期刊
BIOMEDICINE & PHARMACOTHERAPY
卷 101, 期 -, 页码 228-243出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2018.02.088
关键词
Indole-3-carbinol; Doxorubicin; Chemoprotection; Genotoxicity; Cardiotoxicity; Nrf2/ARE pathway; Inflammation
资金
- Science and Engineering Research Board (SERB-DST), New Delhi, India [SB/YS/LS-121/2014]
- University Grant Commission (UGC), New Delhi, India [18-12/2011(ii) EU-V]
- Council of Scientific and Industrial Research (CSIR), New Delhi [09/030(0075)/2015 EMR-I]
- Chittaranjan National Cancer Institute
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 GST pi in bone marrow and cardiac tissues. In connection with that, I3C significantly attenuated DOX-induced inflammation by downregulation of pro-inflammatory mediators, viz., NF-k beta(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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