TYROSINE KINASE INHIBITOR CARDIOTOXICITY AND CARDIAC STEM CELLS

We examined the effect of several recently-introduced anti-oncogenic agents acting against the tyrosine kinase (Trk) receptor family on the survival and biological characteristics of human endogenous cardiac stem cells (eCSCs) in vitro. Three of these Trk inhibitor (Trk-I) drugs (imatinib mesylate; sunitinib malate; sorafenib tosylate) were examined, due to their contrasting ranges of Trk targets, using concentrations comparable to the ‘peak’ and ‘trough’ levels seen in clinical plasma samples (for 24 hours and 7?days respectively). The cardiotoxicity associated with Trk-Is may involve their damaging effects on the resident eCSCs through inhibition of the ability of the CSCs to: maintain their stemness and self-renewal; generate new cardiomyocytes and other cells needed for cardiac tissue homeostasis; produce pro-survival growth factors supporting other injured cells in the myocardium. We identified an impact of all three drugs upon eCSC survival, using a fluorescein diacetate viability assay, with effects seen with ‘peak’ and ‘trough’ concentrations. Expression levels of several genes (Akt, HGF, Wnt2, Nkx2.5) linked with eCSC-to-cardiomyocyte lineage differentiation were significantly reduced by Trk-I application. Further to this, examination of the percentages of eCSCs which committed to the cardiomyocyte lineage during differentiation for 14 days was significantly reduced by sorafenib tosylate. In addition, the Trk-Is’ impacts upon a range of pro-survival growth factors (previously identified as being expressed by eCSCs), and second messenger systems linked with the targeted Trk receptors were examined. In summary, we identified that Trk-Is impact upon human eCSC biology and their ability to contribute to myocardial tissue repair.