Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지

Protective Effects of Silymarin against Doxorubicin-induced Toxicity

Cecen, E;Dost, T;Culhaci, N;Karul, A;Ergur, B;M, Birincioglu

  • Published : 20111000
⟨ Previous Next ⟩

Abstract

Objectives: The aim of the present study was to investigate the effect of silymarin on doxorubicin-induced toxicity to the rat kidney, heart, and liver. Materials and methods: A single dose of 10 mg/kg doxorubicin was injected intraperitoneally (ip) in the doxorubicin group. The silymarin group received silymarin (100 mg/kg) every other day. In the doxorubicin + silymarin group, silymarin was injected ip at 100 mg/kg dose for 5 days before doxorubicin administration (10 mg/kg, single ip injection) and then continued daily thereafter until euthanization. On the seventh day after doxorubicin injection, eight animals from each group were decapitated and liver and heart samples were obtained. The remaining eight animals of each group continued to receive silymarin every other day, till euthanized on the twenty first day. Serum was separated for determination of superoxide dismutase (SOD), glutathione perosidase (GSHPx), catalase (CAT), malondialdehyde (MDA), nitric oxide (NO), creatinine, urea, AST, ALT, lactate dehydrogenase (LDH) and creatinine phosphokinase (CPK) activities. Histopathological and electron microscopic examinations of heart, kidney and liver section were also performed. Results : Doxorubicin caused a significant increase in serum NO levels compared to controls. Silymarin pretreatment group lowered these. Histopathological and electron microscopic examinations of kidney, heart, and liver sections showed doxorubicin to cause myocardial and renal injury which was levv evident in silymarin treated rats. Conclusion(s): Results of the present study indicate that silymatin significantly protected doxorubicin-induced toxicities to the rat kidney, heart, and liver, thus suggesting its administration as a supportive care agent during anti-cancer treatment featuring doxorubicin.

Keywords

References

  1. Barry E, Alvarez JA, Scully RE, Miller TL, Lipshultz SE(2007). Anthracycline-induced cardiotoxicity: course, pathophysiology, prevention and management. Expert Opin Pharmacother, 8, 1039-58. https://doi.org/10.1517/14656566.8.8.1039
  2. Bertani T, Poggi A, Pozzoni R et al(1982). Adriamycin-induced nephrotic syndrome in rats: sequence of pathologic events. Lab Invest, 46, 16-23.
  3. Bokemeyer C, Fels LM, Dunn T et al(1996), Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity. Br J Cancer, 74, 2036-41. https://doi.org/10.1038/bjc.1996.673
  4. Boonsanit D, Kanchanapangka S, Buranakarl C (2006). L-carnitine ameliorates doxorubicin-induced nephrotis syndrome in rats. Nephrology, 11, 313-20. https://doi.org/10.1111/j.1440-1797.2006.00592.x
  5. Chen A, Sheu LF, Ho YS et al(1998). Experimental focal segmental glomerulosclerosis in mice. Nephron, 78, 440-52. https://doi.org/10.1159/000044974
  6. Cheung CW, Gibbons N, Johnson DW, Nicol DL(2010). Silibinin--a promising new treatment for cancer. Anticancer Agents Med Chem, 10, 186-95. https://doi.org/10.2174/1871520611009030186
  7. Comelli MC, Mengs U, Schneider C, Prosdocimi M (2007). Toward the definition of the mechanism of action of silymarin: activities related to cellular protection from toxic damage induced by chemotherapy. Integr Cancer Ther, 6, 120-9. https://doi.org/10.1177/1534735407302349
  8. Deman A, Ceyssens B, Pauwels M et al (2001). Altered antioxidant defence in a mouse adriamycin model of glomerulosclerosis. Nephrol Dial Transplant, 16, 147-50.
  9. Doroshow JH, Locker GY, Myers CE(1980). Enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin. J Clin Invest, 65, 128-35. https://doi.org/10.1172/JCI109642
  10. El-Shitany NA, El-Haggar S, El-desoky K (2008). Silymarin prevents adr iamycin- induced cardiotoxici ty and nephrotoxicity in rats. Food Chem Toxicol, 46, 2422-8. https://doi.org/10.1016/j.fct.2008.03.033
  11. Gaedeke J, Fels LM, Bokemeyer C et al.(1996). Cisplatin nephrotoxicity and protection by silibinin. Nephrol Dial Transplant, 11, 55-62. https://doi.org/10.1093/oxfordjournals.ndt.a027066
  12. Ganey PE, Kauffman FC, Thurman RG (1988). Oxygendependent hepatotoxicity due to doxorubicin: role of reducing equivalent supply in perfused rat liver. Mol Pharmacol, 34, 695-701.
  13. Gatta G, Capocaccia R, Coleman MP, Ries LA, Berrino F(2002). Childhood cancer survival in Europe and the United States. Cancer, 95, 1767-72. https://doi.org/10.1002/cncr.10833
  14. Giantris A, Abdurrahman L, Hinkle A, Asselin B, Lipshultz SE(1998). Anthracycline-induced cardiotoxicity in children and young adults. Crit Rev Oncol Hematol, 27, 53-68. https://doi.org/10.1016/S1040-8428(97)10007-5
  15. Grenier MA, Lipshultz SE(1998) Epidmiology of anthracycline cardiotoxicity in children and adults. Semin Oncol, 25, 72-85.
  16. Injac R, Perse M, Cerne M et al (2009). Protective effects of fullerenol C60(OH)24 against doxorubicin-induced cardiotoxicity and hepatotoxicity in rats with colorectal cancer. Biomaterials, 30, 1184-96. https://doi.org/10.1016/j.biomaterials.2008.10.060
  17. Jeyasseelan R, Poizat C, Wu HY, Kedes L(1997). Molecular mechanisms of doxorubicin-induced cardiomyopathy. Selective suppression of Reiske iron-sulfur protein, ADP/ATP translocase, and phosphofructokinase genes is associated with ATP depletion in rat cardiomyocytes. J Biol Chem, 272, 5828-32. https://doi.org/10.1074/jbc.272.9.5828
  18. Kalender Y, Yel M, Kalender S(2005). Doxorubicin hepatotoxicity and hepatic free radical metabolism in rats. The effects of vitamin E and catechin. Toxicology, 209, 39-45. https://doi.org/10.1016/j.tox.2004.12.003
  19. Karimi G, Ramezani M, Tahoonian Z (2005). Cisplatin nephrotoxicity and protection by milk thistle extract in rats. Evid Based Complement Alternat Med, 2, 383-6. https://doi.org/10.1093/ecam/neh103
  20. Keizer HG, Pinedo HM, Schuurhuis GJ, Joenje H (1990). Doxorubicin (adriamycin): a critical review of free radicaldependent mechanisms of cytotoxicity. Pharmacol Ther, 47, 219-31. https://doi.org/10.1016/0163-7258(90)90088-J
  21. Krischer JP, Epstein S, Cuthbertson DD et al (1997). Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience. J Clin Oncol, 15, 1544-52.
  22. Kroll DJ, Shaw HS, Oberlies NH (2007). Milk thistle nomenclature: why it matters in cancer research and pharmacokinetic studies. Integr Cancer Ther, 6, 110-9. https://doi.org/10.1177/1534735407301825
  23. Ladas EJ, Kroll DJ, Oberlies NH et al. (2007). A randomized controlled, double-blind, pilot study of milk thistle for the treatment of hepatotoxicity in childhood acute lymphoblastic leukemia(ALL). Cancer, 116, 506-13.
  24. Li L, Gao Y, Zhang L et al (2008). Silibinin inhibits cell growth and induces apoptosis by caspase activation, downregulating survivin and blocking EGFR-ERK activation in renal cell carcinoma. Cancer Lett, 272, 61-9. https://doi.org/10.1016/j.canlet.2008.06.033
  25. Li L, Zeng J, Gao Y, He D (2010). Targeting silibinin in the antiproliferative pathway. Expert Opin Investig Drugs, 19, 243-55. https://doi.org/10.1517/13543780903533631
  26. Lipshultz SE, Colan SD, Gelber RD et al (1991). Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Eng J Med, 324, 808-15. https://doi.org/10.1056/NEJM199103213241205
  27. Lipshultz SE, Lipsitz SR, Mone SM et al (1995). Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med, 332, 1738-43. https://doi.org/10.1056/NEJM199506293322602
  28. Lipshultz SE, Lipsitz SR, Sallan SE et al. (2005). Chronic progressive cardiac dysfunction years after doxorubicin therapy for childhood acute lymphoblastic leukemia. J Clin Oncol, 23, 2629-36.
  29. Liu LL, Li QX, Xia L, Li J, Shao L (2007). Differential effects of dihydropyridine calcium antagonists on doxorubicininduced nephrotoxicity in rats. Toxicology, 231, 81-90. https://doi.org/10.1016/j.tox.2006.11.067
  30. Liu Y, Thurman RG (1992). Potentiation of adriamycin toxicity by ethanol in perfused rat liver. J Pharmacol Exp Ther, 263, 651-6.
  31. Mansour HH, Hafez HF, Fahmy NM (2006). Silymarin modulates Cisplatin-induced oxidative stress and hepatotoxicity in rats. J Biochem Mol Biol, 39, 656-61. https://doi.org/10.5483/BMBRep.2006.39.6.656
  32. Myers C (1998). The role of iron in doxorubicin-induced cardiomyopathy. Semin Oncol, 25, 10-4.
  33. Navarro-Gonzalvez JA, Garcia-Benayas C, Arenas J (1998). Semiautomated Measurement of nitrate in biological fluids. Clin Chem, 44, 679-81.
  34. Ohkawa H, Ohishi N, Yagi K (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem, 95, 351-8. https://doi.org/10.1016/0003-2697(79)90738-3
  35. Olson RD, Mushlin PS (1990). Doxorubicin cardiotoxicity: analysis of prevailing hypotheses. FASEB J, 4, 3076-86.
  36. Paglia DE, Valentine WN (1967). Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med, 70, 158-69.
  37. Patel N, Joseph C, Corcoran GB, Ray SD (2010). Silymarin modulates doxotubicin-induced oxidative stress, Bcl-xL and p53 expression while preventing apoptotic and necrotic cell death in the liver. Toxicol Appl Pharmacol, 245, 143-52. https://doi.org/10.1016/j.taap.2010.02.002
  38. Post-White J, Ladas EJ, Kelly KM(2007). Advances in the use of milk thistle (Silybum marianum). Integr Cancer Ther, 6, 104-9. https://doi.org/10.1177/1534735407301632
  39. Pritsos CA, Ma J (2000). Basal and drug-induced antioxidant enzyme activities correlate with age-dependent doxorubicin oxidative toxicity. Chem Biol Interact, 127, 1-11. https://doi.org/10.1016/S0009-2797(00)00159-9
  40. Psotova J, Chlopcikova S, Grambal F, Simanek V, Ulrichova J (2002). Influence of silymarin and its flavonolignans on doxorubicin-iron induced lipid peroxidation in rat heart microsomes and mitochondria in comparison with quercetin. Phytother Res, 16, S63-7.
  41. Ramasamy K, Agarwal R (2008). Multitargeted therapy of cancer by silymarin. Cancer Lett, 269, 352-62. https://doi.org/10.1016/j.canlet.2008.03.053
  42. Rhoden EL, Lucas ML, Pereira-Lima L, Rhoden CR, Souto CA (2001). Effects of L-arginine on the kidney levels of malondialdehyde in rats submitted to renal ischaemiareperfusion. BJU Int, 88, 273-7. https://doi.org/10.1046/j.1464-410x.2001.02303.x
  43. Sayed-Ahmed MM, Khattab MM, Gad MZ, Osman AM (2001). Increased plasma endothelin-1 and cardiac nitric oxide during doxorubicin-induced cardiomyopathy. Pharmacol Toxicol, 89, 140-4. https://doi.org/10.1034/j.1600-0773.2001.d01-148.x
  44. Sun Y, Oberley LW, Li Y (1998). A simple method for clinical assay of superoxide dismutase. Clin Chem, 34, 497-500.
  45. Tietze F (1969). Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem, 27, 502-22. https://doi.org/10.1016/0003-2697(69)90064-5
  46. Wink DA, Cook JA, Christodoulou D et al (1997). Nitric oxide and some nitric oxide donor compounds enhance the cytotoxicity of cisplatin. Nitric Oxide, 1, 88-94. https://doi.org/10.1006/niox.1996.0108
  47. Yagmurca M, Bas O, Mollaoglu H et al (1997). Protective effects of erdosteine on doxorubicin-induced hepatotoxicity in rats. Arch Med Res, 38, 380-5.
  48. Yagmurca M, Erdogan H, Iraz M et al (2004). Caffeic acid phenethyl ester as a protective agent against doxorubicin nephrotoxicity in rats. Clin Chim Acta, 348, 27-34. https://doi.org/10.1016/j.cccn.2004.03.035
  49. Yilmaz S, Atessahin A, Sahna E, Karahan I, Ozer S (2006). Protective effect of lycopene on adriamycin-induced cardiotoxicity and nephrotoxicity. Toxicology, 218, 164-71. https://doi.org/10.1016/j.tox.2005.10.015