Oxidative Stress-Driven Cardiotoicity of Cancer Drugs

  • Thalita Basso Scandolara
  • Bruno Ricardo Pires
  • Rodrigo Kern
  • Vanessa Jacob Victorino
  • Carolina Panis


Despite the recent advances in cancer handling, cytotoxic chemotherapy remains as the main approach for treating patients. These drugs are associated with a variety of acute and long-term side effects, including several levels of cardiac injury. Cardiotoxicity can be found in such patients as subclinical disease – where symptoms are not evidenced but changes can be observed in blood – or clinically symptomatic. The basis of chemotherapy-induced cardiotoxicity is multifactorial, but most of drugs present the same mechanism of damage: the generation of free radicals and redox homeostasis imbalance. In addition, several monoclonal antibodies employed in the personalized medicine against cancer have shown degrees of cardiotoxicity in patients. In this contect, this chapter discusses the main drugs capable to generate oxidative stress during cancer treatment, and highlight the main mechanisms mediated by redox mediators that are involved in cardiac damage.


Cancer Cardiotoxicity Oxidative stress 


  1. 1.
    Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205–219CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2:647–656CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Castaldo SA, Freitas JR, Conchinha NV, Madureira PA (2016) The tumorigenic roles of the cellular REDOX regulatory systems. Oxid Med Cell Longev:8413032Google Scholar
  4. 4.
    Okon IS, Zou M-H (2015) Mitochondrial ROS and cancer drug resistance: implications for therapy. Pharmacol Res 100:170–174CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kasapovic J, Pejic S, Todorovic A, Stojiljkovic V, Pajovic SB (2008) Antioxidant status and lipid peroxidation in the blood of breast cancer patients of different ages. Cell Biochem Funct 26:723–730CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Deavall DG, Martin EA, Horner JM, Roberts R (2012) Drug-induced oxidative stress and toxicity. J Toxicol 2012Google Scholar
  7. 7.
    Gutteridge JMC, Halliwell B (2018) Mini-review: oxidative stress, redox stress or redox success? Biochem Biophys Res Commun 502:183–186. Academic PressCrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Varrichi G, Ameri P, Cadeddu C et al (2018) Antineoplastic drug-induced cardiotoxicity: a redox perspective. Front Physiol 9:167CrossRefGoogle Scholar
  9. 9.
    Min K, Kwon O-S, Smuder AJ, Wiggs MP, Sollanek KJ, Christou DD et al (2015) Increased mitochondrial emission of reactive oxygen species and calpain activation are required for doxorubicin-induced cardiac and skeletal muscle myopathy. J Physiol 593:2017–2036CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Albini A, Pennesi G, Donatelli F et al (2010) Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. J Natl Cancer Inst 102(1):14–25CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Schimmel KJ, Richel DJ, van den Brink RB, Guchelaar HJ (2004) Cardiotoxicity of cytotoxic drugs. Cancer Treat Rev 30(2):181–191CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Florescu M, Cinteza M, Vinereanu D (2013) Chemotherapy-induced cardiotoxicity. Maedica (Buchar) 8(1):59–67Google Scholar
  13. 13.
    Mihalcea DJ, Florescu M, Vinereanu D (2017) Mechanisms and genetic susceptibility of chemotherapy-induced cardiotoxicity in patients with breast cancer. Am J Ther 24(1):e3–e11CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Gorrini C, Harris IS, Mak TW (2013) Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12:931–947. Nature Publishing GroupCrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Victorino VJ, Mencalha AL, Panis C (2015) Post-translational modifications disclose a dual role for redox stress in cardiovascular pathophysiology. Life Sci 129:42–47CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Angsutararux P, Luanpitpong S, Issaragrisil S (2015) Chemotherapy-induced cardiotoxicity: overview of the roles of oxidative stress. Oxid Med Cell Longev 2015:795602CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Rochette L, Guenancia C, Gudjoncik A, Hachet O, Zeller M, Cottin Y, Vergely C (2015) Anthracyclines/trastuzumab: new aspects of cardiotoxicity and molecular mechanisms. Trends Pharmacol Sci 36(6):326–348CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    WHO WHO. Cardiovascular Diseases [Internet]. (cited 2018, August 5). Available from:
  19. 19.
    WHO WHO. Cancer [Internet]. (cited 2018, August 5]. Available from:
  20. 20.
    Yusuf SW, Razeghi P, Yeh ETH (2008) The diagnosis and management of cardiovascular disease in cancer patients. Curr Probl Cardiol 33:163–196CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Murphy KT (2016) The pathogenesis and treatment of cardiac atrophy in cancer cachexia. Am J Physiol – Hear Circ Physiol [Internet] 310:H466–H477. Available from: Scholar
  22. 22.
    Wysong A, Couch M, Shadfar S, Li L, Rodriguez JE, Asher S et al (2011) NF-κB inhibition protects against tumor-induced cardiac atrophy in vivo. Am J Pathol 178:1059–1068CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Springer J, Tschirner A, Haghikia A, Von Haehling S, Lal H, Grzesiak A et al (2014) Prevention of liver cancer cachexia-induced cardiac wasting and heart failure. Eur Heart J 35:932–941CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Xu H, Crawford D, Hutchinson KR, Youtz DJ, Lucchesi PA, Velten M et al (2011) Myocardial dysfunction in an animal model of cancer cachexia. Life Sci 88:406–410CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Tian M, Nishijima Y, Asp ML, Stout MB, Reiser PJ, Belury MA (2010) Cardiac alterations in cancer-induced cachexia in mice. Int J Oncol 37:347–353PubMedPubMedCentralGoogle Scholar
  26. 26.
    Tian M, Asp ML, Nishijima Y, Belury MA (2011) Evidence for cardiac atrophic remodeling in cancer-induced cachexia in mice. Int J Oncol 39:1321–1326PubMedPubMedCentralGoogle Scholar
  27. 27.
    Belloum Y, Rannou-Bekono F, Favier FB (2017) Cancer-induced cardiac cachexia: pathogenesis and impact of physical activity (Review). Oncol Rep 37:2543–2552CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Egea J, Fabregat I, Frapart YM, Ghezzi P, Görlach A, Kietzmann T et al (2017) European contribution to the study of ROS: a summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS). Redox Biol 13:94–162CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hinch ECA, Sullivan-Gunn MJ, Vaughan VC, McGlynn MA, Lewandowski PA (2013) Disruption of pro-oxidant and antioxidant systems with elevated expression of the ubiquitin proteosome system in the cachectic heart muscle of nude mice. J Cachexia Sarcopenia Muscle 4:287–293CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Nathan C, Cunningham-Bussel A (2013) Beyond oxidative stress: an immunologist’s guide to reactive oxygen species. Nat Rev Immunol 13:349–361CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Mencalha A, Victorino VJ, Cecchini R, Panis C (2014) Mapping oxidative changes in breast cancer: understanding the basic to reach the clinics. Anticancer Res 34:1127–1140PubMedGoogle Scholar
  32. 32.
    Ayala A, Muñoz MF, Argüelles S (2014) Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev 2014Google Scholar
  33. 33.
    Marin-Corral J, Fontes CC, Pascual-Guardia S, Sanchez F, Olivan M, Argilés JM et al (2010) Redox balance and carbonylated proteins in limb and heart muscles of cachectic rats. Antioxid Redox Signal 12:365–380CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Borges FH, Marinello PC, Cecchini AL, Blegniski FP, Guarnier FA, Cecchini R (2014) Oxidative and proteolytic profiles of the right and left heart in a model of cancer-induced cardiac cachexia. Pathophysiology 21:257–265CrossRefGoogle Scholar
  35. 35.
    Pavo N, Raderer M, Hülsmann M, Neuhold S, Adlbrecht C, Strunk G et al (2015) Cardiovascular biomarkers in patients with cancer and their association with all-cause mortality. Heart 101:1874–1880CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Singh-Manoux A, Shipley MJ, Bell JA, Canonico M, Elbaz A, Kivimaki M (2017) Association between inflammatory biomarkers and all-cause, cardiovascular and cancer-related mortality. CMAJ 189:E384–E390CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Luan Y, Yao Y (2018) The clinical significance and potential role of c-reactive protein in chronic inflammatory and neurodegenerative diseases. Front Immunol 9:1–8CrossRefGoogle Scholar
  38. 38.
    Panis C, Binato R, Correa S, Victorino VJ, Dias-Alves V, Herrera ACSA et al (2017) Short infusion of paclitaxel imbalances plasmatic lipid metabolism and correlates with cardiac markers of acute damage in patients with breast cancer. Cancer Chemother Pharmacol 80:469–478. Springer, Berlin/HeidelbergCrossRefGoogle Scholar
  39. 39.
    Panis C, Victorino VJ, Herrera ACSA, Freitas LF, De Rossi T, Campos FC et al (2012) Differential oxidative status and immune characterization of the early and advanced stages of human breast cancer. Breast Cancer Res Treat 133:881–888CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Amin KA, Mohamed BM, El-Wakil MAM, Ibrahem SO (2012) Impact of breast cancer and combination chemotherapy on oxidative stress, hepatic and cardiac markers. J Breast Cancer 15:306–312CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Schultz PN, Beck ML, Stava C, Vassilopoulou-Sellin R (2003) Health profiles in 5836 long-term cancer survivors. Int J Cancer 104:488–495CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    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 102:14–25CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Zhu H, Sarkar S, Scott L, Danelisen I, Trush MA, Jia Z et al (2016) Doxorubicin redox biology: redox cycling, topoisomerase inhibition, and oxidative stress. React Oxyg Species (Apex) 1:189–198CrossRefGoogle Scholar
  44. 44.
    Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Pilco-Ferreto N, Calaf GM (2016) Influence of doxorubicin on apoptosis and oxidative stress in breast cancer cell lines. Int J Oncol 49:753–762CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Singal PK, Iliskovic N (1998) Doxorubicin-induced cardiomyopathy. N Engl J Med 339:900–905CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Bahadır A, Kurucu N, Kadıoğlu M, Yenilmez E (2014) The role of nitric oxide in doxorubicin-induced cardiotoxicity: experimental study. Turkish J Hematol 31:68–74CrossRefGoogle Scholar
  48. 48.
    Paulides M, Kremers A, Stohr W, Bielack S, Jurgens H, Treuner J et al (2009) Prospective longitudinal evaluation of doxorubicin-induced cardiomyopathy in sarcoma patients: a report of the late effects surveillance system (LESS). Pediatr Blood Cancer 46:489–495CrossRefGoogle Scholar
  49. 49.
    Zhou S, Palmeira CM, Wallace KB (2001) Doxorubicin-induced persistent oxidative stress to cardiac myocytes. Toxicol Lett 121:151–157CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Sayed-Ahmed MM, Khattab MM, Gad MZ, Osman AMM (2001) Increased plasma endothelin-1 and cardiac nitric oxide during doxorubicin-induced cardiomyopathy. Pharmacol Toxicol 89:140–144CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Guo RM, Xu WM, Lin JC, Mo LQ, Hua XX, Xi Chen P et al (2013) Activation of the p38 MAPK/NF-κB pathway contributes to doxorubicin-induced inflammation and cytotoxicity in H9c2 cardiac cells. Mol Med Rep 8:603–608CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M et al (1979) Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91:710–717CrossRefGoogle Scholar
  53. 53.
    Lipshultz SE, Rifai N, Dalton VM, Levy DE, Silverman LB, Lipsitz SR et al (2004) The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 351:145–153CrossRefGoogle Scholar
  54. 54.
    Lipshultz SE, Alvarez JA, Scully RE (2008) Anthracycline associated cardiotoxicity in survivors of childhood cancer. Heart 94:525–533CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Trachtenberg BH, Landy DC, Franco VI, Henkel JM, Pearson EJ, Miller TL et al (2011) Anthracycline-associated cardiotoxicity in survivors of childhood cancer. Pediatr Cardiol 32:342–353CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Myers CE (1988) Role of iron in anthracycline action. Organ Dir Toxicities Anticancer Drugs Dev Oncol:17–30Google Scholar
  57. 57.
    Jones LW, Haykowsky MJ, Swartz JJ, Douglas PS, Mackey JR (2007) Early breast cancer therapy and cardiovascular injury. J Am Coll Cardiol 50:1435–1441CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Swain SM, Whaley FS, Ewer MS (2003) Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97:2869–2879CrossRefGoogle Scholar
  59. 59.
    Muggia FM (1997) Clinical efficacy and prospects for use of pegylated liposomal doxorubicin in the treatment of ovarian and breast cancers. Drugs 54:22–29CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Iarussi D, Indolfi P, Casale F, Martino V, Di Tullio MT, Calabrò R (2005) Anthracycline-induced cardiotoxicity in children with cancer: strategies for prevention and management. Pediatr Drugs 7:67–76CrossRefGoogle Scholar
  61. 61.
    Wu AH (2008) Cardiotoxic drugs: clinical monitoring and decision making. Heart 94:1503–1509CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Seifert CF, Nesser ME, Thompson DF (1994) Dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity. Ann Pharmacother 28:1063–1072CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Swain BSM, Whaley FS, Gerber MC, Weisberg S, York M, Spicer D et al (1997) Cardioprotection with dexrazoxane for doxorubicin- containing therapy in advanced breast cancer. J Clin Oncol 15:1318–1332CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Manduteanu I, Dragomir E, Voinea M, Capraru M, Simionescu M (2007) Enoxaparin reduces H2O2-induced activation of human endothelial cells by a mechanism involving cell adhesion molecules and nuclear transcription factors. Pharmacology 79:154–162CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Young E (2008) The anti-inflammatory effects of heparin and related compounds. Thromb Res 122:743–752CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Vejpongsa P, Yeh ETH (2014) Prevention of anthracycline-induced cardiotoxicity: challenges and opportunities. J Am Coll Cardiol 64:938–945CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Haq MM, Legha SS, Choksi J, Hortobagyi GN, Benjamin RS, Ewer M et al (1985) Doxorubicin-induced congestive heart failure in adults. Cancer 56:1361–1365CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Marchandise B, Schroeder E, Bosly A, Doyen C, Weynants P, Kremer R et al (1989) Early detection of doxorubicin cardiotoxicity: interest of Doppler echocardiographic analysis of left ventricular filling dynamics. Am Heart J 118:92–98CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Dolci A, Dominici R, Cardinale D, Sandri MT, Panteghini M (2008) Biochemical markers for prediction of chemotherapy-induced cardiotoxicity systematic review of the literature and recommendations for use. Am J Clin Pathol 130:688–695CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Yeh ETH, Tong AT, Lenihan DJ, Yusuf SW, Swafford J, Champion C et al (2004) Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation 109:3122–3131CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Lipschultz SE, Rifai N, Sallan SE, Lipsitz SR, Dalton V, Sacks DB et al (1997) Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation 96:2641–2648CrossRefGoogle Scholar
  72. 72.
    Bryant J, Picot J, Baxter L, Levitt G, Sullivan I, Clegg A (2007) Use of cardiac markers to assess the toxic effects of anthracyclines given to children with cancer: a systematic review. Eur J Cancer 43:1959–1966CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Reichlin T, Reichlin T, Hochholzer W, Hochholzer W, Bassetti S, Bassetti S et al (2009) Early Diagnosis of Myocardial Infarction with Sensitive Cardiac Troponin Assays. N Engl J Med 361:858–867CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    O’Brien PJ, Smith DEC, Knechtel TJ, MArchak MA, Pruimboom-Brees I, Brees DJ et al (2006) Cardiac troponin T is a sensitive, specific biomarker of cardiac injury in laboratory animals. Lab Anim Sci 40:153–171CrossRefGoogle Scholar
  75. 75.
    Dirican A, Levent F, Alacacioglu A, Kucukzeybek Y, Varol U, Kocabas U et al (2014) Acute cardiotoxic effects of adjuvant trastuzumab treatment and its relation to oxidative stress. Angiology 65:944–949CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Rochette L, Guenancia C, Gudjoncik A, Hachet O, Zeller M, Cottin Y et al (2015) Anthracyclines/trastuzumab: new aspects of cardiotoxicity and molecular mechanisms. Trends Pharmacol Sci 36:326–348CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Hudis CA (2007) Trastuzumab — mechanism of action and use in clinical practice. N Engl J Med:39–51Google Scholar
  78. 78.
    Onitilo AA, Engel JM, Stankowski RV (2014) Cardiovascular toxicity associated with adjuvant trastuzumab therapy: prevalence, patient characteristics, and risk factors. Ther Adv Drug Saf 5:154–166CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Gemmete JJ, Mukherji SK (2011) Trastuzumab (Herceptin). AJNR Am J Neuroradiol 32:1373–1374CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Bonci A, Lupica CR, Morales M (2015) Trastuzumab interruption and treatment-induced carciotoxicity in early HER2-positive breast cancer. Breast Cancer Res Treat 149:489–495CrossRefGoogle Scholar
  81. 81.
    Dokmanovic M, Wu WJ (2015) Monitoring trastuzumab resistance and cardiotoxicity: a tale of personalized medicine. 1st ed. Adv Clin ChemGoogle Scholar
  82. 82.
    Ayres LR, de Almeida Campos MS, de Oliveira Gozzo T, Martinez EZ, Ungari AQ, de Andrade JM et al (2015) Trastuzumab induced cardiotoxicity in HER2 positive breast cancer patients attended in a tertiary hospital. Int J Clin Pharm 37:365–372CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Varga ZV, Ferdinandy P, Liaudet L, Pacher P (2015) Drug-induced mitochondrial dysfunction and cardiotoxicity. Am J Physiol – Hear Circ Physiol 309:H1453–H1467CrossRefGoogle Scholar
  84. 84.
    Gorini S, De Angelis A, Berrino L, Malara N, Rosano G, Ferraro E (2018) Chemotherapeutic drugs and mitochondrial dysfunction: focus on doxorubicin, trastuzumab, and sunitinib. Oxid Med Cell Longev 2018:15CrossRefGoogle Scholar
  85. 85.
    Sandoo A, Kitas GD, Carmichael AR (2015) Breast cancer therapy and cardiovascular risk: focus on trastuzumab. Vasc Health Risk Manag 11:223–228CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Kabel AM, Elkhoely AA (2017) Targeting proinflammatory cytokines, oxidative stress, TGF-β1 and STAT-3 by rosuvastatin and ubiquinone to ameliorate trastuzumab cardiotoxicity. Biomed Pharmacother 93:17–26CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Leung HW, Chan AL (2015) Trastuzumab-induced cardiotoxicity in elderly women with HER-2-positive breast cancer: a meta-analysis of real-world data. Expert Opin Drug Saf 14:1661–1671CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Ürün Y, Utkan G, Yalcin B, Akbulut H, Onur H, Oztuna DG et al (2015) The role of cardiac biomarkers as predictors of trastuzumab cardiotoxicity in patients with breast cancer. Exp Oncol 37:53–57CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Goyal V, Bews H, Cheung D, Premecz S, Mandal S, Shaikh B et al (2016) The cardioprotective role of N-acetyl cysteine amide in the prevention of doxorubicin and trastuzumab mediated cardiac dysfunction. Can J CardiolGoogle Scholar
  90. 90.
    Lemos LGT, Victorino VJ, Herrera ACSA, Aranome AMF, Cecchini AL, Simão ANC et al (2015) Trastuzumab-based chemotherapy modulates systemic redox homeostasis in women with HER2-positive breast cancer. Int Immunopharmacol 27:8–14CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Putt M, Hahn VS, Januzzi JL, Sawaya H, Sebag IA, Plana JC et al (2015) Longitudinal changes in multiple biomarkers are associated with cardiotoxicity in breast cancer patients treated with doxorubicin, taxanes, and trastuzumab. Clin Chem 61:1164–1172CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Moilanen T, Jokimäki A, Tenhunen O, Koivunen JP (2018) Trastuzumab-induced cardiotoxicity and its risk factors in real-world setting of breast cancer patients. J Cancer Res Clin OncolGoogle Scholar
  93. 93.
    Riccio G, Antonucci S, Coppola C, D’avino C, Piscopo G, Fiore D et al (2018) Ranolazine attenuates trastuzumab-induced heart dysfunction by modulating ROS production. Front Physiol 9:38CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin L (2016) Melatonin as an antioxidant: under promises but over delivers. J Pineal Res 61:253–278CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Ozturk M, Ozler M, Kurt YG, Ozturk B, Uysal B, Ersoz N et al (2011) Efficacy of melatonin, mercaptoethylguanidine and 1400W in doxorubicin- and trastuzumab-induced cardiotoxicity. J Pineal Res 50:89–96CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Victorino VJ, Panis C, Campos FC, Cayres RC, Colado-Simao AN, Oliveira SR et al (2013) Decreased oxidant profile and increased antioxidant capacity in naturally postmenopausal women. Age 35:1411–1421CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Scripture CD, Figg WD, Sparreboom A (2005) Paclitaxel chemotherapy: from empiricism to a mechanism-based formulation strategy. Ther Clin Risk Manag 1:107–114CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4:253–265CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Victorino VJ, Pizzatti L, Michelletti P, Panis C (2014) Oxidative stress, redox signaling and cancer chemoresistance: putting together the pieces of the puzzle. Curr Med Chem 21:3211–3226CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Hadzic T, Aykin-Burns N, Zhu Y, Coleman MC, Leick K, Jacobson GM et al (2010) Paclitaxel combined with inhibitors of glucose and hydroperoxide metabolism enhances breast cancer cell killing via H2O2-mediated oxidative stress. Free Radic Biol Med 48:1024–1033CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Alexandre J, Hu Y, Lu W, Pelicano H, Huang P (2007) Novel action of paclitaxel against cancer cells: bystander effect mediated by reactive oxygen species. Cancer Res 67:3512–3517CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Ramanathan B, Jan KY, Chen CH, Hour TC, Yu HJ, Pu YS (2005) Resistance to paclitaxel is proportional to cellular total antioxidant capacity. Cancer Res 65:8455–8460CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Polk A, Vistisen K, Vaage-Nilsen M, Nielsen DL (2014) A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity. BMC Pharmacol Toxicol 15:47CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Panis C, Herrera AC, Victorino VJ, Campos FC, Freitas LF, De Rossi T et al (2012) Oxidative stress and hematological profiles of advanced breast cancer patients subjected to paclitaxel or doxorubicin chemotherapy. Breast Cancer Res Treat 133:89–97CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Jezierska-Drutel A, Rosenzweig SA, Neumann CA (2013) Role of oxidative stress and the microenvironment in breast cancer development and progression. Adv Cancer Res 119:107–125CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Guigni BA, Callahan DM, Tourville TW, Miller MS, Fiske B, Voigt T et al (2018) Skeletal muscle atrophy and dysfunction in breast cancer patients: role for chemotherapy-derived oxidant stress. Am J Physiol Cell PhysiolGoogle Scholar
  107. 107.
    Huang HL, Shi YP, He HJ, Wang YH, Chen T, Yang LW et al (2017) MiR-4673 modulates paclitaxel-induced oxidative stress and loss of mitochondrial membrane potential by targeting 8-oxoguanine-DNA glycosylase-1. Cell Physiol Biochem 42:889–900CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Granados-Principal S, Quiles JL, Ramirez-Tortosa CL, Sanchez-Rovira P, Ramirez-Tortosa MC (2010) New advances in molecular mechanisms and the prevention of adriamycin toxicity by antioxidant nutrients. Food Chem Toxicol 48:1425–1438CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Goncalves A, Pierga JY, Ferrero JM, Mouret-Reynier MA, Bachelot T, Delva R et al (2015) UNICANCER-PEGASE 07 study: a randomized phase III trial evaluating postoperative docetaxel-5FU regimen after neoadjuvant dose-intense chemotherapy for treatment of inflammatory breast cancer. Ann Oncol 26:1692–1697CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Kim R, Hahn S, Shin J, Ock CY, Kim M, Keam B et al (2016) The effect of induction chemotherapy using docetaxel, cisplatin, and fluorouracil on survival in locally advanced head and neck squamous cell carcinoma: a meta-analysis. Cancer Res Treat 48:907–916CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Miura K, Kinouchi M, Ishida K, Fujibuchi W, Naitoh T, Ogawa H et al (2010) 5-fu metabolism in cancer and orally-administrable 5-fu drugs. Cancers (Basel) 2:1717–1730CrossRefGoogle Scholar
  112. 112.
    Lestuzzi C, Tartuferi L, Corona G (2011) Capecitabine (and 5 fluorouracil) cardiotoxicity. Metabolic considerations. Breast J 17:564–567CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Wyatt MD, Wilson 3rd DM. Participation of DNA repair in the response to 5-fluorouracil. Cell Mol Life Sci 2009;66:788–799.Google Scholar
  114. 114.
    Lamberti M, Porto S, Zappavigna S, Addeo E, Marra M, Miraglia N et al (2014) A mechanistic study on the cardiotoxicity of 5-fluorouracil in vitro and clinical and occupational perspectives. Toxicol Lett 227:151–156CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Xiao H, Xiong L, Song X, Jin P, Chen L, Chen X et al (2017) Angelica sinensis polysaccharides ameliorate stress-induced premature senescence of hematopoietic cell via protecting bone marrow stromal cells from oxidative injuries caused by 5-fluorouracil. Int J Mol Sci 18Google Scholar
  116. 116.
    Hess JA, Khasawneh MK (2015) Cancer metabolism and oxidative stress: insights into carcinogenesis and chemotherapy via the non-dihydrofolate reductase effects of methotrexate. BBA Clin 3:152–161CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Sener MT, Sener E, Tok A, Polat B, Cinar I, Polat H et al (2012) Biochemical and histologic study of lethal cisplatin nephrotoxicity prevention by mirtazapine. Pharmacol Rep 64:594–602CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Rtibi K, Selmi S, Grami D, Amri M, Sebai H, Marzouki L (2018) Contribution of oxidative stress in acute intestinal mucositis induced by 5 fluorouracil (5-FU) and its pro-drug capecitabine in rats. Toxicol Mech Methods 28:262–267CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Bomfin LE, Braga CM, Oliveira TA, Martins CS, Foschetti DA, Santos AAQA et al (2017) 5-Fluorouracil induces inflammation and oxidative stress in the major salivary glands affecting salivary flow and saliva composition. Biochem Pharmacol 145:34–45CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Afrin S, Giampieri F, Forbes-Hernandez TY, Gasparrini M, Amici A, Cianciosi D et al (2018) Manuka honey synergistically enhances the chemopreventive effect of 5-fluorouracil on human colon cancer cells by inducing oxidative stress and apoptosis, altering metabolic phenotypes and suppressing metastasis ability. Free Radic Biol Med 126:41–54CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Bywater MJ, Pearson RB, McArthur GA, Hannan RD (2013) Dysregulation of the basal RNA polymerase transcription apparatus in cancer. Nat Rev Cancer 13:299–314CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Pommier Y, Leo E, Zhang H, Marchand C (2010) DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol 17:421–433CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Saleh EM (2015) Inhibition of topoisomerase IIalpha sensitizes FaDu cells to ionizing radiation by diminishing DNA repair. Tumour Biol 36:8985–8992CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Kapiszewska M, Cierniak A, Elas M, Lankoff A (2007) Lifespan of etoposide-treated human neutrophils is affected by antioxidant ability of quercetin. Toxicol Vitr 21:1020–1030CrossRefGoogle Scholar
  125. 125.
    Shin HJ, Kwon HK, Lee JH, Anwar MA, Choi S (2016) Etoposide induced cytotoxicity mediated by ROS and ERK in human kidney proximal tubule cells. Sci Rep 6:34064CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Yadav N, Kumar S, Marlowe T, Chaudhary AK, Kumar R, Wang J et al (2015) Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents. Cell Death Dis 6:e1969CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Haim N, Nemec J, Roman J, Sinha BK (1987) Peroxidase-catalyzed metabolism of etoposide (VP-16-213) and covalent binding of reactive intermediates to cellular macromolecules. Cancer Res 47:5835–5840PubMedPubMedCentralGoogle Scholar
  128. 128.
    Kagan VE, Yalowich JC, Borisenko GG, Tyurina YY, Tyurin VA, Thampatty P et al (1999) Mechanism-based chemopreventive strategies against etoposide-induced acute myeloid leukemia: free radical/antioxidant approach. Mol Pharmacol 56:494–506CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Mahbub AA, Le Maitre CL, Haywood-Small SL, Cross NA, Jordan-Mahy N (2015) Glutathione is key to the synergistic enhancement of doxorubicin and etoposide by polyphenols in leukaemia cell lines. Cell Death Dis 6:e2028CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Yadav N, Chandra D (2014) Mitochondrial and postmitochondrial survival signaling in cancer. Mitochondrion 16:18–25CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Attia SM, Ahmad SF, Harisa GI, Mansour AM, El Sayed el SM, Bakheet SA (2013) Wogonin attenuates etoposide-induced oxidative DNA damage and apoptosis via suppression of oxidative DNA stress and modulation of OGG1 expression. Food Chem Toxicol 59:724–730CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Kim DJ, Kim EJ, Lee TY, Won JN, Sung MH, Poo H (2013) Combination of poly-gamma-glutamate and cyclophosphamide enhanced antitumor efficacy against tumor growth and metastasis in a murine melanoma model. J Microbiol Biotechnol 23:1339–1346CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Sekeroglu V, Aydin B, Sekeroglu ZA (2011) Viscum album L. extract and quercetin reduce cyclophosphamide-induced cardiotoxicity, urotoxicity and genotoxicity in mice. Asian Pac J Cancer Prev 12:2925–2931PubMedPubMedCentralGoogle Scholar
  134. 134.
    Wang LF, Gong X, Le GW, Shi YH (2008) Dietary nucleotides protect thymocyte DNA from damage induced by cyclophosphamide in mice. J Anim Physiol Anim Nutr 92:211–218CrossRefGoogle Scholar
  135. 135.
    Esterbauer H, Schaur RJ, Zollner H (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11:81–128CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Rezvanfar M, Sadrkhanlou R, Ahmadi A, Shojaei-Sadee H, Rezvanfar M, Mohammadirad A et al (2008) Protection of cyclophosphamide-induced toxicity in reproductive tract histology, sperm characteristics, and DNA damage by an herbal source; evidence for role of free-radical toxic stress. Hum Exp Toxicol 27:901–910CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Shokrzadeh M, Ahmadi A, Naghshvar F, Chabra A, Jafarinejhad M (2014) Prophylactic efficacy of melatonin on cyclophosphamide-induced liver toxicity in mice. Biomed Res Int 2014:470425CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Sengul E, Gelen V, Gedikli S, Ozkanlar S, Gur C, Celebi F et al (2017) The protective effect of quercetin on cyclophosphamide-Induced lung toxicity in rats. Biomed Pharmacother 92:303–307CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Rehman MU, Tahir M, Ali F, Qamar W, Lateef A, Khan R et al (2012) Cyclophosphamide-induced nephrotoxicity, genotoxicity, and damage in kidney genomic DNA of Swiss albino mice: the protective effect of Ellagic acid. Mol Cell Biochem 365:119–127CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Korkmaz A, Topal T, Oter S (2007) Pathophysiological aspects of cyclophosphamide and ifosfamide induced hemorrhagic cystitis; implication of reactive oxygen and nitrogen species as well as PARP activation. Cell Biol Toxicol 23:303–312CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Chakraborty P, Roy SS, Basu A, Bhattacharya S (2016) Sensitization of cancer cells to cyclophosphamide therapy by an organoselenium compound through ROS-mediated apoptosis. Biomed Pharmacother 84:1992–1999CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Chen XY, Xia HX, Guan HY, Li B, Zhang W (2016) Follicle loss and apoptosis in cyclophosphamide-treated mice: what’s the matter? Int J Mol Sci 17Google Scholar
  143. 143.
    Silva A, Girio A, Cebola I, Santos CI, Antunes F, Barata JT (2011) Intracellular reactive oxygen species are essential for PI3K/Akt/mTOR-dependent IL-7-mediated viability of T-cell acute lymphoblastic leukemia cells. Leukemia 25:960–967CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Park KR, Nam D, Yun HM, Lee SG, Jang HJ, Sethi G et al (2011) beta-Caryophyllene oxide inhibits growth and induces apoptosis through the suppression of PI3K/AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation. Cancer Lett 312:178–188CrossRefPubMedPubMedCentralGoogle Scholar
  145. 145.
    Jonas CR, Puckett AB, Jones DP, Griffith DP, Szeszycki EE, Bergman GF et al (2000) Plasma antioxidant status after high-dose chemotherapy: a randomized trial of parenteral nutrition in bone marrow transplantation patients. Am J Clin Nutr 72:181–189CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Patel JM, Block ER (1985) Cyclophosphamide-induced depression of the antioxidant defense mechanisms of the lung. Exp Lung Res 8:153–165CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Roy SS, Chakraborty P, Biswas J, Bhattacharya S (2014) 2-[5-Selenocyanato-pentyl]-6-amino-benzo[de]isoquinoline-1,3-dione inhibits angiogenesis, induces p53 dependent mitochondrial apoptosis and enhances therapeutic efficacy of cyclophosphamide. Biochimie 105:137–148CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Adams Jr. JD, Klaidman LK. Acrolein-induced oxygen radical formation. Free Radic Biol Med 1993;15:187–193.Google Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Thalita Basso Scandolara
    • 1
  • Bruno Ricardo Pires
    • 1
  • Rodrigo Kern
    • 1
  • Vanessa Jacob Victorino
    • 1
  • Carolina Panis
    • 1
  1. 1.Laboratory of Tumor BiologyState University of West Paraná, UnioesteFrancisco BeltrãoBrazil

Personalised recommendations