title: Functional impairment of human resident cardiac stem cells by the cardiotoxic antineoplastic agent trastuzumab.
abstract: Trastuzumab (TZM), a monoclonal antibody against the ERBB2 protein, increases survival in ERBB2-positive breast cancer patients. Its clinical use, however, is limited by cardiotoxicity. We sought to evaluate whether TZM cardiotoxicity involves inhibition of human adult cardiac-derived stem cells, in addition to previously reported direct adverse effects on cardiomyocytes. To test this idea, we exposed human cardiosphere-derived cells (hCDCs), a natural mixture of cardiac stem cells and supporting cells that has been shown to exert potent regenerative effects, to TZM and tested the effects in vitro and in vivo. We found that ERBB2 mRNA and protein are expressed in hCDCs at levels comparable to those in human myocardium. Although clinically relevant concentrations of TZM had no effect on proliferation, apoptosis, or size of the c-kit-positive hCDC subpopulation, in vitro assays demonstrated diminished potential for cardiogenic differentiation and impaired ability to form microvascular networks in TZM-treated cells. The functional benefit of hCDCs injected into the border zone of acutely infarcted mouse hearts was abrogated by TZM: infarcted animals treated with TZM + hCDCs had a lower ejection fraction, thinner infarct scar, and reduced capillary density in the infarct border zone compared with animals that received hCDCs alone (n = 12 per group). Collectively, these results indicate that TZM inhibits the cardiomyogenic and angiogenic capacities of hCDCs in vitro and abrogates the morphological and functional benefits of hCDC transplantation in vivo. Thus, TZM impairs the function of human resident cardiac stem cells, potentially contributing to TZM cardiotoxicity.
authors.affiliation: Department of Medicine, Division of Cardiology, John Hopkins University, Baltimore, Maryland, USA.
authors.forename: Andreas S
authors.initials: AS
authors.lastname: Barth
authors.forename: Yiqiang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Taosheng
authors.initials: T
authors.lastname: Li
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Smith
authors.forename: Isotta
authors.initials: I
authors.lastname: Chimenti
authors.forename: Ioannis
authors.initials: I
authors.lastname: Terrovitis
authors.forename: Darryl R
authors.initials: DR
authors.lastname: Davis
authors.forename: Eddy
authors.initials: E
authors.lastname: Kizana
authors.forename: Alice S
authors.initials: AS
authors.lastname: Ho
authors.forename: Brian
authors.initials: B
authors.lastname: O'Rourke
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Wolff
authors.forename: Gary
authors.initials: G
authors.lastname: Gerstenblith
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D054715:Cardiotoxins / Q000009:adverse effects* / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D012038:Regeneration / Q000187:drug effects*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D014183:Transplantation, Heterologous; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D054715:Cardiotoxins; D009124:Muscle Proteins; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human