Cancer chemotherapy induces cardiotoxicity by targeting cardiac stem cells

Abstract

Overwhelming data indicate that cancer survivors are at higher risk of cardiovascular diseases because chemotherapy induces cardiotoxicity. Mechanistic explanation of this phenomenon is necessary to advise the clinical practice on the prevention of cardiotoxicity in cancer patients. Here we propose that chemotherapy induces cardiotoxicity by inadvertently interrupting the homeostasis of cardiac stem cells and depleting the resident cardiac stem cells pool. As a result, the heart loses the capability of regeneration and repair and demonstrates the cardiotoxicity symptoms. Our hypothesis is supported by several lines of emerging evidence: the high incidence of cardiotoxicity in paediatric cancer patients who still have more cardiac stem cells in the myocardium; the rescue of anthracycline cardiomyopathy by injection of cardiac stem cells; and the adverse cardiotoxicity induced by inhibitors of oncogenic kinases or pathways which target cardiac stem cells besides cancer cells. This may promote our growing appreciation that cardiac stem cells represent new targets of chemotherapy that contribute to cardiotoxicity and open up novel strategies for the preservation or expansion of the cardiac stem cells pool to overcome cardiotoxicity associated with chemotherapy.

Daunorubicin induces cell death via activation of apoptotic signalling pathway and inactivation of survival pathway in muscle-derived stem cells

“…For example, the enhanced CNS progenitor cell death and suppression of cell division have been seen both in vitro and in vivo after chemotherapeutic treatment (Dietrich et al 2006). Also, it has been shown that cancer chemotherapy induces cardiotoxicity by targeting cardiac stem cells (Li et al 2010). Consequently, the prevention of stem cell loss during cancer treatment could be one of the desirable therapeutic tasks.…”

“…In various organs, the stem cells and cancer cells are subjected to a toxic effect of antineoplastic drugs. It is known that chemotherapy may induce apoptosis in both malignant and normal cells (Hannun 1997;Li et al 2010). Therefore, the protection of stem cells from injuries in tissues is an important therapeutical goal.…”

Local activation of cardiac stem cells for post‐myocardial infarction cardiac repair

“…CSCs express the receptor of growth hormone releasing hormone (GHRH), and GHRH-agonist therapy substantially improved cardiac performance and reduced infarct size, partly via a regenerative process [156]. Pharmacological inhibition of Akt alleviated blockade of lineage commitment in CSCs, and cancer chemotherapy induces cardiotoxicity by targeting CSCs, further confirming pharmacological approaches as modulators of the reservoir of CSCs [89,157]. …”

Drug Discovery Models and Toxicity Testing Using Embryonic and Induced Pluripotent Stem-Cell-Derived Cardiac and Neuronal Cells

“…Drug effects on potassium currents could lead to QT-prolongation, potentially fatal arrhythmias and sometimes cardiomuscular damage without affecting ion channels [ 42 , 74 ]. Cancer chemotherapies might cause cardiomyocyte apoptosis and dysfunction; however, different chemotherapeutics might have different toxicity mechanisms [ 75 , 76 ]. In pharmaceutical industries, the cardiotoxicity test models are based on cell lines, animal cardiomyocytes, and small/large animal models [ 40 , 41 ].…”