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Abstract

Anthracycline-induced cardiotoxicity (AIC) is a serious and common side effect of anthracycline therapy. Identification of genes and genetic variants associated with AIC risk has clinical potential as a cardiotoxicity predictive tool and to allow the development of personalized therapies. In this review, we provide an overview of the function of known AIC genes identified by association studies and categorize them based on their mechanistic implication in AIC. We also discuss the importance of functional validation of AIC-associated variants in human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) to advance the implementation of genetic predictive biomarkers. Finally, we review how patient-specific hiPSC-CMs can be used to identify novel patient-relevant functional targets and for the discovery of cardioprotectant drugs to prevent AIC. Implementation of functional validation and use of hiPSC-CMs for drug discovery will identify the next generation of highly effective and personalized cardioprotectants and accelerate the inclusion of approved AIC biomarkers into clinical practice.

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2024-01-23
2024-12-13
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Literature Cited

  1. 1.
    Venkatesh P, Kasi A. 2022. Anthracyclines Treasure Island, FL: StatPearls
    [Google Scholar]
  2. 2.
    Hudson MM, Ness KK, Gurney JG, Mulrooney DA, Chemaitilly W et al. 2013. Clinical ascertainment of health outcomes among adults treated for childhood cancer. JAMA 309:2371–81
    [Google Scholar]
  3. 3.
    van Dalen EC, Raphaël MF, Caron HN, Kremer LCM. 2014. Treatment including anthracyclines versus treatment not including anthracyclines for childhood cancer. Cochrane Database Syst. Rev. 9:CD006647
    [Google Scholar]
  4. 4.
    Cardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni CA et al. 2015. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 131:1981–88
    [Google Scholar]
  5. 5.
    Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP. 1991. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N. Engl. J. Med. 324:808–15
    [Google Scholar]
  6. 6.
    Lipshultz SE, Cochran TR, Franco VI, Miller TL. 2013. Treatment-related cardiotoxicity in survivors of childhood cancer. Nat. Rev. Clin. Oncol. 10:697–710
    [Google Scholar]
  7. 7.
    Mulrooney DA, Yeazel MW, Kawashima T, Mertens AC, Mitby P et al. 2009. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 339:b4606
    [Google Scholar]
  8. 8.
    van der Pal HJ, van Dalen EC, van Delden E, van Dijk IW, Kok WE et al. 2012. High risk of symptomatic cardiac events in childhood cancer survivors. J. Clin. Oncol. 30:1429–37
    [Google Scholar]
  9. 9.
    Armenian S, Bhatia S. 2018. Predicting and preventing anthracycline-related cardiotoxicity. Am. Soc. Clin. Oncol. Educ. Book 38:3–12
    [Google Scholar]
  10. 10.
    Chang VY, Wang JJ. 2018. Pharmacogenetics of chemotherapy-induced cardiotoxicity. Curr. Oncol. Rep. 20:52
    [Google Scholar]
  11. 11.
    Hasinoff BB, Herman EH. 2007. Dexrazoxane: how it works in cardiac and tumor cells. Is it a prodrug or is it a drug?. Cardiovasc. Toxicol. 7:140–44
    [Google Scholar]
  12. 12.
    Wu V. 2015. Dexrazoxane: a cardioprotectant for pediatric cancer patients receiving anthracyclines. J. Pediatr. Oncol. Nurs. 32:178–84
    [Google Scholar]
  13. 13.
    Tebbi CK, London WB, Friedman D, Villaluna D, De Alarcon PA et al. 2007. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J. Clin. Oncol. 25:493–500
    [Google Scholar]
  14. 14.
    Krischer JP, Epstein S, Cuthbertson DD, Goorin AM, Epstein ML, Lipshultz SE. 1997. Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience. J. Clin. Oncol. 15:1544–52
    [Google Scholar]
  15. 15.
    Macedo AVS, Hajjar LA, Lyon AR, Nascimento BR, Putzu A et al. 2019. Efficacy of dexrazoxane in preventing anthracycline cardiotoxicity in breast cancer. J. Am. Coll. Cardiol. CardioOncol. 1:68–79
    [Google Scholar]
  16. 16.
    D'Angelo NA, Noronha MA, Câmara MCC, Kurnik IS, Feng C et al. 2022. Doxorubicin nanoformulations on therapy against cancer: an overview from the last 10 years. Biomater. Adv. 133:112623
    [Google Scholar]
  17. 17.
    Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ et al. 2022. 2022. AHA/ACC/HFSA Guideline for the Management of Heart Failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 145:e895–1032
    [Google Scholar]
  18. 18.
    Ma Y, Bai F, Qin F, Li J, Liu N et al. 2019. Beta-blockers for the primary prevention of anthracycline-induced cardiotoxicity: a meta-analysis of randomized controlled trials. BMC Pharmacol. Toxicol. 20:18
    [Google Scholar]
  19. 19.
    He D, Hu J, Li Y, Zeng X. 2022. Preventive use of beta-blockers for anthracycline-induced cardiotoxicity: a network meta-analysis. Front. Cardiovasc. Med. 9:968534
    [Google Scholar]
  20. 20.
    Aminkeng F, Bhavsar AP, Visscher H, Rassekh SR, Li Y et al. 2015. A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nat. Genet. 47:1079–84
    [Google Scholar]
  21. 21.
    Schneider BP, Shen F, Gardner L, Radovich M, Li L et al. 2017. Genome-wide association study for anthracycline-induced congestive heart failure. Clin. Cancer Res. 23:43–51
    [Google Scholar]
  22. 22.
    Wells QS, Veatch OJ, Fessel JP, Joon AY, Levinson RT et al. 2017. Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults. Pharmacogenet. Genom. 27:247–54
    [Google Scholar]
  23. 23.
    Wang X, Sun CL, Quinones-Lombrana A, Singh P, Landier W et al. 2016. CELF4 variant and anthracycline-related cardiomyopathy: a Children's Oncology Group genome-wide association study. J. Clin. Oncol. 34:863–70
    [Google Scholar]
  24. 24.
    Park B, Sim SH, Lee KS, Kim HJ, Park IH. 2020. Genome-wide association study of genetic variants related to anthracycline-induced cardiotoxicity in early breast cancer. Cancer Sci. 111:2579–87
    [Google Scholar]
  25. 25.
    Wang X, Singh P, Zhou L, Sharafeldin N, Landier W et al. 2023. Genome-wide association study identifies ROBO2 as a novel susceptibility gene for anthracycline-related cardiomyopathy in childhood cancer survivors. J. Clin. Oncol. 41:1758–69
    [Google Scholar]
  26. 26.
    Velasco-Ruiz A, Nunez-Torres R, Pita G, Wildiers H, Lambrechts D et al. 2021. POLRMT as a novel susceptibility gene for cardiotoxicity in epirubicin treatment of breast cancer patients. Pharmaceutics 13:1942
    [Google Scholar]
  27. 27.
    Aminkeng F, Ross CJD, Rassekh SR, Rieder MJ, Bhavsar AP et al. 2017. Pharmacogenomic screening for anthracycline-induced cardiotoxicity in childhood cancer. Br. J. Clin. Pharmacol. 83:1143–45
    [Google Scholar]
  28. 28.
    Leong SL, Chaiyakunapruk N, Lee SW. 2017. Candidate gene association studies of anthracycline-induced cardiotoxicity: a systematic review and meta-analysis. Sci. Rep. 7:39
    [Google Scholar]
  29. 29.
    Linschoten M, Teske AJ, Cramer MJ, van der Wall E, Asselbergs FW. 2018. Chemotherapy-related cardiac dysfunction: a systematic review of genetic variants modulating individual risk. Circ. Genom. Precis. Med. 11:e001753
    [Google Scholar]
  30. 30.
    Pinheiro EA, Fetterman KA, Burridge PW. 2019. hiPSCs in cardio-oncology: deciphering the genomics. Cardiovasc. Res. 115:935–48
    [Google Scholar]
  31. 31.
    Morash M, Mitchell H, Yu A, Campion T, Beltran H et al. 2018. CATCH-KB: establishing a pharmacogenomics variant repository for chemotherapy-induced cardiotoxicity. AMIA Jt. Summits Transl. Sci. Proc. 2017:168–77
    [Google Scholar]
  32. 32.
    Magdy T, Burridge PW. 2021. Use of hiPSC to explicate genomic predisposition to anthracycline-induced cardiotoxicity. Pharmacogenomics 22:41–54
    [Google Scholar]
  33. 33.
    Garcia-Pavia P, Kim Y, Restrepo-Cordoba MA, Lunde IG, Wakimoto H et al. 2019. Genetic variants associated with cancer therapy-induced cardiomyopathy. Circulation 140:31–41
    [Google Scholar]
  34. 34.
    Burke MA, Cook SA, Seidman JG, Seidman CE. 2016. Clinical and mechanistic insights into the genetics of cardiomyopathy. J. Am. Coll. Cardiol. 68:2871–86
    [Google Scholar]
  35. 35.
    Kim KH, Pereira NL. 2021. Genetics of cardiomyopathy: clinical and mechanistic implications for heart failure. Korean Circ. J. 51:797–836
    [Google Scholar]
  36. 36.
    Pinheiro EA, Magdy T, Burridge PW. 2020. Human in vitro models for assessing the genomic basis of chemotherapy-induced cardiovascular toxicity. J. Cardiovasc. Transl. Res. 13:377–89
    [Google Scholar]
  37. 37.
    Visscher H, Ross CJ, Rassekh SR, Barhdadi A, Dube MP et al. 2012. Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children. J. Clin. Oncol. 30:1422–28
    [Google Scholar]
  38. 38.
    Visscher H, Ross CJ, Rassekh SR, Sandor GS, Caron HN et al. 2013. Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children. Pediatr. Blood Cancer 60:1375–81
    [Google Scholar]
  39. 39.
    Bhatia S. 2020. Genetics of anthracycline cardiomyopathy in cancer survivors: JACC: CardioOncology state-of-the-art review. J. Am. Coll. Cardiol. CardioOncol. 2:539–52
    [Google Scholar]
  40. 40.
    Sapkota Y, Li N, Pierzynski J, Mulrooney DA, Ness KK et al. 2021. Contribution of polygenic risk to hypertension among long-term survivors of childhood cancer. J. Am. Coll. Cardiol. CardioOncol. 3:76–84
    [Google Scholar]
  41. 41.
    Siemens A, Rassekh SR, Ross CJD, Carleton BC. 2023. Development of a dose-adjusted polygenic risk model for anthracycline-induced cardiotoxicity. Ther. Drug Monit. 45:337–44
    [Google Scholar]
  42. 42.
    Magdy T, Jiang Z, Jouni M, Fonoudi H, Lyra-Leite D et al. 2021. RARG variant predictive of doxorubicin-induced cardiotoxicity identifies a cardioprotective therapy. Cell Stem Cell 28:2076–89.e7
    [Google Scholar]
  43. 43.
    Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL. 2012. Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J. Mol. Cell. Cardiol. 52:1213–25
    [Google Scholar]
  44. 44.
    Shi Y, Moon M, Dawood S, McManus B, Liu PP. 2011. Mechanisms and management of doxorubicin cardiotoxicity. Herz 36:296–305
    [Google Scholar]
  45. 45.
    Venditti P, Balestrieri M, De Leo T, Di Meo S. 1998. Free radical involvement in doxorubicin-induced electrophysiological alterations in rat papillary muscle fibres. Cardiovasc. Res. 38:695–702
    [Google Scholar]
  46. 46.
    Kang YJ, Sun X, Chen Y, Zhou Z. 2002. Inhibition of doxorubicin chronic toxicity in catalase-overexpressing transgenic mouse hearts. Chem. Res. Toxicol. 15:1–6
    [Google Scholar]
  47. 47.
    Doroshow JH, Esworthy RS, Chu FF. 2020. Control of doxorubicin-induced, reactive oxygen-related apoptosis by glutathione peroxidase 1 in cardiac fibroblasts. Biochem. Biophys. Rep. 21:100709
    [Google Scholar]
  48. 48.
    Xiong Y, Liu X, Lee CP, Chua BH, Ho YS. 2006. Attenuation of doxorubicin-induced contractile and mitochondrial dysfunction in mouse heart by cellular glutathione peroxidase. Free Radic. Biol. Med. 41:46–55
    [Google Scholar]
  49. 49.
    Townsend DM, Tew KD. 2003. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene 22:7369–75
    [Google Scholar]
  50. 50.
    Mao L, Wang K, Zhang P, Ren S, Sun J et al. 2021. Carbonyl reductase 1 attenuates ischemic brain injury by reducing oxidative stress and neuroinflammation. Transl. Stroke Res. 12:711–24
    [Google Scholar]
  51. 51.
    Oppermann U. 2007. Carbonyl reductases: the complex relationships of mammalian carbonyl- and quinone-reducing enzymes and their role in physiology. Annu. Rev. Pharmacol. Toxicol. 47:293–322
    [Google Scholar]
  52. 52.
    Almontashiri NA, Chen HH, Mailloux RJ, Tatsuta T, Teng AC et al. 2014. SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes. Cell Rep. 7:834–47
    [Google Scholar]
  53. 53.
    Belmonte F, Das S, Sysa-Shah P, Sivakumaran V, Stanley B et al. 2015. ErbB2 overexpression upregulates antioxidant enzymes, reduces basal levels of reactive oxygen species, and protects against doxorubicin cardiotoxicity. Am. J. Physiol. Heart Circ. Physiol. 309:H1271–80
    [Google Scholar]
  54. 54.
    Hordijk PL. 2006. Regulation of NADPH oxidases: the role of Rac proteins. Circ. Res. 98:453–62
    [Google Scholar]
  55. 55.
    Xiang SY, Ouyang K, Yung BS, Miyamoto S, Smrcka AV et al. 2013. PLCε, PKD1, and SSH1L transduce RhoA signaling to protect mitochondria from oxidative stress in the heart. Sci. Signal. 6:ra108
    [Google Scholar]
  56. 56.
    Hildebrandt MAT, Reyes M, Wu X, Pu X, Thompson KA et al. 2017. Hypertension susceptibility loci are associated with anthracycline-related cardiotoxicity in long-term childhood cancer survivors. Sci. Rep. 7:9698
    [Google Scholar]
  57. 57.
    Law CH, Li JM, Chou HC, Chen YH, Chan HL. 2013. Hyaluronic acid-dependent protection in H9C2 cardiomyocytes: a cell model of heart ischemia-reperfusion injury and treatment. Toxicology 303:54–71
    [Google Scholar]
  58. 58.
    Wojnowski L, Kulle B, Schirmer M, Schlüter G, Schmidt A et al. 2005. NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity. Circulation 112:3754–62
    [Google Scholar]
  59. 59.
    Neilan TG, Blake SL, Ichinose F, Raher MJ, Buys ES et al. 2007. Disruption of nitric oxide synthase 3 protects against the cardiac injury, dysfunction, and mortality induced by doxorubicin. Circulation 116:506–14
    [Google Scholar]
  60. 60.
    Riddick DS, Ding X, Wolf CR, Porter TD, Pandey AV et al. 2013. NADPH-cytochrome P450 oxidoreductase: roles in physiology, pharmacology, and toxicology. Drug Metab. Dispos. 41:12–23
    [Google Scholar]
  61. 61.
    Tanaka Y, Nagoshi T, Yoshii A, Oi Y, Takahashi H et al. 2021. Xanthine oxidase inhibition attenuates doxorubicin-induced cardiotoxicity in mice. Free Radic. Biol. Med. 162:298–308
    [Google Scholar]
  62. 62.
    Koczor CA, Jiao Z, Fields E, Russ R, Ludaway T, Lewis W. 2015. AZT-induced mitochondrial toxicity: an epigenetic paradigm for dysregulation of gene expression through mitochondrial oxidative stress. Physiol. Genom. 47:447–54
    [Google Scholar]
  63. 63.
    Minotti G, Ronchi R, Salvatorelli E, Menna P, Cairo G. 2001. Doxorubicin irreversibly inactivates iron regulatory proteins 1 and 2 in cardiomyocytes: evidence for distinct metabolic pathways and implications for iron-mediated cardiotoxicity of antitumor therapy. Cancer Res. 61:8422–28
    [Google Scholar]
  64. 64.
    Gammella E, Maccarinelli F, Buratti P, Recalcati S, Cairo G. 2014. The role of iron in anthracycline cardiotoxicity. Front. Pharmacol. 5:25
    [Google Scholar]
  65. 65.
    Daniłowicz-Szymanowicz L, Swiatczak M, Sikorska K, Starzynski RR, Raczak A, Lipinski P. 2021. Pathogenesis, diagnosis, and clinical implications of hereditary hemochromatosis-the cardiological point of view. Diagnostics 11:1279
    [Google Scholar]
  66. 66.
    Miranda CJ, Makui H, Soares RJ, Bilodeau M, Mui J et al. 2003. Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin. Blood 102:2574–80
    [Google Scholar]
  67. 67.
    Gu J, Song ZP, Gui DM, Hu W, Chen YG, Zhang DD. 2012. Resveratrol attenuates doxorubicin-induced cardiomyocyte apoptosis in lymphoma nude mice by heme oxygenase-1 induction. Cardiovasc. Toxicol. 12:341–49
    [Google Scholar]
  68. 68.
    Otterbein LE, Hedblom A, Harris C, Csizmadia E, Gallo D, Wegiel B. 2011. Heme oxygenase-1 and carbon monoxide modulate DNA repair through ataxia-telangiectasia mutated (ATM) protein. PNAS 108:14491–96
    [Google Scholar]
  69. 69.
    Fedier A, Schwarz VA, Walt H, Carpini RD, Haller U, Fink D. 2001. Resistance to topoisomerase poisons due to loss of DNA mismatch repair. Int. J. Cancer 93:571–76
    [Google Scholar]
  70. 70.
    Lee CC, Hsieh TS. 2018. Wuho/WDR4 deficiency inhibits cell proliferation and induces apoptosis via DNA damage in mouse embryonic fibroblasts. Cell Signal 47:16–26
    [Google Scholar]
  71. 71.
    El-Tokhy MA, Hussein NA, Bedewy AM, Barakat MR. 2014. XPD gene polymorphisms and the effects of induction chemotherapy in cytogenetically normal de novo acute myeloid leukemia patients. Hematology 19:397–403
    [Google Scholar]
  72. 72.
    Inatomi T, Matsuda S, Ishiuchi T, Do Y, Nakayama M et al. 2022. TFB2M and POLRMT are essential for mammalian mitochondrial DNA replication. Biochim. Biophys. Acta Mol. Cell Res. 1869:119167
    [Google Scholar]
  73. 73.
    Matyjaszczyk-Gwarda K, Wojcik T, Lukawska M, Chlopicki S, Walczak M. 2019. Lipophilicity profiling of anthracycline antibiotics by microemulsion electrokinetic chromatography—effects on cardiotoxicity and endotheliotoxicity. Electrophoresis 40:3108–16
    [Google Scholar]
  74. 74.
    Magdy T, Jouni M, Kuo HH, Weddle CJ, Lyra-Leite D et al. 2022. Identification of drug transporter genomic variants and inhibitors that protect against doxorubicin-induced cardiotoxicity. Circulation 145:279–94
    [Google Scholar]
  75. 75.
    Xiao H, Zheng Y, Ma L, Tian L, Sun Q. 2021. Clinically-relevant ABC transporter for anti-cancer drug resistance. Front. Pharmacol. 12:648407
    [Google Scholar]
  76. 76.
    Krajinovic M, Elbared J, Drouin S, Bertout L, Rezgui A et al. 2016. Polymorphisms of ABCC5 and NOS3 genes influence doxorubicin cardiotoxicity in survivors of childhood acute lymphoblastic leukemia. Pharmacogenom. J. 16:530–35
    [Google Scholar]
  77. 77.
    Shinlapawittayatorn K, Chattipakorn SC, Chattipakorn N. 2022. The effects of doxorubicin on cardiac calcium homeostasis and contractile function. J. Cardiol. 80:125–32
    [Google Scholar]
  78. 78.
    Gomes AV, Venkatraman G, Davis JP, Tikunova SB, Engel P et al. 2004. Cardiac troponin T isoforms affect the Ca2+ sensitivity of force development in the presence of slow skeletal troponin I: insights into the role of troponin T isoforms in the fetal heart. J. Biol. Chem. 279:49579–87
    [Google Scholar]
  79. 79.
    Ladd AN, Stenberg MG, Swanson MS, Cooper TA. 2005. Dynamic balance between activation and repression regulates pre-mRNA alternative splicing during heart development. Dev. Dyn. 233:783–93
    [Google Scholar]
  80. 80.
    Cejas RB, Tamano-Blanco M, Fontecha JE, Blanco JG. 2022. Impact of DYRK1A expression on TNNT2 splicing and daunorubicin toxicity in human iPSC-derived cardiomyocytes. Cardiovasc. Toxicol. 22:701–12
    [Google Scholar]
  81. 81.
    Witjas-Paalberends ER, Piroddi N, Stam K, van Dijk SJ, Oliviera VS et al. 2013. Mutations in MYH7 reduce the force generating capacity of sarcomeres in human familial hypertrophic cardiomyopathy. Cardiovasc. Res. 99:432–41
    [Google Scholar]
  82. 82.
    Linschoten M, Teske AJ, Baas AF, Vink A, Dooijes D et al. 2017. Truncating titin (TTN) variants in chemotherapy-induced cardiomyopathy. J. Card. Fail. 23:476–79
    [Google Scholar]
  83. 83.
    Eldemire R, Tharp CA, Taylor MRG, Sbaizero O, Mestroni L. 2021. The sarcomeric spring protein titin: biophysical properties, molecular mechanisms, and genetic mutations associated with heart failure and cardiomyopathy. Curr. Cardiol. Rep. 23:121
    [Google Scholar]
  84. 84.
    Mushlin PS, Cusack BJ, Boucek RJ Jr., Andrejuk T, Li X, Olson RD. 1993. Time-related increases in cardiac concentrations of doxorubicinol could interact with doxorubicin to depress myocardial contractile function. Br. J. Pharmacol. 110:975–82
    [Google Scholar]
  85. 85.
    Zhang Y, Berger SA. 2003. Ketotifen reverses MDR1-mediated multidrug resistance in human breast cancer cells in vitro and alleviates cardiotoxicity induced by doxorubicin in vivo. Cancer Chemother. Pharmacol. 51:407–14
    [Google Scholar]
  86. 86.
    Solanki M, Pointon A, Jones B, Herbert K. 2018. Cytochrome P450 2J2: potential role in drug metabolism and cardiotoxicity. Drug Metab. Dispos. 46:1053–65
    [Google Scholar]
  87. 87.
    Xu X, Zhang XA, Wang DW. 2011. The roles of CYP450 epoxygenases and metabolites, epoxyeicosatrienoic acids, in cardiovascular and malignant diseases. Adv. Drug Deliv. Rev. 63:597–609
    [Google Scholar]
  88. 88.
    Kajiho H, Sakurai K, Minoda T, Yoshikawa M, Nakagawa S et al. 2011. Characterization of RIN3 as a guanine nucleotide exchange factor for the Rab5 subfamily GTPase Rab31. J. Biol. Chem. 286:24364–73
    [Google Scholar]
  89. 89.
    Seebohm G, Strutz-Seebohm N, Birkin R, Dell G, Bucci C et al. 2007. Regulation of endocytic recycling of KCNQ1/KCNE1 potassium channels. Circ. Res. 100:686–92
    [Google Scholar]
  90. 90.
    Liu Y, Yin Z, Xu X, Liu C, Duan X et al. 2021. Crosstalk between the activated Slit2-Robo1 pathway and TGF-β1 signalling promotes cardiac fibrosis. ESC Heart Fail. 8:447–60
    [Google Scholar]
  91. 91.
    Gyongyosi M, Lukovic D, Zlabinger K, Spannbauer A, Gugerell A et al. 2020. Liposomal doxorubicin attenuates cardiotoxicity via induction of interferon-related DNA damage resistance. Cardiovasc. Res. 116:970–82
    [Google Scholar]
  92. 92.
    Litvinukova M, Talavera-Lopez C, Maatz H, Reichart D, Worth CL et al. 2020. Cells of the adult human heart. Nature 588:466–72
    [Google Scholar]
  93. 93.
    Burridge PW, Li YF, Matsa E, Wu H, Ong S-G et al. 2016. Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat. Med. 22:547–56
    [Google Scholar]
  94. 94.
    Sharma A, Burridge PW, McKeithan WL, Serrano R, Shukla P et al. 2017. High-throughput screening of tyrosine kinase inhibitor cardiotoxicity with human induced pluripotent stem cells. Sci. Transl. Med. 9:eaaf2584
    [Google Scholar]
  95. 95.
    Adamcova M, Skarkova V, Seifertova J, Rudolf E 2019. Cardiac troponins are among targets of doxorubicin-induced cardiotoxicity in hiPCS-CMs. Int. J. Mol. Sci. 20:2638
    [Google Scholar]
  96. 96.
    Guo Y, Pu WT. 2020. Cardiomyocyte maturation: new phase in development. Circ. Res. 126:1086–106
    [Google Scholar]
  97. 97.
    Huang H, Christidi E, Shafaattalab S, Davis MK, Tibbits GF, Brunham LR. 2022. RARG S427L attenuates the DNA repair response to doxorubicin in induced pluripotent stem cell-derived cardiomyocytes. Stem Cell Rep. 17:756–65
    [Google Scholar]
  98. 98.
    Wu X, Shen F, Jiang G, Xue G, Philips S et al. 2022. A non-coding GWAS variant impacts anthracycline-induced cardiotoxic phenotypes in human iPSC-derived cardiomyocytes. Nat. Commun. 13:7171
    [Google Scholar]
  99. 99.
    Hasbullah JS, Scott EN, Bhavsar AP, Gunaretnam EP, Miao F et al. 2022. All-trans retinoic acid (ATRA) regulates key genes in the RARG-TOP2B pathway and reduces anthracycline-induced cardiotoxicity. PLOS ONE 17:e0276541
    [Google Scholar]
  100. 100.
    Ivy JR, Gray GA, Holmes MC, Denvir MA, Chapman KE. 2022. Corticosteroid receptors in cardiac health and disease. Adv. Exp. Med. Biol. 1390:109–22
    [Google Scholar]
  101. 101.
    Knowles DA, Burrows CK, Blischak JD, Patterson KM, Serie DJ et al. 2018. Determining the genetic basis of anthracycline-cardiotoxicity by molecular response QTL mapping in induced cardiomyocytes. eLife 7:e33480
    [Google Scholar]
  102. 102.
    Burridge PW, Li YF, Matsa E, Wu H, Ong SG et al. 2016. Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat. Med. 22:547–56
    [Google Scholar]
  103. 103.
    Nordgren KKS, Hampton M, Wallace KB. 2017. Editor's highlight: The altered DNA methylome of chronic doxorubicin exposure in Sprague Dawley rats. Toxicol. Sci. 159:470–79
    [Google Scholar]
  104. 104.
    Ferreira A, Cunha-Oliveira T, Simoes RF, Carvalho FS, Burgeiro A et al. 2017. Altered mitochondrial epigenetics associated with subchronic doxorubicin cardiotoxicity. Toxicology 390:63–73
    [Google Scholar]
  105. 105.
    Pouton CW, Haynes JM. 2005. Pharmaceutical applications of embryonic stem cells. Adv. Drug Deliv. Rev. 57:1918–34
    [Google Scholar]
  106. 106.
    Denning C, Anderson D. 2008. Cardiomyocytes from human embryonic stem cells as predictors of cardiotoxicity. Drug Discov. Today Ther. Strateg. 5:223–32
    [Google Scholar]
  107. 107.
    Lyra-Leite DM, Gutiérrez-Gutiérrez O, Wang M, Zhou Y, Cyganek L, Burridge PW. 2022. A review of protocols for human iPSC culture, cardiac differentiation, subtype-specification, maturation, and direct reprogramming. STAR Protoc. 3:101560
    [Google Scholar]
  108. 108.
    Laco F, Lam AT, Woo TL, Tong G, Ho V et al. 2020. Selection of human induced pluripotent stem cells lines optimization of cardiomyocytes differentiation in an integrated suspension microcarrier bioreactor. Stem Cell Res. Ther. 11:118
    [Google Scholar]
  109. 109.
    Halloin C, Coffee M, Manstein F, Zweigerdt R. 2019. Production of cardiomyocytes from human pluripotent stem cells by bioreactor technologies. Methods Mol. Biol. 1994.55–70
    [Google Scholar]
  110. 110.
    Ito H, Miller SC, Billingham ME, Akimoto H, Torti SV et al. 1990. Doxorubicin selectively inhibits muscle gene expression in cardiac muscle cells in vivo and in vitro. PNAS 87:4275–79
    [Google Scholar]
  111. 111.
    Hayes HB, Nicolini AM, Arrowood CA, Chvatal SA, Wolfson DW et al. 2019. Novel method for action potential measurements from intact cardiac monolayers with multiwell microelectrode array technology. Sci. Rep. 9:11893
    [Google Scholar]
  112. 112.
    Lee J, Ganswein T, Ulusan H, Emmenegger V, Saguner AM et al. 2022. Repeated and on-demand intracellular recordings of cardiomyocytes derived from human-induced pluripotent stem cells. ACS Sens. 7:3181–91
    [Google Scholar]
  113. 113.
    Fermini B, Coyne KP, Coyne ST. 2018. Challenges in designing and executing clinical trials in a dish studies. J. Pharmacol. Toxicol. Methods 94:73–82
    [Google Scholar]
  114. 114.
    Huang CY, Liu CL, Ting CY, Chiu YT, Cheng YC et al. 2019. Human iPSC banking: barriers and opportunities. J. Biomed. Sci. 26:87
    [Google Scholar]
  115. 115.
    Magdy T, Schuldt AJT, Wu JC, Bernstein D, Burridge PW. 2018. Human induced pluripotent stem cell (hiPSC)-derived cells to assess drug cardiotoxicity: opportunities and problems. Annu. Rev. Pharmacol. Toxicol. 58:83–103
    [Google Scholar]
  116. 116.
    Matsui T, Miyamoto K, Yamanaka K, Okai Y, Kaushik EP et al. 2019. Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol. Appl. Pharmacol. 383:114761
    [Google Scholar]
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