Protective effects of BTK inhibition by acalabrutinib on cisplatin-induced renal and testicular injury in mice: Modulation of mTOR/AMPK, NLRP3/GSDMD-N, and apoptotic pathways

Abstract

Background: Cisplatin-induced nephrotoxicity and testicular injury pose significant challenges during chemotherapy.

Aim: The current study evaluates the efficacy of acalabrutinib (ACB), a Bruton's tyrosine kinase inhibitor, in mitigating cisplatin-induced damage in renal and testicular tissues in mice.

Methods: Testicular and renal toxicity was induced by a single I.P. injection of cisplatin (25 mg/kg). Mice were randomized into four groups: Normal (treated with vehicle), Cis (cisplatin + vehicle), Cis + ACB (6 mg/kg), and Cis + ACB (12 mg/kg). ACB was administered orally for three consecutive days, starting at Day 0 (1 h before single I.P. injection of cisplatin) and continued for Day 1 and Day 2.

Results: ACB treatment (6 mg/kg and 12 mg/kg) significantly improved renal function by reducing serum creatinine, BUN, and KIM-1 levels, while also attenuating inflammation and apoptosis, as evidenced by decreased NLRP3, CD68, and caspase-3 expression. Additionally, it mitigated molecular damage by downregulating mTOR, AMPK, and GSDMD-N. In testicular tissues, ACB preserved structure, restored spermatogenesis, and improved sperm viability and testosterone levels. The protective effects were associated with reduced inflammation, apoptosis, and pyroptosis, indicated by lower levels of cathepsin L, NLRP3, and GSDMD-N.

Conclusions: These findings suggest that ACB offers a promising therapeutic approach to reduce the adverse effects of cisplatin, potentially enhancing the overall efficacy and safety of chemotherapy regimens.

Keywords: Acalabrutinib; Apoptosis; BTK inhibition; Cisplatin; mTOR/AMPK.