Hepatoprotective effect of simvastatin in mice with DMBA-induced breast cancer: Histopathological, biochemical and antioxidant status evaluation
DOI:
https://doi.org/10.15419/bmrat.v5i3.421Keywords:
Breast cancer, Liver, Mice, SimvastatinAbstract
Introduction: This study evaluates the effects of simvastatin on the liver, in a mouse model of DMBA-induced breast cancer, with regards to histopathological, biochemical and antioxidant features.
Methods: Mice were randomly divided into two groups: A (control group) and B (mammary tumor group); the latter group received DMBA (50 mg/kg) by oral gavage once a week for 4 consecutive weeks. Animals positive for breast cancer tumors were randomly divided into 3 subgroups: 1) no treatment group (D1), 2) mice that received simvastatin (80 mg/kg) per os (P.O.) daily for 4 consecutive weeks (D2), and 3) mice that received tamoxifen (50 mg/kg) P.O. daily for 4 consecutive weeks (D3).
Results: Administration of simvastatin to D2 mice resulted in significantly higher superoxide dismutase (SOD) activity as well as glutathione peroxidase (GPx) activity and total antioxidant capacity (TAC), and accompanied by reduced malondialdehyde (MDA) content in liver as compared to D1 group. Tamoxifen significantly increased liver glutathione (GSH) content as compared to D1 mice. Moreover, MDA levels in liver of mice treated with tamoxifen were significantly lower than in the D1 group. Mice in the D1 group showed significantly increased levels of alkaline phosphatase (ALP), aspartate transaminase (AST), and gamma-glutamyl transferase (GGT) in liver tissues; these levels were significantly reduced by simvastatin administration. Moreover, tamoxifen decreased ALP and AST activities. Histopathological examination of liver sections from mice in the D1 group showed severe deteriorative changes. The extent and severity of changes in D2 and D3 groups were almost the same and milder than D1 group.
Conclusion: In conclusion, simvastatin appears to have a hepatoprotective role in mice with DMBA-induced breast cancer, due partly to its antioxidant properties.
References
Arca, M., & Pigna, G. (2011). Treating statin-intolerant patients. Diabetes, Metabolic Syndrome and Obesity, 4, 155–166. https://doi.org/10.2147/DMSO.S11244 PMID:21779147
Armitage, J. (2007). The safety of statins in clinical practice. Lancet, 370(9601), 1781–1790. https://doi.org/10.1016/S0140-6736(07)60716-8 PMID:17559928
Arulkumaran, S., Ramprasath, V. R., Shanthi, P., & Sachdanandam, P. (2007). Alteration of DMBA-induced oxidative stress by additive action of a modified indigenous preparation—Kalpaamruthaa. Chemico-Biological Interactions, 167(2), 99–106. https://doi.org/10.1016/j.cbi.2007.01.013 PMID:17349985
Benzie, I. F., & Strain, J. J. (1996). The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: The FRAP assay. Analytical Biochemistry, 239(1), 70–76. https://doi.org/10.1006/abio.1996.0292 PMID:8660627
Björnsson, E. S. (2017). Hepatotoxicity of statins and other lipid‐lowering agents. Liver International, 37(2), 173-178.
Bosch, J., & Forns, X. (2015). Therapy. Statins and liver disease: From concern to ‘wonder’ drugs? Nature Reviews. Gastroenterology & Hepatology, 12(6), 320–321. https://doi.org/10.1038/nrgastro.2015.78 PMID:25963509
Calderon, R. M., Cubeddu, L. X., Goldberg, R. B., & Schiff, E. R. (2010). Statins in the treatment of dyslipidemia in the presence of elevated liver aminotransferase levels: A therapeutic dilemma. Mayo Clinic Proceedings, 85(4), 349–356. https://doi.org/10.4065/mcp.2009.0365 PMID:20360293
Charles, E. C., Olson, K. L., Sandhoff, B. G., McClure, D. L., & Merenich, J. A. (2005). Evaluation of cases of severe statin-related transaminitis within a large health maintenance organization. The American Journal of Medicine, 118(6), 618–624. https://doi.org/10.1016/j.amjmed.2005.02.008 PMID:15922693
Cederbaum, A. I., Lu, Y., & Wu, D. (2009). Role of oxidative stress in alcohol-induced liver injury. Archives of Toxicology, 83(6), 519–548. https://doi.org/10.1007/s00204-009-0432-0 PMID:19448996
Ching, C. K., Smith, P. G., & Long, R. G. (1992). Tamoxifen-associated hepatocellular damage and agranulocytosis. Lancet, 339(8798), 940. https://doi.org/10.1016/0140-6736(92)90991-B PMID:1348345
Choi, J., & Ou, J. H. (2006). Mechanisms of liver injury. III. Oxidative stress in the pathogenesis of hepatitis C virus. American Journal of Physiology. Gastrointestinal and Liver Physiology, 290(5), G847–G851. https://doi.org/10.1152/ajpgi.00522.2005 PMID:16603728
Currier, N., Solomon, S. E., Demicco, E. G., Chang, D. L., Farago, M., Ying, H., . . . Seldin, D. C. (2005). Oncogenic signaling pathways activated in DMBA-induced mouse mammary tumors. Toxicologic Pathology, 33(6), 726–737. https://doi.org/10.1080/01926230500352226 PMID:16263698
Dakrory, A. I., Fahmy, S. R., Soliman, A. M., Mohamed, A. S., & Amer, S. A. (2015). Protective and curative effects of the sea cucumber Holothuria atra extract against DMBA-induced hepatorenal diseases in rats. BioMed Research International, 2015, 563652. https://doi.org/10.1155/2015/563652 PMID:25821811
Gazzerro, P., Proto, M. C., Gangemi, G., Malfitano, A. M., Ciaglia, E., Pisanti, S., . . . Bifulco, M. (2012). Pharmacological actions of statins: A critical appraisal in the management of cancer. Pharmacological Reviews, 64(1), 102–146. https://doi.org/10.1124/pr.111.004994 PMID:22106090
Habeos, I. G., Ziros, P. G., Chartoumpekis, D., Psyrogiannis, A., Kyriazopoulou, V., & Papavassiliou, A. G. (2008). Simvastatin activates Keap1/Nrf2 signaling in rat liver. Journal of Molecular Medicine, 86(11), 1279–1285. https://doi.org/10.1007/s00109-008-0393-4 PMID:18787804
Hu, M., Cheung, B. M., & Tomlinson, B. (2012). Safety of statins: An update. Therapeutic Advances in Drug Safety, 3(3), 133–144. https://doi.org/10.1177/2042098612439884 PMID:25083232
Ip, C., & Lisk, D. J. (1997). Modulation of phase I and phase II xenobiotic-metabolizing enzymes by selenium-enriched garlic in rats. Nutrition and Cancer, 28(2), 184–188. https://doi.org/10.1080/01635589709514573 PMID:9290126
Izzotti, A., Camoirano, A., Cartiglia, C., Grubbs, C. J., Lubet, R. A., Kelloff, G. J., & De Flora, S. (1999). Patterns of DNA adduct formation in liver and mammary epithelial cells of rats treated with 7,12-dimethylbenz(a)anthracene, and selective effects of chemopreventive agents. Cancer Research, 59(17), 4285–4290. PMID:10485473
Kalantari, S., & Naghipour, M. (2014). Statin therapy and hepatotoxicity: Appraisal of the safety profile of atorvastatin in hyperlipidemic patients. Advanced Biomedical Research, 3(1), 168–178. https://doi.org/10.4103/2277-9175.139133 PMID:25221771
Khyade, V. B. (2017). Influence of Sibinin on DMBA Induced Hepatotoxicity and Free-Radical Damage in Norwegian Rat, Rattus norvegicus (L). International Journal of Current Microbiology and Applied Sciences, 6(1), 324–338. https://doi.org/10.20546/ijcmas.2017.601.040
Kumar, R., Kaur, R., Singh, A. P., & Arora, S. (2014). Diminution of hepatic response to 7, 12-dimethylbenz(α)anthracene by ethyl acetate fraction of Acacia catechu willd. through modulation of xenobiotic and anti-oxidative enzymes in rats. PLoS One, 9(2), e90083. https://doi.org/10.1371/journal.pone.0090083 PMID:24587216
Leaver, H., Keng Lim, T., Thomson, P., Leaver, J., Choy, A. M., & Lang, C. C. (2009). Compliance to recommended liver function monitoring in patients on statin therapy. Cardiovascular Therapeutics, 27(2), 96–100. https://doi.org/10.1111/j.1755-5922.2009.00082.x PMID:19426246
Liu, B., Yi, Z., Guan, X., Zeng, Y. X., & Ma, F. (2017). The relationship between statins and breast cancer prognosis varies by statin type and exposure time: A meta-analysis. Breast Cancer Research and Treatment, 164(1), 1–11. https://doi.org/10.1007/s10549-017-4246-0 PMID:28432513
Mulder, A. B., van Lijf, H. J., Bon, M. A., van den Bergh, F. A., Touw, D. J., Neef, C., & Vermes, I. (2001). Association of polymorphism in the cytochrome CYP2D6 and the efficacy and tolerability of simvastatin. Clinical Pharmacology and Therapeutics, 70(6), 546–551. https://doi.org/10.1067/mcp.2001.120251 PMID:11753271
Nelson, H. D., Smith, M. E., Griffin, J. C., & Fu, R. (2013). Use of medications to reduce risk for primary breast cancer: A systematic review for the U.S. Preventive Services Task Force. Annals of Internal Medicine, 158(8), 604–614. https://doi.org/10.7326/0003-4819-158-8-201304160-00005 PMID:23588749
Ohkawa, H., Ohishi, N., & Yagi, K. (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry, 95(2), 351–358. https://doi.org/10.1016/0003-2697(79)90738-3 PMID:36810
Pan, H. J., Chang, H. T., & Lee, C. H. (2016). Association between tamoxifen treatment and the development of different stages of nonalcoholic fatty liver disease among breast cancer patients. Journal of the Formosan Medical Association, 115(6), 411–417. https://doi.org/10.1016/j.jfma.2015.05.006 PMID:26071793
Pradelli, D., Soranna, D., Scotti, L., Zambon, A., Catapano, A., Mancia, G., . . . Corrao, G. (2013). Statins and primary liver cancer: A meta-analysis of observational studies. European Journal of Cancer Prevention, 22(3), 229–234. https://doi.org/10.1097/CEJ.0b013e328358761a PMID:23010949
Rao, G. A., & Pandya, P. K. (2011). Statin therapy improves sustained virologic response among diabetic patients with chronic hepatitis C. Gastroenterology, 140(1), 144–152. https://doi.org/10.1053/j.gastro.2010.08.055 PMID:20833169
Robinson, S. P., Langan-Fahey, S. M., & Jordan, V. C. (1989). Implications of tamoxifen metabolism in the athymic mouse for the study of antitumor effects upon human breast cancer xenografts. European Journal of Cancer & Clinical Oncology, 25(12), 1769–1776. https://doi.org/10.1016/0277-5379(89)90347-7 PMID:2632258
Stancu, C., & Sima, A. (2001). Statins: Mechanism of action and effects. Journal of Cellular and Molecular Medicine, 5(4), 378–387. https://doi.org/10.1111/j.1582-4934.2001.tb00172.x PMID:12067471
Wang, W., Zhao, C., Zhou, J., Zhen, Z., Wang, Y., & Shen, C. (2013). Simvastatin ameliorates liver fibrosis via mediating nitric oxide synthase in rats with non-alcoholic steatohepatitis-related liver fibrosis. PLoS One, 8(10), e76538. https://doi.org/10.1371/journal.pone.0076538 PMID:24098525
Armitage, J. (2007). The safety of statins in clinical practice. Lancet, 370(9601), 1781–1790. https://doi.org/10.1016/S0140-6736(07)60716-8 PMID:17559928
Arulkumaran, S., Ramprasath, V. R., Shanthi, P., & Sachdanandam, P. (2007). Alteration of DMBA-induced oxidative stress by additive action of a modified indigenous preparation—Kalpaamruthaa. Chemico-Biological Interactions, 167(2), 99–106. https://doi.org/10.1016/j.cbi.2007.01.013 PMID:17349985
Benzie, I. F., & Strain, J. J. (1996). The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: The FRAP assay. Analytical Biochemistry, 239(1), 70–76. https://doi.org/10.1006/abio.1996.0292 PMID:8660627
Björnsson, E. S. (2017). Hepatotoxicity of statins and other lipid‐lowering agents. Liver International, 37(2), 173-178.
Bosch, J., & Forns, X. (2015). Therapy. Statins and liver disease: From concern to ‘wonder’ drugs? Nature Reviews. Gastroenterology & Hepatology, 12(6), 320–321. https://doi.org/10.1038/nrgastro.2015.78 PMID:25963509
Calderon, R. M., Cubeddu, L. X., Goldberg, R. B., & Schiff, E. R. (2010). Statins in the treatment of dyslipidemia in the presence of elevated liver aminotransferase levels: A therapeutic dilemma. Mayo Clinic Proceedings, 85(4), 349–356. https://doi.org/10.4065/mcp.2009.0365 PMID:20360293
Charles, E. C., Olson, K. L., Sandhoff, B. G., McClure, D. L., & Merenich, J. A. (2005). Evaluation of cases of severe statin-related transaminitis within a large health maintenance organization. The American Journal of Medicine, 118(6), 618–624. https://doi.org/10.1016/j.amjmed.2005.02.008 PMID:15922693
Cederbaum, A. I., Lu, Y., & Wu, D. (2009). Role of oxidative stress in alcohol-induced liver injury. Archives of Toxicology, 83(6), 519–548. https://doi.org/10.1007/s00204-009-0432-0 PMID:19448996
Ching, C. K., Smith, P. G., & Long, R. G. (1992). Tamoxifen-associated hepatocellular damage and agranulocytosis. Lancet, 339(8798), 940. https://doi.org/10.1016/0140-6736(92)90991-B PMID:1348345
Choi, J., & Ou, J. H. (2006). Mechanisms of liver injury. III. Oxidative stress in the pathogenesis of hepatitis C virus. American Journal of Physiology. Gastrointestinal and Liver Physiology, 290(5), G847–G851. https://doi.org/10.1152/ajpgi.00522.2005 PMID:16603728
Currier, N., Solomon, S. E., Demicco, E. G., Chang, D. L., Farago, M., Ying, H., . . . Seldin, D. C. (2005). Oncogenic signaling pathways activated in DMBA-induced mouse mammary tumors. Toxicologic Pathology, 33(6), 726–737. https://doi.org/10.1080/01926230500352226 PMID:16263698
Dakrory, A. I., Fahmy, S. R., Soliman, A. M., Mohamed, A. S., & Amer, S. A. (2015). Protective and curative effects of the sea cucumber Holothuria atra extract against DMBA-induced hepatorenal diseases in rats. BioMed Research International, 2015, 563652. https://doi.org/10.1155/2015/563652 PMID:25821811
Gazzerro, P., Proto, M. C., Gangemi, G., Malfitano, A. M., Ciaglia, E., Pisanti, S., . . . Bifulco, M. (2012). Pharmacological actions of statins: A critical appraisal in the management of cancer. Pharmacological Reviews, 64(1), 102–146. https://doi.org/10.1124/pr.111.004994 PMID:22106090
Habeos, I. G., Ziros, P. G., Chartoumpekis, D., Psyrogiannis, A., Kyriazopoulou, V., & Papavassiliou, A. G. (2008). Simvastatin activates Keap1/Nrf2 signaling in rat liver. Journal of Molecular Medicine, 86(11), 1279–1285. https://doi.org/10.1007/s00109-008-0393-4 PMID:18787804
Hu, M., Cheung, B. M., & Tomlinson, B. (2012). Safety of statins: An update. Therapeutic Advances in Drug Safety, 3(3), 133–144. https://doi.org/10.1177/2042098612439884 PMID:25083232
Ip, C., & Lisk, D. J. (1997). Modulation of phase I and phase II xenobiotic-metabolizing enzymes by selenium-enriched garlic in rats. Nutrition and Cancer, 28(2), 184–188. https://doi.org/10.1080/01635589709514573 PMID:9290126
Izzotti, A., Camoirano, A., Cartiglia, C., Grubbs, C. J., Lubet, R. A., Kelloff, G. J., & De Flora, S. (1999). Patterns of DNA adduct formation in liver and mammary epithelial cells of rats treated with 7,12-dimethylbenz(a)anthracene, and selective effects of chemopreventive agents. Cancer Research, 59(17), 4285–4290. PMID:10485473
Kalantari, S., & Naghipour, M. (2014). Statin therapy and hepatotoxicity: Appraisal of the safety profile of atorvastatin in hyperlipidemic patients. Advanced Biomedical Research, 3(1), 168–178. https://doi.org/10.4103/2277-9175.139133 PMID:25221771
Khyade, V. B. (2017). Influence of Sibinin on DMBA Induced Hepatotoxicity and Free-Radical Damage in Norwegian Rat, Rattus norvegicus (L). International Journal of Current Microbiology and Applied Sciences, 6(1), 324–338. https://doi.org/10.20546/ijcmas.2017.601.040
Kumar, R., Kaur, R., Singh, A. P., & Arora, S. (2014). Diminution of hepatic response to 7, 12-dimethylbenz(α)anthracene by ethyl acetate fraction of Acacia catechu willd. through modulation of xenobiotic and anti-oxidative enzymes in rats. PLoS One, 9(2), e90083. https://doi.org/10.1371/journal.pone.0090083 PMID:24587216
Leaver, H., Keng Lim, T., Thomson, P., Leaver, J., Choy, A. M., & Lang, C. C. (2009). Compliance to recommended liver function monitoring in patients on statin therapy. Cardiovascular Therapeutics, 27(2), 96–100. https://doi.org/10.1111/j.1755-5922.2009.00082.x PMID:19426246
Liu, B., Yi, Z., Guan, X., Zeng, Y. X., & Ma, F. (2017). The relationship between statins and breast cancer prognosis varies by statin type and exposure time: A meta-analysis. Breast Cancer Research and Treatment, 164(1), 1–11. https://doi.org/10.1007/s10549-017-4246-0 PMID:28432513
Mulder, A. B., van Lijf, H. J., Bon, M. A., van den Bergh, F. A., Touw, D. J., Neef, C., & Vermes, I. (2001). Association of polymorphism in the cytochrome CYP2D6 and the efficacy and tolerability of simvastatin. Clinical Pharmacology and Therapeutics, 70(6), 546–551. https://doi.org/10.1067/mcp.2001.120251 PMID:11753271
Nelson, H. D., Smith, M. E., Griffin, J. C., & Fu, R. (2013). Use of medications to reduce risk for primary breast cancer: A systematic review for the U.S. Preventive Services Task Force. Annals of Internal Medicine, 158(8), 604–614. https://doi.org/10.7326/0003-4819-158-8-201304160-00005 PMID:23588749
Ohkawa, H., Ohishi, N., & Yagi, K. (1979). Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry, 95(2), 351–358. https://doi.org/10.1016/0003-2697(79)90738-3 PMID:36810
Pan, H. J., Chang, H. T., & Lee, C. H. (2016). Association between tamoxifen treatment and the development of different stages of nonalcoholic fatty liver disease among breast cancer patients. Journal of the Formosan Medical Association, 115(6), 411–417. https://doi.org/10.1016/j.jfma.2015.05.006 PMID:26071793
Pradelli, D., Soranna, D., Scotti, L., Zambon, A., Catapano, A., Mancia, G., . . . Corrao, G. (2013). Statins and primary liver cancer: A meta-analysis of observational studies. European Journal of Cancer Prevention, 22(3), 229–234. https://doi.org/10.1097/CEJ.0b013e328358761a PMID:23010949
Rao, G. A., & Pandya, P. K. (2011). Statin therapy improves sustained virologic response among diabetic patients with chronic hepatitis C. Gastroenterology, 140(1), 144–152. https://doi.org/10.1053/j.gastro.2010.08.055 PMID:20833169
Robinson, S. P., Langan-Fahey, S. M., & Jordan, V. C. (1989). Implications of tamoxifen metabolism in the athymic mouse for the study of antitumor effects upon human breast cancer xenografts. European Journal of Cancer & Clinical Oncology, 25(12), 1769–1776. https://doi.org/10.1016/0277-5379(89)90347-7 PMID:2632258
Stancu, C., & Sima, A. (2001). Statins: Mechanism of action and effects. Journal of Cellular and Molecular Medicine, 5(4), 378–387. https://doi.org/10.1111/j.1582-4934.2001.tb00172.x PMID:12067471
Wang, W., Zhao, C., Zhou, J., Zhen, Z., Wang, Y., & Shen, C. (2013). Simvastatin ameliorates liver fibrosis via mediating nitric oxide synthase in rats with non-alcoholic steatohepatitis-related liver fibrosis. PLoS One, 8(10), e76538. https://doi.org/10.1371/journal.pone.0076538 PMID:24098525
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Hepatoprotective effect of simvastatin in mice with DMBA-induced breast cancer: Histopathological, biochemical and antioxidant status evaluation. (2018). Biomedical Research and Therapy, 5(3), 2064-2077. https://doi.org/10.15419/bmrat.v5i3.421
