Adriamycin (ADR), a potent anticancer chemotherapeutic agent, used to treat divergent human neoplasms. Its clinical use is limited by various side effects. Various studies have demonstrated that ADR-induced cardiotoxicity is narrated to myocardial oxidative stress, disruption of cellular and mitochondrial Ca2+ homeostasis and DNA damage. Nevertheless, the clear-cut mechanism underlying ADR cardiotoxicity is still not well-defined. Here we describe that development of ADR-induced cardiotoxic mouse model and effect of NAD+/NADH modulation by NQO1 action.
ADR was intraperitoneally injected on C57BL/6 male mice and WK0202 was orally administrated with 20 mg/kg body weight of mice. Cardiac biomarkers (CPK, Trop I, LDH and SGOT) in plasma levels, oxidative biomarkers and mRNA levels of pro-inflammatory cytokines were assayed.
Cardiac biomarkers in sera, oxidative biomarkers, and mRNA levels of pro-inflammatory cytokines were significantly increased in ADR-treated mice. However, these increases were significantly alleviated by WK0202. We also demonstrated that the drop in SIRT1 and SIRT3 activities is critically involved in ADR-induced cardiotoxicity through acetylation of NF-κB p65 and p53. However, increase of NAD+/NADH by WK0202 through NQO1 enzymatic action attenuated ADR-induced cardiotoxicity through recovery of SIRT1 and SIRT3 activities and subsequent deacetylation of NF-κB p65 and p53.
WK0202 has a protective effect against ADR-induced acute cardiotoxicity through NQO1 enzymatic action. Therefore, WK0202 might be a new therapeutic option for preventing chemotherapy-associated side effects.
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All authors have declared no conflicts of interest.