Increased Intracellular Free Zinc Has Pleiotropic Effects on Doxorubicin-Induced Cytotoxicity in hiPCS-CMs Cells

(1) the mechanisms and outcomes of doxorubicin (DOX)-dependent toxicity upon changed intracellular zinc (Zn) concentrations in the cardiomyocytes obtained from human-induced pluripotent stem cells (hiPCS-CMs) were investigated; (2) cells exposed to the DOX were pretreated or cotreated with zinc pyrythione (ZnPyr) and various cellular endpoints and mechanisms were analyzed via cytometric methods; (3) both DOX concentrations (0.3 and 1 µM) induced a concentration-dependent loss of viability, an activation of autophagy, cell death, and the appearance of senescence. These phenotypes were preceded by an oxidative burst, DNA damage, and a loss of mitochondrial and lysosomal integrity. Furthermore, in DOX-treated cells, proinflammatory and stress kinase signaling (in particular, JNK and ERK) were upregulated upon the loss of free intracellular Zn pools. Increased free Zn concentrations proved to have both inhibitory and stimulatory effects on the investigated DOX-related molecular mechanisms, as well as on signaling pathways on the resulting cell fates; and (4) free intracellular Zn pools, their status, and their elevation might have, in a specific context, a pleiotropic impact upon DOX-dependent cardiotoxicity.