Molecular and Cellular Biochemistry

, Volume 273, Issue 1–2, pp 151–160 | Cite as

Combined efficacy of tamoxifen and coenzyme Q10 on the status of lipid peroxidation and antioxidants in DMBA induced breast cancer

  • Selvanathan Saravana Perumal
  • Palanivelu Shanthi
  • Panchanadham Sachdanandam


An increasing amount of experimental and epidemiological evidence implicates the involvement of oxygen derived radicals in the pathogenesis of cancer development. It is well known that chemical carcinogenesis is multistage process. Free radicals are found to be involved in both initiation and promotion of multistage carcinogenesis. Tamoxifen (TAM) is a potent antioxidant and a non-steroidal antiestrogen drug most used in the chemotherapy and chemoprevention of breast cancer. Besides its anticarcinogenic potential, it also produces some adverse toxic side effects, while taken for a long time. In order to minimise the side effects and to improve the antioxidant efficacy of tamoxifen, coenzyme Q10 (CoQ10) was added. Hence the present study was designed to investigate the combined efficacy of TAM along with CoQ10 in 7, 12 dimethyl benz(a)anthracene (DMBA) induced peroxidative damage in rat mammary carcinoma. The experimental setup comprised of one control and five experimental groups and it was carried out in adult female Sprague-Dawley rats. Mammary carcinoma was induced by oral administration of DMBA (25 mg kg−1 body wt) and the treatment was started by the oral administration of TAM (10 mg kg−1 body wt day−1) and CoQ10 (40 mg kg−1 body wt day−1) dissolved in olive oil and continued for 28 days. Rats induced with DMBA showed a decline in the thiol capacity of the cell accompanied by high malondialdehyde content levels along with lowered activities of antioxidant status (superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione). In contrast, glutathione metabolising enzymes (glutathione reductase, glucose-6-phosphate dehydrogenase and glutathione-S-transferase) were increased significantly in chemically induced carcinoma bearing rats. Administration of TAM along with CoQ10 restored the activities to a significant level thereby preventing cancer cell proliferation. This study highlights the increased antioxidant enzyme activities in relation to the susceptibility of cells to carcinogenic agents and the response of tumour cells to the chemotherapeutic agents.


antioxidants breast cancer coenzyme Q10 lipid peroxidation tamoxifen 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Cross CE, Halliwell B, Borish ET, Pryor WA, Ames BN, Saul RL, McCord JM, Harman D: Oxygen radicals and human disease. Ann Intern Med 107: 526–545, 1987PubMedGoogle Scholar
  2. 2.
    Troll W, Frenkel K, Teebor G: Free oxygen radicals necessary contributions to tumor promotion and carcinogenesis. In: H. Fukiki (ed). Cellular Interactions by Environmental Tumor Promoters. VNU Science Press, Utrecht, 1984, pp 207–210Google Scholar
  3. 3.
    Cerutti PA: Prooxidant states and tumor promotion. Science 227: 375–381, 1985PubMedGoogle Scholar
  4. 4.
    Sun Y: Free radicals, antioxidant enzymes, and carcinogenesis. Free Radic Biol Med 8: 583–599, 1990CrossRefPubMedGoogle Scholar
  5. 5.
    Michaels ML, Cruz C, Grollman AP, Miller JH: Free Radicals: Mitochondria’s worst nightmare. Proc Natl Acad Sci (USA) 89: 7022–7025, 1992Google Scholar
  6. 6.
    Halliwell B, Gutteridge JMC: Free radicals in biology and medicine. Clarendon Press, Oxford, 1985Google Scholar
  7. 7.
    Tisdales MJ : Biology of Cachexia. J Natl Cancer Inst 89: 1763–1773, 1997CrossRefPubMedGoogle Scholar
  8. 8.
    McPherson K, Steel CM, Dixon JM: ABC of the breast diseases, breast cancer epidemiology, risk factors and genetics. Br Med J 321: 624–628, 2000Google Scholar
  9. 9.
    Parton M, Dowsett M, Smith I: Studies of apoptosis in breast cancer. Br Med J 322: 1528–1532, 2001Google Scholar
  10. 10.
    Rutqvist LE, Johansson H, Signomklao T, Johansson U, Fornande T, Wilking N: Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. J Natl Cancer Inst 87: 645–651, 1995PubMedGoogle Scholar
  11. 11.
    Jordan VC: A current view of tamoxifen for the treatment and prevention of breast cancer. Br J Pharmacol 110: 507–517, 1993PubMedGoogle Scholar
  12. 12.
    Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet 351: 1451–1467, 1998Google Scholar
  13. 13.
    Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Shiu E, Fore L, Wolmark N: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90: 1371–1388, 1998CrossRefPubMedGoogle Scholar
  14. 14.
    Han X, Liehr JG: Induction of covalent DNA adducts in rodents by tamoxifen. Cancer Res 52: 1360–1363, 1992PubMedGoogle Scholar
  15. 15.
    Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM: Endometrial cancer in tamoxifen treated breast cancer patients. J Natl Cancer Inst 86: 527–537, 1994PubMedGoogle Scholar
  16. 16.
    Crane, F: The essential functions of coenzyme Q. Clinical Investigator 71: S55–S59, 1993PubMedGoogle Scholar
  17. 17.
    Ernster L: Ubiquinol: An endogenous antioxidant in aerobic organisms. Clinical Investigator 71: S60–S65, 1993PubMedGoogle Scholar
  18. 18.
    Lockwood K, Moesgaard S, Folkers K: Partial and complete regression of breast cancer in patients in relation to dosage of coenzyme Q10: Biochem Biophys Res Commun 199: 1504–1508, 1994CrossRefPubMedGoogle Scholar
  19. 19.
    Lockwood K, Moesgaard S, Yamamoto T, Folkers, K: Progress on therapy of breast cancer with vitamin Q10 and the regression of metastases. Biochem Biophys Res Commun 212(1): 172–177, 1995CrossRefPubMedGoogle Scholar
  20. 20.
    Sujatha V, Muthumanickam V, Rani G, Sachdanandam P: Effect of Semecarpus anacardium Linn. Nut extract on glucose metabolizing enzymes in experimentally induced mammary carcinoma in rats. J Pharm Pharmacol 51: 241, 1999Google Scholar
  21. 21.
    Geren RJ, Greenberg NH, McDonald MM, Schumacher AM: Protocols for screening chemical agents and natural products against animal tumours and other biological system. Cancer Chemother Rep 3: 103, 1972Google Scholar
  22. 22.
    Roberto LC, Edward WB, Jerry AP: Experimental immunotherapy of human breast carcinoma implanted in nude mice with a mixture of monoclonal antibodies against human milk fat globule components. Cancer Res 47: 532, 1987PubMedGoogle Scholar
  23. 23.
    Devasagayam TPA: Lipid peroxidation in rat uterus. Biochim Biophys Acta 876: 507–514, 1986PubMedGoogle Scholar
  24. 24.
    Marklund S, Marklund G: Involvement of superoxide anion radical in autooxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem 47: 469–474, 1974PubMedGoogle Scholar
  25. 25.
    Sinha AK: Colorimetric assay of catalase. Anal Biochem 47: 389–394, 1972PubMedGoogle Scholar
  26. 26.
    Rotruck JT, Pope L, Ganther HE, Swanson AB, Hajeman, AG, Hoekstra WG, Selenium: Biochemical role as a component of glutathione purification and assay. Science 179: 588–590, 1973PubMedGoogle Scholar
  27. 27.
    Moron MS, Despierre JW, Minnervik B: Levels of glutathione, glutathione reductase and glutathione-S-transferase activities in rat lung and liver. Biochim Biophys Acta 582: 67–78, 1979PubMedGoogle Scholar
  28. 28.
    Habig WH, Pabst UJ, Jacob WB: Glutathione-S-transferase. J Biol Chem 249: 7130–7139, 1973Google Scholar
  29. 29.
    Staal GEJ, Visser J, Veeger C: Purification and properties of glutathione reductase of human erythrocytes. Biochim Biophys Acta 185: 39–48, 1969PubMedGoogle Scholar
  30. 30.
    Beutler E: Active transport of glutathione disulfide from erythrocytes. In: A. Larson, S. Orrenius, A. Holmgren, B. Mannerwik, (eds). Functions of Glutathione-Biochemical, Physiological, Toxicological and Clinical Aspects. Raven Press, New York, 1983, p 65Google Scholar
  31. 31.
    Lowry OH, Rosebrough NJ, Farr AI, Randall RJ: Protein measurement with the Folin-phenol reagent. J Biol Chem 193: 265–275, 1951PubMedGoogle Scholar
  32. 32.
    Beauchamp C, Fridovich I: Superoxide dismutase: Improved assays and an assay applicable to acrylamide gels. Anal Biochem 44: 276–287, 1971CrossRefGoogle Scholar
  33. 33.
    Chen CN, Pan SM: Assay of superoxide dismutase activity by combining electrophoresis and densitometry. Bot Bull Acad Sin 37: 107–111, 1996Google Scholar
  34. 34.
    Woodbury W, Spencer AK, Stahmann MA: An improved procedure using ferricyanide for detecting catalase isozymes. Anal Biochem 443: 301–305, 1971CrossRefGoogle Scholar
  35. 35.
    Halliwell B, Gutteridge JMC: Role of free radicals and catalytic metal ions in human disease: An overview. Meth Enzymol 186: 1–85, 1989Google Scholar
  36. 36.
    Kensler TM, Taffe BG: Free radicals in tumour promotion. Free Rad Biol Med 2: 347–387, 1986Google Scholar
  37. 37.
    Troll W, Wiesner R: The role of oxygen radicals as a possible mechanism of tumor promotion. Ann Rev Pharmacol Toxicol 25: 509–528, 1985CrossRefGoogle Scholar
  38. 38.
    Ellis PA, Saccani-Jotti G, Clarke R, Johnston SR, Anderson E, Howell A, A’Hern R, Salter J, Detre S, Nicholson R, Robertson J, Smith IE, Dowsett M: Induction of apoptosis by tamoxifen and ICI 182780 in primary breast cancer. Int J Cancer 72: 608–613, 1997CrossRefPubMedGoogle Scholar
  39. 39.
    Arteaga CL, Osborne CK. Growth factors as mediators of estro-gen/antiestrogen action in human breast cancer cells. In: M.E.Lippman, R.B. Dickson (eds). Regulatory Mechanisms in Breast Cancer: Advances in Cellular and Molecular Biology of Breast Cancer. Kluwer Academic, Boston,1991, pp 289–304Google Scholar
  40. 40.
    Okawa H, Ohishi N, Yagi K: Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95: 351–358, 1979PubMedGoogle Scholar
  41. 41.
    Wang M, Dhingra K, Hittelman WN: Lipid peroxidation-induced putative malondialdehyde-DNA adducts in human breast cancer tissue. Cancer Epi Biom Prev 5: 705–710, 1996Google Scholar
  42. 42.
    Caporaso N: The Molecular Epidemiology of Oxidative Damage to DNA and Cancer. J Natl Cancer Inst 95: 1263–1265, 2003PubMedGoogle Scholar
  43. 43.
    Das UN: Cis-unsaturated fatty acids as potential anti-mutagenic, tumoricidal and anti-metastatic agents. Asia Pacific J Pharmacol 7: 305–327, 1992Google Scholar
  44. 44.
    Dianzani MU, Rossi MA: Lipid peroxidation in tumors. In: P. Pani, F. Feo, A. Columbano, E.S.A. Cagliari (eds), Recent Trends in Chemical Carcinogenesis. Cagliari, Italy, 1981, pp. 243–257.Google Scholar
  45. 45.
    Diplock AT, Rice-Evans K, Burdon RH: Is there a significant role for lipid peroxidation in the causation of malignancy and for antioxidants. Cancer Prevent 54: 1952–1956, 1993Google Scholar
  46. 46.
    Rossi MA: Lipid peroxidation of hepatomas of different degree of deviation. Cell Biochem Funct 1: 49–54, 1983PubMedGoogle Scholar
  47. 47.
    Thangaraju M, Vijayalakshmi T, Sachdanandam P: Effect of tamoxifen on lipid peroxide and antioxidative system in postmenopausal women with breast cancer. Cancer 74: 78–82, 1994PubMedGoogle Scholar
  48. 48.
    Custodio JB, Dinis TC, Almeida LM, Madeira VM: Tamoxifen and hydroxytamoxifen as intramembraneous inhibitors of lipid peroxidation. Evidence for peroxyl radical scavenging activity. Biochem Pharmacol, 47: 1989–1998, 1994CrossRefPubMedGoogle Scholar
  49. 49.
    Ernster L, Beyer RE: Antioxidant functions of coenzyme Q: Some biochemical and pathophysiological implications. Biomed Clin Aspects of CoQ10 6: 45–58, 1991Google Scholar
  50. 50.
    O’Brien PJ: Antioxidants and cancer. Molecular mechanism. In: D. Armstrong (ed). Free Radicals in Diagnostic Medicine. Plenum Press, New York, 1994, pp 215–239Google Scholar
  51. 51.
    Zhao Y, Xue Y, Oberley TD, Kiningham KK, Lin S, Yen H, Majima H, Hines J, St Clair DK: Overexpression of Manganese superoxide dismutase suppresses tumor formation by modulation of activator protein-1 signaling in a multistage skin carcinogenesis model. Cancer Res 61: 6082–6088, 2001PubMedGoogle Scholar
  52. 52.
    Oberley LW, Buettner GR: Role of superoxide dismutase in cancer: A review. Cancer Res 39: 1141–1149, 1979PubMedGoogle Scholar
  53. 53.
    Xu Y, Krishnan A, Wan XS, Majima H, Yeh CC, Ludewig G, Kasarskis EJ, St Clair DK: Mutations in the promoter reveal a cause for the reduced expression of the human manganese superoxide dismutase gene in cancer cells. Oncogene 18: 93–102, 1999CrossRefPubMedGoogle Scholar
  54. 54.
    Zhong W, Oberley LW, Oberley TD, St Clair DK: Suppression of the malignant phenotype of human glioma cells by overexpression of manganese superoxide dismutase. Oncogene 14: 481–490, 1997CrossRefPubMedGoogle Scholar
  55. 55.
    Daosukho C, Kiningham K, Kasarskis EJ, Ittarat W, St Clair DK: Tamoxifen enhancement of TNF-α induced MnSOD expression: Modulation of NF-κB dimerization. Oncogene 21: 3603–3610, 2002CrossRefPubMedGoogle Scholar
  56. 56.
    Fridovich, I: Oxygen toxicity: A radical explanation. J Exp Biol 201: 1203–1209, 1998PubMedGoogle Scholar
  57. 57.
    Ahmad S: Antioxidant mechanisms of enzymes and proteins. In: S. Ahmad (ed). Oxidative Stress and Antioxidant Defenses in Biology, Chapman & Hall, New York, 1995, pp 238–272Google Scholar
  58. 58.
    Murphy C, Fotsis T, Pantzar P, Adlercreutz H Martin F: Analysis of tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen levels in cytosol and KCl-nuclear extracts of breast tumours from tamoxifen treated patients by gas chromatography-mass spectrometry (GC-MS) using selected ion monitoring (SIM). J Steroid Biochem 28: 609–618, 1987CrossRefPubMedGoogle Scholar
  59. 59.
    Wiseman H, Laughton MJ Armsteinn HRV: The antioxidant action of tamoxifen and its metabolites. FEBS Lett 263: 192–194, 1990CrossRefPubMedGoogle Scholar
  60. 60.
    Jolliet P, Simon N: Plasma Co-enzyme Q10 concentration in breast cancer: Prognosis and therapeutic consequence. Int J Clin Pharm Therapeut 36: 506–509, 1998Google Scholar
  61. 61.
    Meister A: Glutathione metabolism and its selective modification. J Biol Chem 263: 17205–17208, 1988PubMedGoogle Scholar
  62. 62.
    Meister A, Anderson M: Glutathione. Ann Rev Biochem 52: 711–760, 1983CrossRefPubMedGoogle Scholar
  63. 63.
    Kirkman HN, Gaetani GF: Catalase: A tetrameric enzyme with four tightly bound molecules of NADPH. Proc Natl Acad Sci USA 81: 4343–4374, 1984PubMedGoogle Scholar
  64. 64.
    Gaetani GF, Galiano S, Canepa L, Ferraris AM, Kirkman HN: Catalase and glutathione peroxidase are equally active in detoxification of hydrogen peroxide in human erythrocytes. Blood 73: 334–339, 1989PubMedGoogle Scholar
  65. 65.
    Bray TM, Taylor CG: Tissue glutathione, nutrition and oxidative stress. Can J Physiol Pharmacol 71: 746–751, 1993PubMedGoogle Scholar
  66. 66.
    Chandra RK, Kumari S: Effects of nutrition on the immune system. Nutrition 10: 207–210, 1994PubMedGoogle Scholar
  67. 67.
    Folkers K, Shizukuishi S, Takemura K, Drzewoski J, Richardson P, Ellis J, Kuzell WC: Increase in levels of IgG in serum of patients treated with coenzyme Q10. Res Commun Chem Pathol Pharmacol 38(2): 335–338, 1982PubMedGoogle Scholar
  68. 68.
    Leibau E, Wildenburg G, Walter RD, Henkle-Duhrsen K: A novel type of glutathione S-transferase in Onchocerca volvulus. Infect Immunol 62: 4762–4767, 1994Google Scholar
  69. 69.
    Jensson H, Eriksson LC, Mannervik B: Selective expression of glutathione transferase isoenzymes in chemically induced preneoplastic rat, hepatocyte nodules. FEBS Lett 187: 115–120, 1995CrossRefGoogle Scholar
  70. 70.
    Sato K, Satoh K, Hatayama I, Tsuchida S, Soma Y, Shiratori Y, Tateoka N, Inaba Y, Kitahara A: Placental glutathione S- transferase as a marker for neoplastic tissues. In: T.J. Mantle, C.B. Pickett, J.D. Hayes (eds). Glutathione S-transferase and carcinogenesis, New York, Taylor and Francis, 1987, pp 127–137Google Scholar
  71. 71.
    Di Ilio C, Sacchetta P, Boccio GD, Rovere GL, Federici G: Glutathione peroxidase, glutathione S-transferase and glutathione reductase activities in normal and neoplastic breast tissue. Cancer Res 44: 4137–4139, 1984PubMedGoogle Scholar
  72. 72.
    Poulsen HS, Fredericksen P: Glucose-6-phosphate dehydrogenase activity in human breast cancer. Acta Pathol Microbiol Scand 89: 263–270, 1981Google Scholar
  73. 73.
    Bokun R, Bakotin J, Milasinovic D: Semiquantitative cytichemical estimation of glucose-6-phosphate dehydrogenase activity in benign diseases and carcinoma of breast. Acta Cytol 31: 249–252, 1987PubMedGoogle Scholar
  74. 74.
    Cocco P: Does G6PD deficiency protect against cancer? A critical review. J Epidemiol Community Health 41: 89–93, 1987PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Selvanathan Saravana Perumal
    • 1
  • Palanivelu Shanthi
    • 2
  • Panchanadham Sachdanandam
    • 1
    • 3
  1. 1.Department of Medical Biochemistry, Dr. A.L. Mudaliar Post-Graduate Institute of Basic Medical SciencesUniversity of MadrasChennaiIndia
  2. 2.Department of Pathology, Dr. A.L. Mudaliar Post-Graduate Institute of Basic Medical SciencesUniversity of MadrasChennaiIndia
  3. 3.Department of Medical Biochemistry, Dr. A.L.M. Post-Graduate Institute of Basic Medical SciencesUniversity of MadrasChennaiIndia

Personalised recommendations