Dichloroacetate Induces Apoptosis of Epithelial Ovarian Cancer Cells Through a Mechanism Involving Modulation of Oxidative Stress


Epithelial ovarian cancer (EOC) cells are under intrinsic oxidative stress, which alters metabolic activity and reduces apoptosis. Key oxidative stress enzymes, including myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS), are upregulated and colocalized in EOC cells. Oxidative stress is also regulated, in part, by superoxide dismutase (SOD) and hypoxia-inducible factor (HIF) 1a. Dichloroacetate (DCA) converts anaerobic to aerobic metabolism and thus was utilized to determine the effects on apoptosis, iNOS, MPO, extracellular SOD (SOD-3), and HIF-1a, in EOC cells. Protein and messenger RNA (mRNA) levels of iNOS, MPO, SOD-3, and HIF-1a were evaluated by immunoprecipitation/Western blot and real-time reverse transcriptase-polymerase chain reaction (RT-PCR), respectively, utilizing SKOV-3 and MDAH-2774 treated with DCA. Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and caspase 3 assays. Dichloroacetate induced apoptosis, reduced MPO, iNOS, and HIF-1a, whereas increased SOD, in both EOC cell lines. In conclusion, reduction of enhanced oxidative stress-induced apoptosis of EOC cells, which may serve as future therapeutic intervention for ovarian cancer.

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  1. 1.

    Barakat RR, Markman M, Randall M. Principles and Practice of Gynecologic Oncology. 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2009.

  2. 2.

    Flora SJ. Role of free radicals and antioxidants in health and disease. Cell Mol Biol (Noisy-le-grand). 2007;53(1):1–2.

  3. 3.

    Wiseman H, Halliwell B. Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J. 1996;313(Pt 1):17–29.PMCID: 1216878.

  4. 4.

    Li H, Fan X, Houghton J. Tumor microenvironment: the role of the tumor stroma in cancer. J Cell Biochem. 2007;101(4):805–815.

  5. 5.

    Saed GM, Ali-Fehmi R, Jiang ZL, et al. Myeloperoxidase serves as a redox switch that regulates apoptosis in epithelial ovarian cancer. Gynecol Oncol. 2010;116(2):276–281.

  6. 6.

    Motoo Y, Shimasaki T, Ishigaki Y, Nakajima H, Kawakami K, Minomoto T. Metabolic disorder, inflammation, and deregulated molecular pathways converging in pancreatic cancer development: implications for new therapeutic strategies. Cancers. 2011;3(1):446–460.

  7. 7.

    Ozben T. Oxidative stress and apoptosis: impact on cancer therapy. J Pharm Sci. 2007;96(9):2181–2196.

  8. 8.

    Gibellini L, Pinti M, Nasi M, et al. Interfering with ROS metabolism in cancer cells: the potential role of quercetin. Cancers. 2010(2):1288–1311.

  9. 9.

    Pelicano H, Carney D, Huang P. ROS stress in cancer cells and therapeutic implications. Drug Resist Updat. 2004;7(2):97–110.

  10. 10.

    Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 2010;49(11):1603–1616.PMCID: 2990475.

  11. 11.

    Zelko IN, Mariani TJ, Folz RJ. Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Rad Biol Med. 2002;33(3):337–349.

  12. 12.

    Michelakis ED, Webster L, Mackey JR. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer. 2008;99(7):989–994. PMCID: 2567082.

  13. 13.

    Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell. 2008;13(6):472–482.

  14. 14.

    Fang J, Seki T, Maeda H. Therapeutic strategies by modulating oxygen stress in cancer and inflammation. Adv Drug Deliv Rev. 2009;61(4):290–302.

  15. 15.

    Virgili F, Marino M. Regulation of cellular signals from nutritional molecules: a specific role for phytochemicals, beyond antioxidant activity. Free Radic Biol Med. 2008;45(9):1205–1216.

  16. 16.

    Surh YJ, Kundu JK, Na HK, Lee JS. Redox-sensitive transcription factors as prime targets for chemoprevention with antiinflammatory and antioxidative phytochemicals. J Nutr. 2005;135(12 suppl):2993S-3001S.

  17. 17.

    Kato M, Li J, Chuang JL, Chuang DT. Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol. Structure. 2007;15(8):992–1004. PMCID: 2871385.

  18. 18.

    Diamond MP, El-Hammady E, Wang R, Saed G. Regulation of matrix metalloproteinase-1 and tissue inhibitor of matrix metalloproteinase-1 by dichloroacetic acid in human fibroblasts from normal peritoneum and adhesions. Fertil Steril. 2004;81(1):185–190.

  19. 19.

    Saed GM, Diamond MP. Modulation of the expression of tissue plasminogen activator and its inhibitor by hypoxia in human peritoneal and adhesion fibroblasts. Fertil Steril. 2003;79(1):164–168.

  20. 20.

    Suh YA, Arnold RS, Lassegue B, et al. Cell transformation by the superoxide-generating oxidase Mox1. Nature. 1999;401(6748):79–82.

  21. 21.

    Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4(11):891–899.

  22. 22.

    Geiszt M, Kopp JB, Varnai P, Leto TL. Identification of renox, an NAD(P)H oxidase in kidney. Proc Natl Acad Sci USA. 2000;97(14):8010–8014. PMCID: 16661.

  23. 23.

    Nemoto S, Takeda K, Yu ZX, Ferrans VJ, Finkel T. Role for mitochondrial oxidants as regulators of cellular metabolism. Mol Cell Biol. 2000;20(19):7311–7318. PMCID: 86285.

  24. 24.

    Banerjee S, Randeva H, Chambers AE. Mouse models for preeclampsia: disruption of redox-regulated signaling. Reprod Biol Endocrinol. 2009;7:4. PMCID: 2632643.

  25. 25.

    Tapia PC. Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction, intermittent fasting, exercise and dietary phytonutrients: “Mitohormesis” for health and vitality. Med Hypotheses. 2006;66(4):832–843.

  26. 26.

    Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011;11(2):85–95.

  27. 27.

    Kinnula VL, Crapo JD. Superoxide dismutases in malignant cells and human tumors. Free Radic Biol Med. 2004;36(6):718–744.

  28. 28.

    Tandon V, Sharma S, Mahajan A, Bardi G. Oxidative stress: a novel strategy in cancer treatment. JK Sci. 2005;7(1):56.

  29. 29.

    Hileman EO, Liu J, Albitar M, Keating MJ, Huang P. Intrinsic oxidative stress in cancer cells: a biochemical basis for therapeutic selectivity. Cancer Chemother Pharmacol. 2004;53(3):209–219.

  30. 30.

    Bhosle SM, Pandey BN, Huilgol NG, Mishra KP. Membrane oxidative damage and apoptosis in cervical carcinoma cells of patients after radiation therapy. Methods Cell Sci. 2002;24(1–3):65–68.

  31. 31.

    Huang P, Feng L, Oldham EA, Keating MJ, Plunkett W. Superoxide dismutase as a target for the selective killing of cancer cells. Nature. 2000;407(6802):390–395.

  32. 32.

    Storz P. Reactive oxygen species in tumor progression. Front Biosci. 2005;10:1881–1896.

  33. 33.

    Fleischauer AT, Olson SH, Mignone L, Simonsen N, Caputo TA, Harlap S. Dietary antioxidants, supplements, and risk of epithelial ovarian cancer. Nutr Cancer. 2001;40(2):92–98.

  34. 34.

    Schuurman AG, Goldbohm RA, Brants HA, van den Brandt PA. A prospective cohort study on intake of retinol, vitamins C and E, and carotenoids and prostate cancer risk (Netherlands). Cancer Causes Control. 2002;13(6):573–582.

  35. 35.

    Moriya K, Nakagawa K, Santa T, et al. Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res. 2001;61(11):4365–4370.

  36. 36.

    Semenza GL, Roth PH, Fang HM, Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem. 1994;269(38):23757–23763.

  37. 37.

    Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3(3):177–185.

  38. 38.

    Stacpoole PW, Kerr DS, Barnes C, et al. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics. 2006;117(5):1519–1531.

  39. 39.

    Stacpoole PW, Gilbert LR, Neiberger RE, et al. Evaluation of long-term treatment of children with congenital lactic acidosis with dichloroacetate. Pediatrics. 2008;121(5):el223–el228.

  40. 40.

    Berendzen K, Theriaque DW, Shuster J, Stacpoole PW. Therapeutic potential of dichloroacetate for pyruvate dehydrogenase complex deficiency. Mitochondrion. 2006;6(3):126–135.

  41. 41.

    Sun RC, Fadia M, Dahlstrom JE, Parish CR, Board PG, Blackburn AC. Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat. 2010;120(1):253–260.

  42. 42.

    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(1):37–51.

  43. 43.

    Dhar S, Lippard SJ. Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate. Proc Natl Acad Sci U S A. 2009;106(52):22199–22204. PMCID: 2799774.

  44. 44.

    Plas DR, Thompson CB. Cell metabolism in the regulation of programmed cell death. Trends Endocrinol Metab. 2002;13(2):75–78.

  45. 45.

    Kim JW, Dang CV. Multifaceted roles of glycolytic enzymes. Trends Biochem Sci. 2005;30(3):142–150.

  46. 46.

    Kim JW, Dang CV. Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res. 2006;66(18):8927–8930.

  47. 47.

    Xu RH, Pelicano H, Zhou Y, et al. Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res. 2005;65(2):613–621.

  48. 48.

    Stacpoole PW. The pharmacology of dichloroacetate. Metabolism. 1989;38(11): 1124–1144.

  49. 49.

    Sugden MC, Holness MJ. Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs. Am J Physiol Endocrinol Metab. 2003;284(5):E855–E862.

  50. 50.

    Howlett RA, Heigenhauser GJ, Hultman E, Hollidge-Horvat MG, Spriet LL. Effects of dichloroacetate infusion on human skeletal muscle metabolism at the onset of exercise. Am J Physiol. 1999;277(1 Pt 1):E18–E25.

  51. 51.

    Parolin ML, Spriet LL, Hultman E, et al. Effects of PDH activation by dichloroacetate in human skeletal muscle during exercise in hypoxia. Am J Physiol Endocrinol Metab. 2000;279(4):E752–E761.

  52. 52.

    Beckman KB, Ames BN. The free radical theory of aging matures. Physiol Rev. 1998;78(2):547–581.

  53. 53.

    Choi JY, Neuhouser ML, Barnett MJ, et al. Iron intake, oxidative stress-related genes (MnSOD and MPO) and prostate cancer risk in CARET cohort. Carcinogenesis. 2008;29(5):964–970. PMCID: 2902382.

  54. 54.

    Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–867. PMCID: 2803035.

  55. 55.

    Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000;408(6809):239–247.

  56. 56.

    Galijasevic S, Saed GM, Diamond MP, Abu-Soud HM. Myeloperoxidase up-regulates the catalytic activity of inducible nitric oxide synthase by preventing nitric oxide feedback inhibition. Proc Natl Acad Sci USA. 2003;100(25):14766–14771.

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Correspondence to Ghassan M. Saed PhD.

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Saed, G.M., Fletcher, N.M., Jiang, Z.L. et al. Dichloroacetate Induces Apoptosis of Epithelial Ovarian Cancer Cells Through a Mechanism Involving Modulation of Oxidative Stress. Reprod. Sci. 18, 1253–1261 (2011) doi:10.1177/1933719111411731

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  • epithelial ovarian cancer
  • dichloroacetate
  • real-time RT-PCR
  • apoptosis
  • oxidative stress