BS39 The angiotensin II receptor blocker candesartan attenuates cisplatin cardiovascular toxicity by suppressing TLR4/NF-κB signalling and oxidative stress

Background The significant progress in cancer treatment has led to a remarkable improvement in the prognosis of patients with cancer. However, cardiovascular complications of cancer treatments represent one of the greatest challenges in the management of patients. The platinum-based drug cisplatin (CIS) is a potent anti-cancer agent and still broadly used in first-line chemotherapy regimens against various solid tumors. Endothelial dysfunction, acute thrombosis, and myocardial infarction are cardiovascular adverse effects of CIS that limit its clinical applications. We have recently reported the protective effect of candesartan against chemotherapy-associated lung oxidative stress. Here, we investigated the involvement of TLR4/NF-κB signalling and oxidative stress in CIS-induced myocardial and vascular injury in rats and the potential protective role of candesartan. Methods Male Wistar rats received candesartan for 10 days and a single dose of CIS on day 7. Blood, heart, and thoracic aorta samples were collected for biochemical, histopathological, immunohistochemical, and immunoblotting assays. The binding affinity of candesartan towards NF-κB p65, Keap1, and cytoglobin was explored in silico. Results Myocardial and aortic tissue injury, elevated reactive oxygen species (ROS), lipid peroxidation (LPO), and myeloperoxidase (MPO), and declined antioxidants were observed in CIS-treated rats. TLR-4, NF-kB, iNOS, and the pro-inflammatory cytokines TNF-α and IL-1β were upregulated in the heart and aorta of CIS-administered rats. Candesartan mitigated tissue injury, suppressed ROS, LPO, MPO, TLR-4, NF-kB, iNOS, and pro-inflammatory cytokines and enhanced antioxidant enzymes. In addition, candesartan improved the contractile function of thoracic aorta, and revealed binding affinity towards NF-κB p65, Keap1, and cytoglobin in silico. Conclusion Cardiovascular toxicity of CIS is associated with oxidative stress and upregulation of TLR4/NF-κB signalling. The angiotensin II receptor blocker candesartan attenuated CIS cardiovascular toxicity via suppression of oxidative stress and inflammation. Conflict of Interest None