A new 1,4-dihydropyridine-based L-/T-type calcium channel inhibitor, provides in- vivo and silico cardioprotective effects in doxorubicin toxicity in rats

Introduction Doxorubicin (DOX) is an anthracycline anticancer agent whose clinical utility is constrained by dose-dependent cardiotoxicity. This exploratory experimental-focused study evaluated HM12, a 1,4-dihydropyridine calcium channel blocker (CCB) derivative, for protective effects against DOX-induced toxicity. Methods Eight groups of adult male Wistar rats received saline, DOX (20 mg/kg, i.p. ), lower and upper HM12 doses (5 or 20 mg/kg, p.o. ), nifedipine (NFD, 20 mg/kg, p.o. ), 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 the human topoisomerase IIβ (PDB ID: 3QX3). Results DOX induced marked cardiotoxicity, evidenced by elevated tumor necrosis factor-alpha, C - reactive protein, lactate dehydrogenase, interleukin-6 and malondialdehyde. Renal and hepatic toxicity were also observed. However, HM12 improved heart weight, selectively reduced cardiac biomarkers, and improved antioxidant defenses. The HM12 doses mitigated cardiac damage, but offered limited protection to renal and hepatic tissues. Notably, in silico HM12 exhibited greater binding affinity than NFD and engaged in distinct interaction patterns with 3QX3. Discussion HM12 exhibits cardioprotective effects against DOX-induced toxicity through antioxidant enhancement and modulation of inflammatory markers, although its protection of renal and hepatic tissues is limited.