Functional Impairment of Human Resident Cardiac Stem Cells Contributes to Trastuzumab (Herceptin®) Cardiotoxicity

摘要: Background: 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 (hCDCs), in addition to previously-reported direct adverse effects on cardiomyocytes. Methods and Results: We found that ERBB2 mRNA and protein (measured by real time PCR and flow cytometry, respectively) were expressed in hCDCs (n=8 patients) at levels comparable to human myocardium. While clinically-relevant concentrations of TZM had no effect on proliferation (by colorimetric quantitative assay), apoptosis, or size of the c-kit positive hCDC subpopulation (both by flow cytometry), in vitro assays demonstrated diminished potential for cardiogenic differentiation (p<0.01; assay: cardiogenic …