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Pravastatin attenuates carboplatin-induced cardiotoxicity via inhibition of oxidative stress associated apoptosis

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Abstract

The objective of this study was to evaluate the cardiac toxicity induced by carboplatin, a second generation platinum-containing anti-cancer drug, and to test whether pravastatin can reduce this cardio-toxicity. In the present study, infusion of carboplatin (100 mg/kg) to mice resulted in decreased survival rates and abnormal cardiac histology, concomitant with increased cardiac apoptosis. In addition, treatment of cultured rat cardiomyocytes with carboplatin (100 μM for 48 h) caused marked apoptosis and increased caspase-3, -9, and cytochrome C, but decreased BCL-XL protein expression, and this was inhibited by reactive oxygen species (ROS) scavenger n-acetylcysteine. Furthermore, pretreatment of cardiomyocytes with pravastatin (20 μM) before carboplatin exposure significantly attenuated apoptosis and decreased caspase-3, -9, cytochrome C activity. Lastly, mice pre-treated with pravastatin before carboplatin treatment showed improved survival rate and cardiac function, with reduced cardiomyocyte apoptosis via activating Akt and restoring normal mitochondrial HAX-1 in heart tissue. In summary, our results show that carboplatin can induce cardiotoxicity in vivo and in cultured cells via a mitochondrial pathway related to ROS production, whereas pravastatin administration can reduce such oxidative stress thus prevented cardiac apoptosis. Therefore, pravastatin can be used as a cytoprotective agent prior to carboplatin chemotherapy.

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References

  1. Fujiwara K, Sakuragi N, Suzuki S et al (2003) First-line intraperitoneal carboplatin-based chemotherapy for 165 patients with epithelial ovarian carcinoma: results of long term follow up. Gynecol Oncol 90:637–643

    Article  PubMed  CAS  Google Scholar 

  2. Pivot X, Cals L, Cupissol D et al (2001) Phase II trial of a paclitaxel–carboplatin combination in recurrent squamous cell carcinoma of head and neck. Oncology 60:66–71

    Article  PubMed  CAS  Google Scholar 

  3. Alberts DS (1995) Carboplatin versus cisplatin in ovarian cancer. Semin Oncol 22:88–90

    PubMed  CAS  Google Scholar 

  4. Husain K, Scott RB, Whitworth C et al (2001) Dose response of carboplatin-induced hearing loss in rats: antioxidant defense system. Hear Res 151:71–78

    Article  PubMed  CAS  Google Scholar 

  5. Tiersten A, Wo J, Jacobson C et al (2004) Cardiac toxicity observed in association with high-dose cyclophosphamide-based chemotherapy for metastatic breast cancer. Breast 13:341–346

    Article  PubMed  Google Scholar 

  6. Husain K, Whitworth C, Hazelrigg S, Rybak L (2003) Carboplatin-induced oxidative injury in rat inferior colliculus. Int J Toxicol 22:335–342

    Article  PubMed  CAS  Google Scholar 

  7. Dhalla AK, Hill MF, Singal PK (1996) Role of oxidative stress in transition of hypertrophy to heart failure. J Am Coll Cardiol 28:506–514

    Article  PubMed  CAS  Google Scholar 

  8. Bergmann MW, Rechner C, Freund C et al (2004) Statins inhibit reoxygenation-induced cardiomyocyte apoptosis: role for glycogen synthase kinase 3b and transcription factor b-catenin. J Mol Cell Cardiol 37:681–690

    Article  PubMed  CAS  Google Scholar 

  9. Hayashidani S, Tsutsui H, Shiomi T et al (2002) Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation 105:868–873

    Article  PubMed  CAS  Google Scholar 

  10. Yao HW, Mao LG, Zhu JP (2006) Protective effects of pravastatin in murine lipopolysaccharide-induced acute lung injury. Clin Exp Pharmacol Physiol 33:793–797

    Article  PubMed  CAS  Google Scholar 

  11. Fujio Y, Nguyen T, Wencker D et al (2002) Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart. Circulation 101:660–667

    Google Scholar 

  12. Lin H, Lin TN, Cheung WM et al (2002) Cyclooxygenase-1 and bicistronic cyclooxygenase-1/prostacyclin synthase gene transfer protect against ischemic cerebral infarction. Circulation 105:1962–1969

    Article  PubMed  CAS  Google Scholar 

  13. Piech A, Dessy C, Havaux X, Feron O, Balligand JJ (2003) Differential regulation of nitric oxide synthases and their allosteric regulators in heart and vessels of hypertensive rats. Cardiovasc Res 57:456–467

    Article  PubMed  CAS  Google Scholar 

  14. Han Y, Chen YS, Liu Z et al (2006) Overexpression of HAX-1 protects cardiac myocytes from apoptosis through caspase-9 inhibition. Circ Res 99:415–423

    Article  PubMed  CAS  Google Scholar 

  15. Vafiadaki E, Sanoudou D, Arvanitis DA et al (2007) Phospholaban interacts with HAX-1, a mitochondrial protein with anti-apoptotic function. J Mol Biol 367:65–79

    Article  PubMed  CAS  Google Scholar 

  16. Husain K, Whitworth C, Somani SM, Rybak LP (2001) Carboplatin-induced oxidative stress in rat cochlea. Hear Res 159:14–22

    Article  PubMed  CAS  Google Scholar 

  17. Zver S, Zadnik V, Bunc M, Rogel P, Cernelc P, Kozelj M (2007) Cardiac toxicity of high-dose cyclophosphamide in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation. Int J Hematol 85:408–414

    Article  PubMed  CAS  Google Scholar 

  18. Meinardi MT, van Veldhuisen DJ, Gietema JA et al (2001) Prospective evaluation of early cardiac damage induced by epirubicin-containing adjuvant chemotherapy and locoregional radiotherapy in breast cancer patients. J Clin Oncol 19:2746–2753

    PubMed  CAS  Google Scholar 

  19. Ide T, Tsutsui H, Kinugawa S et al (1999) Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ Res 85:357–363

    PubMed  CAS  Google Scholar 

  20. Spallarossa P, Garibaldi S, Altieri P et al (2004) Carvedilol prevents doxorubicin-induced free radical release and apoptosis in cardiomyocytes in vitro. J Mol Cell Cardiol 37:837–846

    Article  PubMed  CAS  Google Scholar 

  21. Ferdinandy P, Danial H, Ambrus I et al (2000) Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res 87:241–247

    PubMed  CAS  Google Scholar 

  22. Kang PM, Haunstetter A, Aoki H et al (2000) Morphological and molecular characterization of adult cardiomyocyte apoptosis during hypoxia and reoxygenation. Circ Res 87:118–125

    PubMed  CAS  Google Scholar 

  23. Suzuki Y, Demoliere C, Kitamura D et al (1997) HAX-1, a novel intracellular protein, localized on mitochondria, directly associates with HS1, a substrate of Src family tyrosine kinases. J Immunol 158:2736 2744

    PubMed  CAS  Google Scholar 

  24. Wang H, Li M, Rinehart JJ, Zhang R (2004) Pretreatment with dexamethasone increases antitumor activity of carboplatin and gemcitabine in mice bearing human cancer xenografts: in vivo activity, pharmacokinetics, and clinical implications for cancer chemotherapy. Clin Cancer Res 10:1633–1644

    Article  PubMed  CAS  Google Scholar 

  25. Boughattas NA, Levi F, Fournier C et al (1990) Stable circadian mechanisms of toxicity of two platinum analogs (cisplatin and carboplatin) despite repeated dosages in mice. J Pharmacol Exp Ther 255:672–679

    PubMed  CAS  Google Scholar 

  26. Wang H, Li M, Rinehart JJ, Zhang R (2004) Dexamethasone as a chemoprotectant in cancer chemotherapy: hematoprotective effects and altered pharmacokinetics and tissue distribution of carboplatin and gemcitabine. Cancer Chemother Pharmacol 53:459–467

    Article  PubMed  CAS  Google Scholar 

  27. Iseri S, Ercan F, Gedik N, Yuksel M, Alican I (2007) Simvastatin attenuates cisplatin-induced kidney and liver damage in rats. Toxicology 12:256–264

    Article  CAS  Google Scholar 

  28. Damrot J, Nubel T, Epe B, Roos WP, Kaina B, Fritz G (2006) Lovastatin protects human endothelial cells from the genotoxic and cytotoxic effects of the anticancer drugs doxorubicin and etoposide. Br J Pharmacol 149:988–997

    Article  PubMed  CAS  Google Scholar 

  29. Yamato M, Watanabe T, Higuchi K et al (2007) Anti-inflammatory effects of pravastatin on helicobacter pylori-induced gastritis in mice. Dig Dis Sci 52:2833–2839

    Article  PubMed  CAS  Google Scholar 

  30. Yao HW, Mao LG, Zhu JP (2006) Protective effects of pravastatin in murine lipopolysaccharide-induced acute lung injury. Clin Exp Pharmacol Physiol 33:793–797

    Article  PubMed  CAS  Google Scholar 

  31. Kozar K, Kaminski R, Legat M et al (2004) Cerivastatin demonstrates enhanced antitumor activity against human breast cancer cell lines when used in combination with doxorubicin or cisplatin. Int J Oncol 24:1149–1157

    PubMed  CAS  Google Scholar 

  32. Cafforio P, Dammacco F, Gernone A, Silvestris F (2005) Stains activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells. Carcinogenesis 26:883–891

    Article  PubMed  CAS  Google Scholar 

  33. Werner M, Sacher J, Hohenegger M (2004) Mutual amplification of apoptosis by statin-induced mitochondrial stress and doxorubicin toxicity in human rhabdomyosarcoma cells. Br J Pharmacol 143:715–724

    Article  PubMed  CAS  Google Scholar 

  34. Weis M, Heeschen C, Glassford AJ, Cooke JP (2002) Statins have biphasic effects on angiogenesis. Circulation 105:739–745

    Article  PubMed  CAS  Google Scholar 

  35. Feleszko W, Mlynarczuk I, Bakowiec-Iskra EZ et al (2000) Lovastatin potentiates antitumor activity and attenuates cardiotoxicity of doxorubicin in three tumor models in mice. Clin Cancer Res 6:2044–2052

    PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by a grant (NSC 94-2314-B-303-009) from National Science Council to C.-F. Cheng. The authors have no competing financial interests to disclose regarding this manuscript.

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Grant support (NSC 94-2314-B-303-009) from National Science Council, Taiwan to C.-F. Cheng.

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Correspondence to Heng Lin.

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Ching-Feng Cheng and Shu-Hui Juan contributed equally to the work.

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Cheng, CF., Juan, SH., Chen, JJ. et al. Pravastatin attenuates carboplatin-induced cardiotoxicity via inhibition of oxidative stress associated apoptosis. Apoptosis 13, 883–894 (2008). https://doi.org/10.1007/s10495-008-0214-9

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  • DOI: https://doi.org/10.1007/s10495-008-0214-9

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