Awad, Heba HEl-Derany, Marwa OMantawy, Eman MMichel, Haidy EEl-Naa, Mona MSalah El-Din, Rania AEl-Brairy, Amany IEl-Demerdash, Ebtehal2021-06-082021-06-082021https://doi.org/10.1016/j.biopha.2021.111679https://qrgo.page.link/664BRScopusThe use of doxorubicin (DOX) to treat various tumors is limited by its cardiotoxicity. This study aimed to investigate and compare the cardioprotective effects of nicotinamide (NAM) and alfacalcidol (1α(OH)D3), against DOX-induced cardiotoxicity. Sprague Dawley male rats received DOX (5 mg/kg, i.p.) once/week for four consecutive weeks. Treated groups received either NAM (600 mg/kg, p.o.) for 28 consecutive days or 1α(OH)D3 (0.5 ug/kg, i.p.) once/week for four consecutive weeks. DOX elicited marked cardiac tissue injury manifested by elevated serum cardiotoxicity indices, conduction and histopathological abnormalities. Both NAM and 1α(OH)D3 successfully reversed all these changes. From the mechanistic point of view, DOX provoked intense cytosolic and mitochondrial calcium (Ca2+) overload hence switching on calpain1 (CPN1) and mitochondrial-mediated apoptotic cascades as confirmed by upregulating Bax and caspase-3 while downregulating Bcl-2 expression. DOX also disrupted cardiac bioenergetics as evidenced by adenosine triphosphate (ATP) depletion and a declined ATP/ADP ratio. Moreover, DOX upregulated the Ca2+ sensor; calmodulin kinase II gamma (CaMKII-δ) which further contributed to cardiac damage. Interestingly, co-treatment with either NAM or 1α(OH)D3 reversed all DOX associated abnormalities by preserving Ca2+ homeostasis, replenishing ATP stores and obstructing apoptotic events. Additionally, DOX prompted nuclear factor kappa B (NF-κB) dependent inflammatory re- sponses and subsequently upregulated interleukin-6 (IL-6) expression. Co-treatment with NAM or 1α(OH)D3 effectively obstructed these inflammatory signals. Remarkably, NAM showed superior beneficial cardioprotective properties over 1α(OH)D3. Both NAM and 1α(OH)D3 efficiently attenuated DOX-cardiomyopathy mainly via preserving Ca2+ homeostasis and diminishing apoptotic and inflammatory pathways. NAM definitely exhibited effective cardioprotective capabilities over 1α(OH)D3.en-USDoxorubicinCardiotoxicityCalciumNicotinamideVitamin DAlfacalcidolArticlehttps://doi.org/10.1016/j.biopha.2021.111679