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

Publication date: May 2018
Source:Biomedicine & Pharmacotherapy, Volume 101
Author(s): Subhadip Hajra, Arup Ranjan Patra, Abhishek Basu, Sudin Bhattacharya
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.



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