Cilostazol alleviates imatinib-induced myocardial injury in rats by modulating the TGF-β1/MAPK, SHC/Grb2/SOS signaling pathways and upregulating miRNA-195-5P.

Abstract

Tyrosine kinase inhibitors have revolutionized cancer treatment, yet their association with cardiotoxicity remains a challenge. While the pathophysiological consequences of imatinib therapy involve diverse pathways, our understanding of these mechanisms is limited. Cilostazol, a selective phosphodiesterase 3 inhibitor used in intermittent claudication treatment, is known for its antioxidant and anti-inflammatory effects. In this study, we aimed to counteract the cardiotoxic effects of imatinib by administering cilostazol, concurrently investigating the precise mechanisms underlying imatinib-induced myocardial injury. Twenty-eight male Wistar rats were categorized into four groups: control (2 mL/kg normal saline, orally), cilostazol (10 mg/kg, orally), imatinib (40 mg/kg, intraperitonially), and combination (cilostazol and imatinib). Daily treatments were administered for 28 consecutive days. Imatinib therapy induced oxidative stress, pro-inflammatory responses, and cardiotoxicity biomarkers, alongside dysregulation of various protein and gene expressions. The addition of cilostazol to imatinib mitigated these deleterious effects, notably restoring measured biomarkers close to normal values. Histopathological investigations corroborated the biochemical findings. The co-administration of cilostazol with imatinib effectively protects against imatinib-induced myocardial injury in rats, reducing oxidative stress, apoptotic and inflammatory biomarkers, and modulating protein, gene, and miRNA-195-5p expression levels. While promising for alleviating and protecting against myocardial injury in imatinib-treated patients, these findings necessitate further confirmation through clinical studies.