Abdel-Wahab Basel A, El-Shoura Ehab A M, Alqahtani Saad Misfer, Saad Hebatallah M, Bakir Marwa B, Zaafar Dalia
Department of Pharmacology, College of Pharmacy, Najran University, P.O. Box 1988, Najran, Saudi Arabia.
Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 18. doi: 10.1007/s00210-025-03946-x.
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.
酪氨酸激酶抑制剂彻底改变了癌症治疗方式，但其与心脏毒性的关联仍是一个挑战。虽然伊马替尼治疗的病理生理后果涉及多种途径，但我们对这些机制的了解有限。西洛他唑是一种用于间歇性跛行治疗的选择性磷酸二酯酶3抑制剂，以其抗氧化和抗炎作用而闻名。在本研究中，我们旨在通过给予西洛他唑来抵消伊马替尼的心脏毒性作用，同时研究伊马替尼诱导心肌损伤的精确机制。将28只雄性Wistar大鼠分为四组：对照组（口服2 mL/kg生理盐水）、西洛他唑组（口服10 mg/kg）、伊马替尼组（腹腔注射40 mg/kg）和联合组（西洛他唑和伊马替尼）。连续28天每日给药。伊马替尼治疗诱导了氧化应激、促炎反应和心脏毒性生物标志物，同时各种蛋白质和基因表达失调。在伊马替尼中添加西洛他唑减轻了这些有害影响，显著使测得的生物标志物恢复到接近正常水平。组织病理学研究证实了生化结果。西洛他唑与伊马替尼联合给药可有效保护大鼠免受伊马替尼诱导的心肌损伤，降低氧化应激、凋亡和炎症生物标志物，并调节蛋白质、基因和miRNA-195-5p的表达水平。虽然这些发现有望减轻和预防伊马替尼治疗患者的心肌损伤，但仍需要通过临床研究进一步证实。
