Prevention of doxorubicin (DOX)-induced genotoxicity and cardiotoxicity: Effect of plant derived small molecule indole-3-carbinol (I3C) on oxidative stress and inflammation

Abstract

Doxorubicin (DOX) is an anthracycline group of antibiotic available for the treatment of broad spectrum of human cancers. However, patient receiving DOX-therapy, myelosuppression and genotoxicity which may lead to secondary malignancy and dose dependent cardiotoxicity is an imperative adverse effect. Mechanisms behind the DOX-induced toxicities are increased level of oxidative damage, inflammation and apoptosis. Therefore, in search of a potential chemoprotectant, naturally occurring glucosinolate breakdown product Indole-3-Carbinol (I3C) was evaluated against DOX-induced toxicities in Swiss albino mice. DOX was administered (5 mg/kg b.w., i.p.) and I3C was administered (20 mg/kg b.w., p.o.) in concomitant and 15 days pretreatment schedule. Results of the present study showed that I3C appreciably mitigated DOX-induced chromosomal aberrations, micronuclei formation, DNA damage and apoptosis in bone marrow niche. Histopathological observations revealed that DOX-intoxication resulted in massive structural and functional impairment of heart and bone marrow niche. However, oral administration of I3C significantly attenuated DOX-induced oxidative stress in the cardiac tissues as evident from decreased levels of ROS/RNS and lipid peroxidation, and by increased level of glutathione (reduced) and the activity of phase-II antioxidant enzymes. Additionally, administration of I3C significantly (P < 0.05) stimulated Nrf2-mediated activation of antioxidant response element (ARE) pathway and promoted expression of cytoprotective proteins heme oxygenase 1 (HO-1), NAD(P)H:quinine oxidoreductase 1 (NQO1) and GSTπ in bone marrow and cardiac tissues. In connection with that, I3C significantly attenuated DOX-induced inflammation by downregulation of pro-inflammatory mediators, viz., NF-kβ(p50), iNOS, COX-2 and IL-6 expression. Moreover, I3C attenuate DOX-induced apoptosis by up-regulation of Bcl2 and down-regulation of Bax and caspase-3 expression in bone marrow cells. Thus, this study suggests that I3C has promising chemoprotective efficacy against DOX-induced toxicities and indicates its future use as an adjuvant in chemotherapy.

Keywords: Cardiotoxicity; Chemoprotection; Doxorubicin; Genotoxicity; Indole-3-carbinol; Inflammation; Nrf2/ARE pathway.