Targeting the proinflammatory cytokines, oxidative stress, apoptosis and TGF-ß1/STAT-3 signaling by irbesartan to ameliorate doxorubicin-induced hepatotoxicity.

ABSTRACT

Doxorubicin (DOX) is an anthracycline antibiotic that is used frequently for treatment of various types of malignancies. Hepatotoxicity is one of the serious complications of DOX. The aim of this study was to explore the effect of different doses of irbesartan on doxorubicin-induced hepatotoxicity in mice. Sixty male BALB/c mice were divided into six equal groups as follows Control group; DOX group; Irbesartan (Small dose) group; Irbesartan (Large dose) group; DOX + Irbesartan (Small dose) group and DOX + Irbesartan (Large dose) group. Liver weight/body weight ratio, food intake, serum albumin, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and total bilirubin were measured. Also, tissue antioxidant enzymes, transforming growth factor beta 1 (TGF-ß1), nuclear factor (erythroid-derived 2)-like 2/heme oxygenase-1 (Nrf2/HO-1) content, tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and signal transducer and activator of transcription-3 (STAT-3) were assessed. Parts of the hepatic tissues were subjected to histopathological examination. Irbesartan administration to DOX-treated mice induced significant decrease in serum ALT, AST, ALP, total bilirubin, tissue TGF-ß1, TNF-α, IL-6 and liver weight/body weight ratio associated with significant increase in food intake, serum albumin, tissue Nrf2/HO-1 content, STAT-3 and antioxidant enzymes and significant improvement in the histopathological picture compared to DOX group. This improvement was significant with DOX + Irbesartan large dose compared to DOX + Irbesartan small dose. In conclusion, irbesartan - in a dose-dependent manner - might represent a promising hope for cancer patients to ameliorate DOX-induced hepatotoxicity.