Abstract
Despite its broad applications, cisplatin affords considerable nephro- and hepatotoxicity through triggering inflammatory and oxidative stress cascades. The aim of the current investigation was to study the possible protective effects of tangeretin on cisplatin-induced hepatotoxicity. The impact of tangeretin on cisplatin-evoked hepatic dysfunction and histopathologic changes along with oxidative stress, inflammatory and apoptotic biomarkers were investigated compared to silymarin. Tangeretin pre-treatment significantly improved liver function tests (ALT and AST), inhibited cisplatin-induced lipid profile aberrations (total cholesterol and triglycerides) and diminished histopathologic structural damage in liver tissues. Tangeretin also attenuated cisplatin-induced hepatic inflammatory events as indicated by suppression of tumor necrosis factor-α (TNF-α) and enhancement of interleukin-10 (IL-10). Meanwhile, it lowered malondialdehyde (MDA), nitric oxide (NO) and nuclear factor erythroid 2-related factor 2 (NRF-2) levels with restoration of glutathione (GSH), and glutathione peroxidase (GPx). Regarding mitogen-activated protein kinase (MAPK) pathway, tangeretin attenuated cisplatin-induced increase in phospho-p38, phospho-c-Jun N-terminal kinase (p-JNK) and phospho-extracellular signal-regulated kinase (p-ERK1/2) in liver tissues. In addition, tangeretin downregulated Bax expression with augmentation of Bcl-2 promoting liver cell survival. Our results highlight the protective effects of tangeretin against cisplatin-induced acute hepatic injury via the concerted modulation of inflammation, oxidative stress, MAPKs and apoptotic pathways.
Highlights
Cisplatin is one of the most widely used anticancer agents in the management of different malignancies
In a previous study from our laboratory, we have reported that pretreatment of cisplatin-resistant human ovarian cancer cells with tangeretin synergistically enhanced the growth inhibitory effects induced by low dose of cisplatin [23]
Results revealed that the used dose of cisplatin triggered severe liver injury as indicated by elevated serum alanine aminotransferase (ALT) and aspartate transaminase (AST) enzyme activities
Summary
Cisplatin is one of the most widely used anticancer agents in the management of different malignancies. Tangeretin Protects from Cisplatin-Induced Hepatotoxicity related factor 2; ROS, reactive oxygen species; TNFα, tumor necrosis factor-α. The dose scale necessary to overcome even a small increase in cellular resistance can lead to severe cytotoxicity in normal cells, such as nephrotoxicity, hepatotoxicity and spermiotoxicity which radically limits the clinical usefulness of cisplatin-based therapy [4,5,6]. Cisplatin-induces nephrotoxicity through multiple mechanisms, including hypoxia, the generation of free radicals, inflammation, and apoptosis with an increase in the pro-apoptotic protein Bax and a decrease in the anti-apoptotic protein Bcl-2 [7]. Several reports have implicated free radicals and reactive oxygen species (ROS) in cisplatin toxicity associated with an increase in lipid peroxidation (LPO), decreased levels of protein bound sulfhydryl groups and glutathione [11]
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