Cirsiliol confers cardio-protection against sunitinib induced cardiotoxicity via synergistic modulation of SIRT1/FOXO3a and endothelin axis: A biochemical, histopathological, and computational experimentation

Abstract

Cardiotoxicity remains a major clinical challenge associated with various environmental and chemotherapeutic toxicants. Sunitinib (SNB) is a potent targeted cancer drug that is reported to induce severe organ damage including renal failure. Cirsiliol (CSL) is a natural flavone that exhibits marvelous pharmacological properties. In this investigation, we explored the potential cardioprotective nature of CSL to counter SNB induced cardiac impairments. Sprague Dawley rats (n = 36) were categorized into control, SNB (25 mgkg⁻¹), SNB (25 mgkg⁻¹) + CSL (10 mgkg⁻¹), and CSL (10 mgkg⁻¹) alone experimented group. SNB exposure led to a notable reduction in the expression of Endothelin Receptor Type B (EDNRB), Forkhead box O3a (FOXO3a), and sirtuin 1 (SIRT1) while exacerbating the expression of P21, P53, Endothelin-1 (EDN-1), Endothelin Receptor Type A (EDNRA). The levels of reactive oxygen species (ROS) and malondialdehyde (MDA) were promoted while the enzymatic activities of hemeoxygenase-1 (HO-1), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GSR), catalase (CAT), and glutathione (GSH) contents were reduced following the SNB exposure. Moreover, SNB intoxication led to a marked elevation in the concentrations of C-reactive protein, creatine kinase-myocardial band (CK-MB), Pro-B-Type natriuretic peptide (ProBNP), troponin-T, Lactate dehydrogenase (LDH), Creatine phosphokinase (CPK), troponin-I and Brain natriuretic peptide (BNP). Cardiac tissues showed sever immune-inflammatory responses after SNB intoxication as confirmed by augmented levels and expressions of cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and total fraction of nuclear factor-kappa B (NF-κB). Furthermore, the SNB administration upregulated the concentrations of cysteine-aspartic proteases-9 (Caspase-9), cysteine-aspartic proteases-3 (Capase-3), and Bcl-2–associated X protein (Bax) while declining the concentration of B-cell lymphoma 2 (Bcl-2). SNB intoxication caused histological disarrays including myofibrillar degeneration, capillary dilation, wavy fibers, necrosis of focal regions, hypertrophy of cardiomyocytes, inflammation and interstitial edema. Nonetheless, CSL therapy notably reversed these pathological changes via upregulating SIRT1/FOXO3a and endothelin pathways while reducing cardiac inflammation, apoptosis and cardiac function markers. Our results are validated through in-silico which showed that CSL showed high binding affinity with key regulatory pathways.