Structural and functional screening in human induced-pluripotent stem cell-derived cardiomyocytes accurately identifies cardiotoxicity of multiple drug types

Toxicology and Applied Pharmacology

Volumn 285, Issue 1, 2015, Pages 51-60

  Doherty, Kimberly R ^a   Talbert, Dominique R ^a   Trusk, Patricia B ^a   Moran, Diarmuid M ^a   Shell, Scott A ^a   Bacus, Sarah ^a  

^a IQVIA   (United States)

Author keywords

Cardiomyocytes; Cardiotoxicity; Drug evaluation; In vitro; Preclinical; Stem cells

Indexed keywords

ANTINEOPLASTIC AGENT; BIOLOGICAL MARKER; REACTIVE OXYGEN METABOLITE; TROPONIN I;

CELL CULTURE; CELL SURVIVAL; CHEMICAL STRUCTURE; CHEMICALLY INDUCED; CLASSIFICATION; DOSE RESPONSE; DRUG EFFECTS; HEART DISEASE; HEART MUSCLE CELL; HIGH THROUGHPUT SCREENING; HUMAN; LIPID METABOLISM; METABOLISM; OXIDATIVE STRESS; PATHOLOGY; PLURIPOTENT STEM CELL; PROCEDURES; REPRODUCIBILITY; RISK ASSESSMENT; STRUCTURE ACTIVITY RELATION; TIME; TOXICITY TESTING;

ANTINEOPLASTIC AGENTS; BIOLOGICAL MARKERS; CELL SURVIVAL; CELLS, CULTURED; DOSE-RESPONSE RELATIONSHIP, DRUG; HEART DISEASES; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; INDUCED PLURIPOTENT STEM CELLS; LIPID METABOLISM; MOLECULAR STRUCTURE; MYOCYTES, CARDIAC; OXIDATIVE STRESS; REACTIVE OXYGEN SPECIES; REPRODUCIBILITY OF RESULTS; RISK ASSESSMENT; STRUCTURE-ACTIVITY RELATIONSHIP; TIME FACTORS; TOXICITY TESTS; TROPONIN I;

EID: 84934294920     PISSN: 0041008X     EISSN: 10960333     Source Type: Journal    
DOI: 10.1016/j.taap.2015.03.008     Document Type: Article

References (60)

1. Abassi Y.A., et al. Dynamic monitoring of beating periodicity of stem cell-derived cardiomyocytes as a predictive tool for preclinical safety assessment. Br. J. Pharmacol. 2012, 165(5):1424-1441.
2. Arola O.J., et al. Acute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis. Cancer Res. 2000, 60(7):1789-1792.
3. Brueggemann L.I., et al. Novel actions of nonsteroidal anti-inflammatory drugs on vascular ion channels: accounting for cardiovascular side effects and identifying new therapeutic applications. Mol. Cell. Pharmacol. 2010, 2(1):15-19.
4. Cardinale D., Sandri M.T. Role of biomarkers in chemotherapy-induced cardiotoxicity. Prog. Cardiovasc. Dis. 2010, 53(2):121-129.
5. Cohen J.D., et al. Use of human stem cell derived cardiomyocytes to examine sunitinib mediated cardiotoxicity and electrophysiological alterations. Toxicol. Appl. Pharmacol. 2011, 257:74-83.
6. Colombo A., et al. Cardiac toxicity of anticancer agents. Curr. Cardiol. Rep. 2013, 15(5):362.
7. Deavall D.G., et al. Drug-induced oxidative stress and toxicity. J. Toxicol. 2012, 2012:645460.
8. Doherty K.R., et al. Multi-parameter in vitro toxicity testing of crizotinib, sunitinib, erlotinib, and nilotinib in human cardiomyocytes. Toxicol. Appl. Pharmacol. 2013, 272(1):245-255.
9. Eisner D.A., et al. The effects of metabolic inhibition on intracellular calcium and pH in isolated rat ventricular cells. J. Physiol. 1989, 411:393-418.
10. Ernande L., et al. Impaired myocardial radial function in asymptomatic patients with type 2 diabetes mellitus: a speckle-tracking imaging study. J. Am. Soc. Echocardiogr. 2010, 23(12):1266-1272.
11. FDA FDA Drug Safety Communication: FDA requires removal of some prescribing and dispensing restrictions for rosiglitazone-containing diabetes medicines 2013, ([cited 2015 February 24]; Available from: http://www.fda.gov/Drugs/DrugSafety/ucm376389.htm).
12. Force T., Kolaja K.L. Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes. Nat. Rev. Drug Discov. 2011, 10:111-126.
13. Glenn D.J., Gardner D.G. Lipids and the heart: neither feast nor famine. Hypertension 2007, 50(3):463-464.
14. Guo L., et al. Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol. Sci. 2011, 123(1):281-289.
15. Guo L., et al. Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. Toxicol. Sci. 2013, 136(2):581-594.
16. ICH S7A Safety Pharmacology Studies for Human Pharmaceuticals 2000, (February 15, 2012; available from:
17. ICH S7B The Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Prolongation) by Human Pharmaceuticals 2005, (February 15, 2012; available from: ).
18. Harrigan E.P., et al. A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition. J. Clin. Psychopharmacol. 2004, 24(1):62-69.
19. Hartigan-Go K., et al. Concentration-related pharmacodynamic effects of thioridazine and its metabolites in humans. Clin. Pharmacol. Ther. 1996, 60(5):543-553.
20. Hasinoff B.B., Patel D. Mechanisms of myocyte cytotoxicity induced by the multikinase inhibitor sorafenib. Cardiovasc. Toxicol. 2010, 10(1):1-8.
21. Hull B.E., Lockwood T.D. Toxic cardiomyopathy: the effect of antipsychotic-antidepressant drugs and calcium on myocardial protein degradation and structural integrity. Toxicol. Appl. Pharmacol. 1986, 86(2):308-324.
22. Jonsson M.K., Wang Q.D., Becker B. Impedance-based detection of beating rhythm and proarrhythmic effects of compounds on stem cell-derived cardiomyocytes. Assay Drug Dev. Technol. 2011, 9(6):589-599.
23. Kelly H.G. Thioridazine and electrocardiographic abnormalities. Can. Med. Assoc. J. 1963, 89(25):1297-1298.
24. Kerkela R., et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat. Med. 2006, 12(8):908-916.
25. Kerkela R., et al. Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase. Clin. Transl. Sci. 2009, 2(1):15-25.
26. Khan J.M., Lyon A.R., Harding S.E. The case for induced pluripotent stem cell-derived cardiomyocytes in pharmacological screening. Br. J. Pharmacol. 2013, 169(2):304-317.
27. Korantzopoulos P., et al. The role of oxidative stress in the pathogenesis and perpetuation of atrial fibrillation. Int. J. Cardiol. 2007, 115(2):135-143.
28. Lamore S.D., et al. Cellular impedance assays for predictive preclinical drug screening of kinase inhibitor cardiovascular toxicity. Toxicol. Sci. 2013, 135(2):402-413.
29. Laverty H., et al. How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines?. Br. J. Pharmacol. 2011, 163(4):675-693.
30. Lipshultz S.E., et al. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N. Engl. J. Med. 1991, 324(12):808-815.
31. Ma J., et al. High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents. Am. J. Physiol. Heart Circ. Physiol. 2011, 301(5):H2006-H2017.
32. MacDonald J.S., Robertson R.T. Toxicity testing in the 21st century: a view from the pharmaceutical industry. Toxicol. Sci. 2009, 110(1):40-46.
33. Minotti G., et al. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol. Rev. 2004, 56(2):185-229.
34. Morton M.J., et al. Predicting changes in cardiac myocyte contractility during early drug discovery with in vitro assays. Toxicol. Appl. Pharmacol. 2014, 279(2):87-94.
35. Newby L.K., et al. Troponin measurements during drug development-considerations for monitoring and management of potential cardiotoxicity: an educational collaboration among the Cardiac Safety Research Consortium, the Duke Clinical Research Institute, and the US Food and Drug Administration. Am. Heart J. 2011, 162(1):64-73.
36. Ng A.C., et al. Findings from left ventricular strain and strain rate imaging in asymptomatic patients with type 2 diabetes mellitus. Am. J. Cardiol. 2009, 104(10):1398-1401.
37. Orphanos G.S., Ioannidis G.N., Ardavanis A.G. Cardiotoxicity induced by tyrosine kinase inhibitors. Acta Oncol. 2009, 48:964-970.
38. Paakkari I. Cardiotoxicity of new antihistamines and cisapride. Toxicol. Lett. 2002, 127(1-3):279-284.
39. Palmer J.A., et al. Establishment and assessment of a new human embryonic stem cell-based biomarker assay for developmental toxicity screening. Birth Defects Res. B Dev. Reprod. Toxicol. 2013, 98(4):343-363.
40. Park E., et al. The impact of drug-related QT prolongation on FDA regulatory decisions. Int. J. Cardiol. 2013, 168(5):4975-4976.
41. Peters M.F., et al. Human stem cell-derived cardiomyocytes in cellular impedance assays: bringing cardiotoxicity screening to the front line. Cardiovasc. Toxicol. 2015, 15(2):317-326.
42. Pointon A., et al. Phenotypic profiling of structural cardiotoxins in vitro reveals dependency on multiple mechanisms of toxicity. Toxicol. Sci. 2013, 132(2):317-326.
43. Redfern W.S., et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. 2003, 58(1):32-45.
44. Sager P.T., et al. Rechanneling the cardiac proarrhythmia safety paradigm: a meeting report from the Cardiac Safety Research Consortium. Am. Heart J. 2014, 167(3):292-300.
45. Salvo F., et al. Cardiovascular events associated with the long-term use of NSAIDs: a review of randomized controlled trials and observational studies. Expert Opin. Drug Saf. 2014, 13(5):573-585.
46. Sawyer D.B., et al. Mechanisms of anthracycline cardiac injury: can we identify strategies for cardioprotection?. Prog. Cardiovasc. Dis. 2010, 53(2):105-113.
47. Seidman A., et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J. Clin. Oncol. 2002, 20(5):1215-1221.
48. Shapiro M.S. An ion channel hypothesis to explain divergent cardiovascular safety of cyclooxygenase-2 inhibitors: the answer to a hotly debated puzzle?. Mol. Pharmacol. 2009, 76(5):942-945.
49. Simunek T., et al. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol. Rep. 2009, 61(1):154-171.
50. Sirenko O., et al. Assessment of beating parameters in human induced pluripotent stem cells enables quantitative in vitro screening for cardiotoxicity. Toxicol. Appl. Pharmacol. 2013, 273(3):500-507.
51. Stone J.C., et al. Was there really any evidence that rosiglitazone increased the risk of myocardial infarction or death from cardiovascular causes?. Pharmacoepidemiol. Drug Saf. 2015, 24(3):223-227.
52. Sugamura K., Keaney J.F. Reactive oxygen species in cardiovascular disease. Free Radic. Biol. Med. 2011, 51(5):978-992.
53. Szczepaniak L.S., et al. Forgotten but not gone: the rediscovery of fatty heart, the most common unrecognized disease in America. Circ. Res. 2007, 101(8):759-767.
54. ter Keurs H.E., et al. Damage induced arrhythmias: mechanisms and implications. Can. J. Physiol. Pharmacol. 2001, 79(1):73-81.
55. Thomas S.H. Drugs, QT interval abnormalities and ventricular arrhythmias. Adverse Drug React. Toxicol. Rev. 1994, 13(2):77-102.
56. van de Water F.M., et al. High content screening analysis of phospholipidosis: validation of a 96-well assay with CHO-K1 and HepG2 cells for the prediction of in vivo based phospholipidosis. Toxicol. In Vitro 2011, 25(8):1870-1882.
57. Volkova M., Russell R. Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr. Cardiol. Rev. 2011, 7(4):214-220.
58. Whelan R.S., Kaplinskiy V., Kitsis R.N. Cell death in the pathogenesis of heart disease: mechanisms and significance. Annu. Rev. Physiol. 2010, 72:19-44.
59. Wolf A., et al. Preclinical evaluation of potential nilotinib cardiotoxicity. Leuk. Res. 2011, 35:631-637.
60. Yeh E.T., et al. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation 2004, 109(25):3122-3131.