title: Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes.
abstract: Doxorubicin is a highly effective anticancer agent but causes cardiotoxicity in many patients. The mechanisms of doxorubicin-induced cardiotoxicity remain incompletely understood. Here we investigated doxorubicin-induced cytotoxicity in human induced pluripotent stem cells-derived cardiomyocytes (iPS-CMs). We found that doxorubicin and related anthracycline agents (e.g., daunorubicin, idarubicin, and epirubicin) significantly upregulated the expression of death receptors (DRs) (TNFR1, Fas, DR4 and DR5) in iPS-derived cardiomyocytes at both protein and mRNA levels. The resulting iPS-CMs cells underwent spontaneous apoptosis which was further enhanced by physiologically relevant death ligands including TNF-related apoptosis inducing ligand (TRAIL). Furthermore, TRAIL potentiated doxorubicin-induced decrease in beating rate and amplitude of iPS-derived cardiomyocytes. These data demonstrate that the induction of death receptors in cardiomyocytes is likely a critical mechanism by which doxorubicin causes cardiotoxicity.
authors.affiliation: Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Liqun
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Baolin
authors.initials: B
authors.lastname: Zhang
mesh_terms: D018943:Anthracyclines / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D066126:Cardiotoxicity / Q000378:metabolism* / Q000473:pathology*; D002460:Cell Line; D004317:Doxorubicin / Q000009:adverse effects*; D055724:Electrophysiological Phenomena / Q000187:drug effects; D053222:Fas Ligand Protein / Q000494:pharmacology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D053218:Receptors, Death Domain / Q000235:genetics* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
chemical_list: D018943:Anthracyclines; D053222:Fas Ligand Protein; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin