Comparative study on beneficial effects of vitamins B and D in attenuating doxorubicin induced cardiotoxicity in rats: Emphasis on calcium homeostasis
Date
2021
Journal Title
Journal ISSN
Volume Title
Type
Article
Publisher
Elsevier
Series Info
Biomedicine & Pharmacotherapy;140 (2021) 111679
Scientific Journal Rankings
Abstract
The 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.
Description
Scopus
Keywords
Doxorubicin, Cardiotoxicity, Calcium, Nicotinamide, Vitamin D, Alfacalcidol