Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Articles
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

    Google Scholar 

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

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

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

    Google Scholar 

  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.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Google Scholar 

  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.

    Google Scholar 

  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.

    Google Scholar 

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

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

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

    Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, The C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, 275 E. Hancock, Detroit, MI, 48201, USA

    Ghassan M. Saed PhD, Nicole M. Fletcher BS, Zhong L. Jiang MD, PhD, Husam M. Abu-Soud PhD & Michael P. Diamond MD

Authors
  1. Ghassan M. Saed PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicole M. Fletcher BS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhong L. Jiang MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Husam M. Abu-Soud PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael P. Diamond MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ghassan M. Saed PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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). https://doi.org/10.1177/1933719111411731

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719111411731

Keywords

Search

Navigation