A new 1,4-Dihydropyridine-Based L-/T-Type Calcium Channel Inhibitor, HM12, Provides in Vivo and in silico Cardioprotective Effects in Doxorubicin-Treated Rats

Abstract

BackgroundDoxorubicin (DOX), an anthracycline anticancer agent, has limited use due to its cardiotoxicity via oxidative stress and mitochondrial dysfunction. This study evaluated HM12, a 1,4-dihydropyridine calcium channel blocker (CCB) derivative, for protective effects against DOX-induced toxicity. MethodsEight groups of adult male Wistar rats received saline, DOX (20 mg/kg), HM12 (5 or 20 mg/kg), nifedipine (NFD, 20 mg/kg), or combinations of DOX with HM12 or NFD. Assessments included blood biochemistry, cardiac biomarkers, oxidative-antioxidant indices, renal and hepatic function tests, and organ histology. In silico docking was performed using human topoisomerase II{beta} (3QX3). ResultsDOX induced marked cardiotoxicity, evidenced by elevated TNF-, IL-6, C-RP, LDH, and cardiac MDA. Renal and hepatic toxicity were also observed, with increased MDA levels. HM12 improved heart weight and significantly reduced IL-6, C-RP, and LDH, though not TNF- . Antioxidant defenses improved, with increased glutathione, catalase, and superoxide dismutase activity. HM12 offered limited protection to renal and hepatic tissues. Histologically, the higher HM12 dose ameliorated cardiac damage. Notably, in silico HM12 exhibited greater binding affinity than NFD and engaged in distinct interaction patterns with 3QX3 that were not observed with DOX. ConclusionHM12 shows cardioprotective effects against DOX-induced toxicity, likely via antioxidant enhancement and modulation of inflammatory markers, though its protection of renal and hepatic tissues is limited.