Doxorubicin causes depletion of cardiac primitive cell pool that may add to the mechanisms of doxorubicin-mediated delayed cardiotoxicity

Doxorubicin is one of the most active anti-cancer drugs, widely used for the treatment of several malignancies, however its clinical implementation is limited by high incidence of cardiovascular events, most serious of them being the cardiomyopathy followed by congestive heart failure. Known studies of the mechanisms of doxorubicin toxicity focused on cardiomyocyte damage. But then cardiac primitive cells are considered to provide the adult heart with a substantial growth reserve determining the function of the heart throughout life. The role of this cell population in the myocardial response to different pathologic stimuli has been documented in animals and humans, suggesting cardiac primitive cells as possible pathophysiologic target in cardiac diseases. We advance the hypothesis that cardiotoxicity of doxorubicin may be due to its effects on cardiac primitive cells. Hence, we examined doxorubicin toxicity on this cell population. CD117-positive cells isolated from adult human normal atria were incubated with increasing concentrations of doxorubicin hydrochloride (0.1, 0.5 and 1μM), followed by the evaluation of proliferation and apoptosis after 12, 24, 48 and 60 hours. Proliferation was evaluated by BrdU incorporation and its rate dropped from 12.84±1.83% (control, n=4) to 2.41±0.27% (24 hours, 1μM, n=4, p