Attenuation of Paclitaxel-induced toxicities by polyphenolic natural compound rutin through inhibition of apoptosis and activation of NRF2/ARE signaling pathways

Abstract

Paclitaxel is the first microtubule-stabilizing drug widely used as an antineoplastic agent. Hepatotoxicity, nephrotoxicity and myeloid suppression may lead to secondary malignancy which is an important adverse effect of paclitaxel-therapy. In this study, we have evaluated the potential protective role of natural flavonoid rutin against paclitaxel-induced toxicities in BALB/cmice. Paclitaxel was administered intraperitoneally (in alternate days at a dose of 8.5 mg/kg b.w.) and rutin was given every day by oral gavages (20 mg/kg b.w.) in BALB/c mice. Results showed that administration of paclitaxel significantly (P<0.05) increased the generation of ROS and NO in bone marrow, liver and kidney tissues. In contrast, co-administration of rutin and paclitaxel significantly (p<0.05) reduced the intracellular ROS and NO levels, reversed the toxic effects of paclitaxel through NRF2-mediated activation of antioxidant response element (ARE) pathway and upregulated activity of several phase-II antioxidant enzymes. Furthermore, rutin treatment inhibited apoptosis by downregulated expression of Bax, caspase-3 and cPARP in bone marrow, liver and kidney tissues. Additionally, the chemoprotective potential of rutin was confirmed by histopathological analysis. Thus, our results suggest that co-administration of rutin may serve as a promising preventive strategy against paclitaxel induced toxicities and indicate its future use as an adjuvant in chemotherapy.