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The role of antioxidants in the era of cardio-oncology

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Abstract

Although most chemotherapeutic drugs have the potential to exert cardiotoxicity, these drugs have been chosen for use in cancer treatment because survival and curability benefits outweigh the risk of these complications. Anthracyclines, for example, are a powerful class of chemotherapeutic agents; however, their use is restricted by dose-related cardiotoxicity. Experimental evidence strongly supports the role of reactive oxygen species in this process, suggesting that antioxidants may be effective in protecting the heart from toxicity. Clinical use of antioxidants to protect the heart during anthracycline chemotherapy has been controversial due to the potential for reduced cytotoxic efficacy toward cancer cells. Results from randomized clinical trials addressing whether antioxidants either reduce the incidence of clinical heart failure among patients undergoing anthracycline-based chemotherapy or reduce the response rates to anthracycline-based chemotherapy have been unclear. While anthracyclines are by far the most well-studied antitumor agents with cardiotoxic properties, evidence now shows that reactive oxygen species may play roles in cardiotoxicity induced by other chemotherapeutic agents such as cyclophosphamide, cisplatin, 5-fluorouracil, and trastuzumab. Thus, in the new era of combination therapy and long-term survival of cancer patients, the use of antioxidants to support cancer therapy should be revisited.

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References

  1. Aird KM, Allensworth JL, Batinic-Haberle I, Lyerly HK, Dewhirst MW, Devi GR (2012) ErbB1/2 tyrosine kinase inhibitor mediates oxidative stress-induced apoptosis in inflammatory breast cancer cells. Breast Cancer Res Treat 132:109–119

    Article  PubMed  CAS  Google Scholar 

  2. Al-Majed AA, Sayed-Ahmed MM, Al-Yahya AA, Aleisa AM, Al-Rejaie SS, Al-Shabanah OA (2006) Propionyl-l-carnitine prevents the progression of cisplatin-induced cardiomyopathy in a carnitine-depleted rat model. Pharmacol Res 53:278–286

    Article  PubMed  CAS  Google Scholar 

  3. Albini A, Pennesi G, Donatelli F, Cammarota R, De Flora S, Noonan DM (2010) Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. J Natl Cancer Inst 102:14–25

    Article  PubMed  CAS  Google Scholar 

  4. Alter P, Herzum M, Soufi M, Schaefer JR, Maisch B (2006) Cardiotoxicity of 5-fluorouracil. Cardiovasc Hematol Agents Med Chem 4:1–5

    Article  PubMed  CAS  Google Scholar 

  5. Asiri YA (2010) Probucol attenuates cyclophosphamide-induced oxidative apoptosis, p53 and Bax signal expression in rat cardiac tissues. Oxid Med Cell Longev 3:308–316

    Article  PubMed  Google Scholar 

  6. Bates DA, Winterbourn CC (1982) Deoxyribose breakdown by the adriamycin semiquinone and H2O2: evidence of hydroxyl radical participation. FEBS Lett 145:137–142

    Article  PubMed  CAS  Google Scholar 

  7. Berrazzoli C, Sala L, Tosana MG (1975) Antagonistic action of ubiquinone on the experimental cardiotoxicity of adriamycin in the isolated rabbit heart. Int Res Commun Syst Med Sci 3:342–367

    Google Scholar 

  8. Bjelogrlic SK, Radic J, Jovic V, Radulovic S (2005) Activity of d, l-alpha-tocopherol (vitamin E) against cardiotoxicity induced by doxorubicin and doxorubicin with cyclophosphamide in mice. Basic Clin Pharmacol Toxicol 97:311–319

    Article  PubMed  CAS  Google Scholar 

  9. Buyukokuroglu ME, Taysi S, Buyukavci M, Bakan E (2004) Prevention of acute adriamycin cardiotoxicity by dantrolene in rats. Hum Exp Toxicol 23:251–256

    Article  PubMed  CAS  Google Scholar 

  10. Buzdar AU, Legha SS, Tashima CK, Hortobagyi GN, Yap HY, Krutchik AN, Luna MA, Blumenschein GR (1978) Adriamycin and mitomycin C: possible synergistic cardiotoxicity. Cancer Treat Rep 62:1005–1008

    PubMed  CAS  Google Scholar 

  11. Cervantes A, Pinedo HM, Lankelma J, Schuurhuis CJ (1988) The role of oxygen-derived free radicals in the cytotoxicity of doxorubicin in multidrug resistant and sensitive human ovarian cancer cells. Cancer Lett 41:169–177

    Article  PubMed  CAS  Google Scholar 

  12. Chabner BA, Bertino J, Cleary J, Ortiz T, Lane A, Supko JG, Ryan D (2011) Chapter 61. Cytotoxic agents. In: Brunton LL, Chabner BA, Knollmann BC (eds) Goodman & Gilman’s the pharmacological basis of therapeutics, 12th edn. McGraw-Hill, New York

    Google Scholar 

  13. Cortes EP, Gupta M, Chou C, Amin VC, Folker K (1978) Adriamycin cardiotoxicity: early detection by systolic time interval and possible prevention by coenzyme Q. Cancer Treat Rep 62:887–892

    PubMed  CAS  Google Scholar 

  14. Dogan I, Cumaoglu A, Aricioglu A, Ekmekci A (2011) Inhibition of ErbB2 by herceptin reduces viability and survival, induces apoptosis and oxidative stress in Calu-3 cell line. Mol Cell Biochem 347:41–51

    Article  PubMed  CAS  Google Scholar 

  15. Doroshow JH, Locker GY, Myers CE (1980) Enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin. J Clin Invest 65:128–135

    Article  PubMed  CAS  Google Scholar 

  16. Durak I, Karaayvaz M, Kavutcu M, Cimen MY, Kaçmaz M, Büyükkoçak S, Oztürk HS (2000) Reduced antioxidant defense capacity in myocardial tissue from guinea pigs treated with 5-fluorouracil. J Toxicol Environ Health A 59:585–589

    Article  PubMed  CAS  Google Scholar 

  17. DuVernay VH Jr, Pachter JA, Crooke ST (1979) Deoxyribonucleic acid binding studies on several new anthracycline antitumor antibiotics. Sequence preference and structure activity relationships of marcellomycin and its analogues as compared to adriamycin. Biochemistry 18:4024–4030

    Article  PubMed  CAS  Google Scholar 

  18. Early Breast Cancer Trials Collaborative Group (EBCTCG) (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomized trials. Lancet 365:1687–1717

    Article  Google Scholar 

  19. El-Awady el-SE, Moustafa YM, Abo-Elmatty DM, Radwan A (2011) Cisplatin-induced cardiotoxicity: mechanisms and cardioprotective strategies. Eur. J. Pharmacol 650:335–341

    Google Scholar 

  20. Eliot H, Gianni L, Myers C (1984) Oxidative destruction of DNA by the adriamycin-iron complex. Biochemistry 23:928–936

    Article  PubMed  CAS  Google Scholar 

  21. Feliz V, Saiyad S, Ramarao SM, Khan H, Leonelli F, Guglin M (2011) Melphalan-induced supraventricular tachycardia: incidence and risk factors. Clin Cardiol 34:356–359

    Article  PubMed  Google Scholar 

  22. Gallegos-Castorena S, Martínez-Avalos A, Mohar-Betancourt A, Guerrero-Avendaño G, Zapata-Tarrés M, Medina-Sansón A (2007) Toxicity prevention with amifostine in pediatric osteosarcoma patients treated with cisplatin and doxorubicin. Pediatr Hematol Oncol 24:403–408

    Article  PubMed  CAS  Google Scholar 

  23. Geetha A, Sankar R, Marar T, Devi CS (1990) Alpha-tocopherol reduces doxorubicin-induced toxicity in rats histological and biochemical evidences. Ind JPhysiol Pharmacol 34:94–100

    CAS  Google Scholar 

  24. Gewirtz DA (1999) A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol 57:727–741

    Article  PubMed  CAS  Google Scholar 

  25. Goormaghtigh E, Huart P, Brasseur R, Ruysschaert JM (1990) Structure of the adriamycin-cardiolipin complex. Role in mitochondrial toxicity. Biophys Chem 35:247–257

    Article  PubMed  CAS  Google Scholar 

  26. Gordon LI, Burke MA, Singh AT, Prachand S, Lieberman ED, Sun L, Naik TJ, Prasad SV, Ardehali H (2009) Blockade of the erbB2 receptor induces cardiomyocyte death through mitochondrial and reactive oxygen species-dependent pathways. J Biol Chem 284:2080–2087

    Article  PubMed  CAS  Google Scholar 

  27. Gottdiener JS, Appelbaum FR, Ferrans VJ, Deisseroth A, Ziegler J (1981) Cardiotoxicity associated with high-dose cyclophosphamide therapy. Arch Intern Med 141:758–763

    Article  PubMed  CAS  Google Scholar 

  28. Hahn T, Bradley-Dunlop DJ, Hurley LH, Von-Hoff D, Gately S, Mary DL, Lu H, Penichet ML, Besselsen DG, Cole BB, Meeuwsen T, Walker E, Akporiaye ET (2011) The vitamin E analog, alpha-tocopheryloxyacetic acid enhances the anti-tumor activity of trastuzumab against HER2/neu-expressing breast cancer. BMC Cancer 11:471

    Article  PubMed  CAS  Google Scholar 

  29. Halliwell B, Gutteridge J (1985) Free radicals in biology and medicine. Oxford University Press, Oxford

    Google Scholar 

  30. Herman E, Ardalan B, Bier C, Waravdekar V (1979) Reduction of daunorubicin lethality and myocardial cellular alterations by pretreatment with ICRF-187 in Syrian golden hamsters. Cancer Treat Rep 63:89–92

    PubMed  CAS  Google Scholar 

  31. Herman EH, Ferrans VJ (1981) Reduction of chronic doxorubicin cardiotoxicity in dogs by pretreatment with (+/−)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187). Cancer Res 41:3436–3440

    PubMed  CAS  Google Scholar 

  32. Herman EH, Ferrans VJ (1983) Influence of vitamin E and ICRF-187 on chronic doxorubicin cardiotoxicity in miniature swine. Lab Invest 49:69–77

    PubMed  CAS  Google Scholar 

  33. Husken BC, de Jong J, Beekman B, Onderwater RC, Van der Vijgh WJ, Bast A (1995) Modulation of the in vitro cardiotoxicity of doxorubicin by flavonoids. Cancer Chemother Pharmacol 37:55–62

    Article  PubMed  CAS  Google Scholar 

  34. Hussein A, Ahmed AA, Shouman SA, Sharawy S (2012) Ameliorating effect of DL-α-lipoic acid against cisplatin-induced nephrotoxicity and cardiotoxicity in experimental animals. Drug Discov Ther 6:147–156

    PubMed  CAS  Google Scholar 

  35. Iarussi D, Auricchio U, Agretto A, Murano A, Giuliano M, Casale F, Indolfi P, Iacono A (1994) Protective effect of coenzyme Q10 on anthracyclines cardiotoxicity: control study in children with acute lymphoblastic leukemia and non-Hodgkin lymphoma. Mol Aspects Med 15:s207–s212

    Article  PubMed  Google Scholar 

  36. Iliskovic N, Hasinoff BB, Malisza KL, Li T, Danelisen I, Singal PK (1999) Mechanism of beneficial effects of probucol in adriamycin cardiomyopathy. Mol Cell Biochem 196:43–49

    Article  PubMed  CAS  Google Scholar 

  37. Judy WV, Hall JM, Dugan W, Toth PD, Folkers K (1984) Coenzyme Q10 reduction of adriamycin cardiotoxicity. In: Folkers K, Yamamura Y (eds) Biomedical and clinical aspects of coenzyme Q, vol 4. Elsevier, Amsterdam, pp 231–240

    Google Scholar 

  38. Kalay N, Basar E, Ozdogru I, Er O, Cetinkaya Y, Dogan A, Inanc T, Oguzhan A, Eryol NK, Topsakal R, Ergin A (2006) Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol 48:2258–2262

    Article  PubMed  CAS  Google Scholar 

  39. Kandylis K, Vassilomanolakis M, Tsoussis S, Efremidis AP (1989) Ifosfamide cardiotoxicity in humans. Cancer Chemother Pharmacol 24:395–396

    Article  PubMed  CAS  Google Scholar 

  40. Keefe DL (2002) Trastuzumab-associated cardiotoxicity. Cancer 95:1592–1600

    Article  PubMed  CAS  Google Scholar 

  41. Shan K, Lincoff AM, Young JB (1996) Anthracycline-induced cardiotoxicity. Ann Intern Med 125:47–58

    Article  PubMed  CAS  Google Scholar 

  42. Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA (1973) A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer 32:302–314

    Article  PubMed  CAS  Google Scholar 

  43. Keizer HG, Pinedo HM, Schuurhuis GJ, Joenje H (1990) Doxorubicin (adriamycin): a critical review of free radical dependent mechanisms of cytotoxicity. Pharmacol Ther 47:219–231

    Article  PubMed  CAS  Google Scholar 

  44. Kinhult S, Albertsson M, Eskilsson J, Cwikiel M (2003) Effects of probucol on endothelial damage by 5-fluorouracil. Acta Oncol 42:304–308

    Article  PubMed  CAS  Google Scholar 

  45. Kumar D, Kirshenbaum LA, Li T, Danelisen I, Singal PK (2001) Apoptosis in adriamycin cardiomyopathy and its modulation by probucol. Antioxid Redox Signal 3:135–145

    Article  PubMed  CAS  Google Scholar 

  46. Lamberti M, Porto S, Marra M, Zappavigna S, Grimaldi A, Feola D, Pesce D, Naviglio S, Spina A, Sannolo N, Caraglia M (2012) 5-Fluorouracil induces apoptosis in rat cardiocytes through intracellular oxidative stress. J Exp Clin Cancer Res 31:60

    Article  PubMed  CAS  Google Scholar 

  47. Li T, Singal PK (2000) Adriamycin-induced early changes in myocardial antioxidant enzymes and their modulation by probucol. Circulation 102:2105–2110

    Article  PubMed  CAS  Google Scholar 

  48. Lipshultz SE, Rifai N, Dalton VM, Levy DE, Silverman LB, Lipsitz SR, Colan SD, Asselin BL, Barr RD, Clavell LA, Hurwitz CA, Moghrabi A, Samson Y, Schorin MA, Gelber RD, Sallan SE (2004) The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 351:145–153

    Article  PubMed  CAS  Google Scholar 

  49. Lissoni P, Barni S, Mandalà M, Ardizzoia A, Paolorossi F, Vaghi M, Longarini R, Malugani F, Tancini G (1999) Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. Eur J Cancer 35:1688–1692

    Article  PubMed  CAS  Google Scholar 

  50. Lopez M, Vici P, Di Lauro K, Conti F, Paoletti G, Ferraironi A, Sciuto R, Giannarelli D, Maini CL (1998) Randomized prospective clinical trial of high-dose epirubicin and dexrazoxane in patients with advanced breast cancer and soft tissue sarcomas. J Clin Oncol 16:86–92

    PubMed  CAS  Google Scholar 

  51. Lubawy WC, Whaley J, Hurley LH (1979) Coenzyme Q10 or alpha-tocopherol reduces the acute toxicity of anthramycin in mice. Res Commun Chem Pathol Pharmacol 24:401–404

    PubMed  CAS  Google Scholar 

  52. Maher J, Yamamoto M (2010) The rise of antioxidant signaling—the evolution and hormetic actions of Nrf2. Toxicol Appl Pharmacol 244:4–15

    Article  PubMed  CAS  Google Scholar 

  53. Mao SJ, Yates MT, Rechtin AE, Jackson RL, Van Sickle WA (1991) Antioxidant activity of probucol and its analogues in hypercholesterolemic Watanabe rabbits. J Med Chem 34:298–302

    Article  PubMed  CAS  Google Scholar 

  54. Marty M, Espie M, Llombart A, Monnier A, Rapoport BL, Stahalova V (2006) Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Ann Oncol 17:614–622

    Article  PubMed  CAS  Google Scholar 

  55. Matsui H, Morishima I, Numaguchi Y, Toki Y, Okumura K, Hayakawa T (1999) Protective effects of carvedilol against doxorubicin-induced cardiomyopathy in rats. Life Sci 65:1265–1274

    Article  PubMed  CAS  Google Scholar 

  56. Milei J, Boveris A, Llesuy S, Molina HA, Storino R, Ortega D, Milei SE (1986) Amelioration of adriamycin- induced cardiotoxicity in rabbits by prenylamine and vitamins A and E. Am Heart J 111:95–102

    Article  PubMed  CAS  Google Scholar 

  57. Minotti G, Salvatorelli E, Menna P (2010) Pharmacological foundations of cardio-oncology. J Pharmacol Exp Ther 334:2–8

    Article  PubMed  CAS  Google Scholar 

  58. Myers CE, Bonow R, Palmeri S, Jenkins J, Corden C, Locke C, Doroshow J, Epstein SA (1983) A randomized controlled trial assessing the prevention of doxorubicin cardiomyopathy by N-acetylcysteine. Semin Oncol 10:53–55

    PubMed  CAS  Google Scholar 

  59. Myers CE, McGuire WP, Liss KH, Ifrim I, Grotzinger K, Young RC (1977) Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response. Science 197:165–167

    Article  PubMed  CAS  Google Scholar 

  60. Myers CE, Mcguire W, Young R (1976) Adriamycin: amelioration of toxicity by α-tocopherol. Cancer Treat Rep 60:961–962

    PubMed  CAS  Google Scholar 

  61. Mythili Y, Sudharsan PT, Amudha G, Varalakshmi P (2007) Effect of DL-alpha-lipoic acid on cyclophosphamide induced lysosomal changes in oxidative cardiotoxicity. Life Sci 80:1993–1998

    Article  PubMed  CAS  Google Scholar 

  62. Mythili Y, Sudharsan PT, Sudhahar V, Varalakshmi P (2006) Protective effect of DL-alpha-lipoic acid on cyclophosphamide induced hyperlipidemic cardiomyopathy. Eur J Pharmacol 543:92–96

    Article  PubMed  CAS  Google Scholar 

  63. Nhata R, Esteva FJ (2003) HER-2-targeted therapy—lessons learned and future directions. Clin Cancer Res 9:5078–5084

    Google Scholar 

  64. Oliveira PJ, Bjork JA, Santos MS, Leino RL, Froberg MK, Moreno AJ, Wallace KB (2004) Carvedilol-mediated antioxidant protection against doxorubicin-induced cardiac mitochondrial toxicity. Toxicol Appl Pharmacol 200:159–168

    Article  PubMed  CAS  Google Scholar 

  65. O’Malley FP, Chia S, Tu D, Shepherd LE, Levine MN, Bramwell VH, Andrulis IL, Pritchard KI (2009) Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst 101:644–650

    Article  PubMed  Google Scholar 

  66. Ozturk M, Ozler M, Kurt YG, Ozturk B, Uysal B, Ersoz N, Yasar M, Demirbas S, Kurt B, Acikel C, Oztas Y, Arpaci F, Topal T, Ozet A, Ataergin S, Kuzhan O, Oter S, Korkmaz A (2011) Efficacy of melatonin, mercaptoethyl guanidine and 1400 W in doxorubicin- and trastuzumab-induced cardiotoxicity. J Pineal Res 50:89–96

    Article  PubMed  CAS  Google Scholar 

  67. Pai VB, Nahata MC (2000) Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf 22:263–302

    Article  PubMed  CAS  Google Scholar 

  68. Pentassuglia L, Timolati F, Seifriz F, Abudukadier K, Suter TM, Zuppinger C (2007) Inhibition of ErbB2/neuregulin signaling augments paclitaxel-induced cardiotoxicity in adult ventricular myocytes. Exp Cell Res 313:1588–1601

    Article  PubMed  CAS  Google Scholar 

  69. Perotti S, Cresta G, Grasselli G, Capri G, Minotti G, Gianni L (2003) Cardiotoxic effects of anthracycline-taxane combinations. Expert Opin Drug Saf 2:59–71

    Article  PubMed  CAS  Google Scholar 

  70. Ritchie DS, Seymour JF, Roberts AW, Szer J, Grigg AP (2001) Acute left ventricular failure following melphalan and fludarabine conditioning. Bone Marrow Transplant 28:101–103

    Article  PubMed  CAS  Google Scholar 

  71. Roskoski R Jr (2004) The ErbB/HER receptor protein-tyrosine kinases and cancer. Biochem Biophys Res Commun 319:1–11

    Article  PubMed  CAS  Google Scholar 

  72. Salvatorelli E, Menna P, Cascegna S, Liberi G, Calafiore A, Gianni L, Minotti G (2006) Paclitaxel and docetaxel stimulation of doxorubicinol formation in the human heart: implications for cardiotoxicity of doxorubicin-taxane chemotherapies. J Pharmacol Exp Ther 318:424–433

    Article  PubMed  CAS  Google Scholar 

  73. Salvatorelli E, Menna P, Gianni L, Minotti G (2007) Defective taxane stimulation of epirubicinol formation in the human heart: insight into the cardiac tolerability of epirubicin-taxane chemotherapies. J Pharmacol Exp Ther 320:790–800

    Article  PubMed  CAS  Google Scholar 

  74. Santos GW, Sensenbrenner LL, Burke PJ, Colvin M, Owens AH Jr, Bias WB, Slavin RE (1971) Marrow transplantation in man following cyclophosphamide. Transplant Proc 3:400–404

    PubMed  CAS  Google Scholar 

  75. Schwartz CL, Constine LS, Villaluna D, London WB, Hutchison RE, Sposto R, Lipshultz SE, Turner CS, deAlarcon PA, Chauvenet A (2009) A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate and high-risk Hodgkin lymphoma: the results of P9425. Blood 114:2051–2059

    Article  PubMed  CAS  Google Scholar 

  76. Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, Murphy M, Stewart SJ, Keefe D (2002) Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20:1215–1221

    Article  PubMed  CAS  Google Scholar 

  77. Serrano J, Palmeira CM, Kuehl DW, Wallace KB (1999) Cardioselective and cumulative oxidation of mitochondrial DNA following subchronic doxorubicin administration. Biochim Biophys Acta 1411:201–205

    Article  PubMed  CAS  Google Scholar 

  78. Shimpo K, Nagatsu T, Yamada K, Sato T, Niimi H, Shamoto M, Takeuchi T, Umezawa H, Fujita K (1991) Ascorbic acid and adriamycin toxicity. Am J Clin Nutr 54:1298S–1301S

    PubMed  CAS  Google Scholar 

  79. Singal PK, Iliskovic N, Li T, Kumar D (1997) Adriamycin cardiomyopathy: pathophysiology and prevention. FASEB J 11:931–936

    PubMed  CAS  Google Scholar 

  80. Singal PK, Siveski-Iliskovic N, Hill M, Thomas TP, Li T (1995) Combination therapy with probucol prevents adriamycin-induced cardiomyopathy. J Mol Cell Cardiol 27:1055–1063

    Article  PubMed  CAS  Google Scholar 

  81. Siveski-Iliskovic N, Kaul N, Singal PK (1994) Probucol promotes endogenous antioxidants and provides protection against adriamycin-induced cardiomyopathy in rats. Circulation 89:2829–2835

    Article  PubMed  CAS  Google Scholar 

  82. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707–712

    Article  PubMed  CAS  Google Scholar 

  83. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792

    Article  PubMed  CAS  Google Scholar 

  84. Speyer JL, Green MD, Zeleniuch-Jacquotte A, Wernz JC, Rey M, Sanger J, Kramer E, Ferrans V, Hochster H, Meyers M et al (1992) ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol 10:117–127

    PubMed  CAS  Google Scholar 

  85. Stathopoulos GP, Malamos NA, Dontas I, Deliconstantinos G, Perrea-Kotsareli D, Karayannacos PE (1998) Inhibition of adriamycin cardiotoxicity by 5-fluorouracil: a potential free oxygen radical scavenger. Anticancer Res 18:4387–4392

    PubMed  CAS  Google Scholar 

  86. Swain SM, Whaley FS, Gerber MC, Weisberg S, York M, Spicer D, Jones SE, Wadler S, Desai A, Vogel C, Speyer J, Mittelman A, Reddy S, Pendergrass K, Velez-Garcia E, Ewer MS, Bianchine JR, Gams RA (1997) Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 15:1318–1332

    PubMed  CAS  Google Scholar 

  87. Tesoriere L, Ciaccio M, Valenza M, Bongiorno A, Maresi E, Albiero R, Livrea MA (1994) Effect of vitamin-A administration on resistance of rat-heart against doxorubi- cin-induced cardiotoxicity and lethality. J Pharm Exp Ther 269:430–436

    CAS  Google Scholar 

  88. Timolati F, Ott D, Pentassuglia L, Giraud MN, Perriard JC, Suter TM, Zuppinger C (2006) Neuregulin-1 beta attenuates doxorubicin-induced alterations of excitation-contraction coupling and reduces oxidative stress in adult rat cardiomyocytes. J Mol Cell Cardiol 41:845–854

    Article  PubMed  CAS  Google Scholar 

  89. van Acker SA, Boven E, Kuiper K, van der Berg DJ, Grimbergen JA, Kramer K, Bast A, van der Vijgh WJ (1997) Monohydroxyethylrutoside, a dose-dependent cardioprotective agent, does not affect the antitumor activity of doxorubicin. Clin Cancer Res 3:1747–1754

    PubMed  Google Scholar 

  90. van Dalen EC, Caron HN, Dickinson HO, Kremer LC (2011) Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev 6:CD003917

    PubMed  Google Scholar 

  91. Venturini M, Michelotti A, Del Mastro L, Gallo L, Carnino F, Garrone O, Tibaldi C, Molea N, Bellina RC, Pronzato P, Cyrus P, Vinke J, Testore F, Guelfi M, Lionetto R, Bruzzi P, Conte PF, Rosso R (1996) Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer. J Clin Oncol 14:3112–3120

    PubMed  CAS  Google Scholar 

  92. Verweij J, Funke-Küpper AJ, Teule GJ, Pinedo HM (1988) A prospective study on the dose dependency of cardiotoxicity induced by mitomycin C. Med Oncol Tumor Pharmacother 5:159–163

    PubMed  CAS  Google Scholar 

  93. Wadhwa D, Fallah-Rad N, Grenier D, Krahn M, Fang T, Ahmadie R, Walker JR, Lister D, Arora RC, Barac I, Morris A, Jassal DS (2009) Trastuzumab mediated cardiotoxicity in the setting of the adjuvant chemotherapy for breast cancer: a retrospective study. Breast Cancer Res Treat 117:357–364

    Article  PubMed  CAS  Google Scholar 

  94. Waldner R, Laschan C, Lohninger A, Gessner M, Tuchler H, Huemer M, Spiegel W, Karlic H (2006) Effects of doxorubicin-containing chemotherapy and a combination with l-carnitine on oxidative metabolism in patients with non-Hodgkin lymphoma. J Cancer Res Clin Oncol 132:121–128

    Article  PubMed  Google Scholar 

  95. Walker JR, Sharma A, Lytwyn M, Bohonis S, Thliveris J, Singal PK, Jassal DS (2011) The cardioprotective role of probucol against anthracycline and trastuzumab-mediated cardiotoxicity. J Am Soc Echocardiogr 24:699–705

    Article  PubMed  Google Scholar 

  96. Wang J, He D, Zhang Q, Han Y, Jin S, Qi F (2009) Resveratrol protects against Cisplatin-induced cardiotoxicity by alleviating oxidative damage. Cancer Biother Radiopharm 24:675–680

    Article  PubMed  CAS  Google Scholar 

  97. Woodman RJ, Cysyk RL, Kline I, Gang M, Venditti JM (1975) Enhancement of the effectiveness of daunorubicin (NSC-82151) or adriamycin (NSC-123127) against early mouse L1210 leukemia with ICRF-159 (NSC-129943). Cancer Chemother Rep 59:689–695

    PubMed  CAS  Google Scholar 

  98. Yoda Y, Nakazawa M, Abe T, Kawakami Z (1986) Prevention of doxorubicin myocardial toxicity in mice by reduced glutathione. Cancer Res 46:2551–2556

    PubMed  CAS  Google Scholar 

  99. Yousef MI, Saad AA, El-Shennawy LK (2009) Protective effect of grape seed proanthocyanidin extract against oxidative stress induced by cisplatin in rats. Food Chem Toxicol 47:1176–1183

    Article  PubMed  CAS  Google Scholar 

  100. Zver S, Zadnik V, Cernelc P, Kozelj M (2008) Cardiac toxicity of high-dose cyclophosphamide and melphalan in patients with multiple myeloma treated with tandem autologous hematopoietic stem cell transplantation. Int J Hematol 88:227–236

    Article  PubMed  Google Scholar 

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Correspondence to Yuichiro J. Suzuki.

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Vincent, D.T., Ibrahim, Y.F., Espey, M.G. et al. The role of antioxidants in the era of cardio-oncology. Cancer Chemother Pharmacol 72, 1157–1168 (2013). https://doi.org/10.1007/s00280-013-2260-4

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  • DOI: https://doi.org/10.1007/s00280-013-2260-4

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