
Ben Sahra I, Laurent K, Loubat A, et al. The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level. Oncogene. 2008; 27: 3576-86.
Choi YW, Lim IK. Sensitization of metformin-cytotoxicity by dichloroacetate via reprogramming glucose metabolism in cancer cells. Cancer Lett. 2014; 346: 300-8.
All opinions and reports within the articles that are published in the Gazi Medical Journal are the personal opinions of author(s). Gazi University, Editors and the publisher do not accept any responsibility for these articles. The journal is printed on acid-free paper.