Attenuation of doxorubicin-induced cardiotoxicity and genotoxicity by an indole-based natural compound 3,3′-diindolylmethane (DIM) through activation of Nrf2/ARE signaling pathways and inhibiting apoptosis

Abstract

The most crucial complication related to doxorubicin (DOX) therapy is nonspecific cytotoxic effect on healthy normal cells. The clinical use of this broad-spectrum chemotherapeutic agent is restricted due to development of severe form of cardiotoxicity, myelosuppression, and genotoxicity which interfere with therapeutic schedule, compromise treatment outcome and may lead to secondary malignancy. 3,3′-diindolylmethane (DIM) is a naturally occurring plant alkaloid formed by the hydrolysis of indolylmethyl glucosinolate (glucobrassicin). Therefore, the present study was undertaken to investigate the protective role of DIM against DOX-induced toxicity in mice. DOX was administered (5 mg/kg b.w., i.p.) and DIM was administered (25 mg/kg b.w., p.o.) in concomitant and 15 days pretreatment schedule. Results showed that DIM significantly attenuated DOX-induced oxidative stress in the cardiac tissues by reducing the levels of free radicals and lipid peroxidation, and by enhancing the level of glutathione (reduced) and the activity of antioxidant enzymes. The chemoprotective potential of DIM was confirmed by histopathological evaluation of heart and bone marrow niche. Moreover, DIM considerably mitigated DOX-induced clastogenicity, DNA damage, apoptosis, and myeloid hyperplasia in bone marrow niche. In addition, oral administration of DIM significantly (p < .05) stimulated the Nrf2-mediated activation of antioxidant response element (ARE) pathway and promoted expression of ARE-driven cytoprotective proteins, HO-1, NQO1, and glutathione-S-transferase (GST). In connection with that, DIM significantly attenuated DOX-induced apoptosis by upregulation of Bcl-2 expression and downregulation of Bax and caspase-3 expression. Thus, this study suggests that DIM has promising chemoprotective efficacy against DOX-induced toxicity and indicates its future use as an adjuvant in chemotherapy.

Keywords:

• Chemoprotection
• doxorubicin
• 3,3’-diindolylmethane (DIM)
• oxidative stress
• Nrf2/ARE pathway
• apoptosis

Acknowledgements

The authors wish to thank the Director, Chittaranjan National Cancer Institute for his support in this Study.

Disclosure statement

The authors declare that there are no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Funding

This project was funded by Science and Engineering Research Board (SERB), New Delhi, India for Young Scientist scheme (SB/YS/LS-121/2014). Abhishek Basu and Somnath Singha Roy gratefully acknowledge Council of Scientific and Industrial Research (CSIR), New Delhi, for Research Associateship [09/030(0075)/2015 EMR-I] and [02 (0141)/13/EMR-II], respectively, whereas, Arup Ranjan Patra gratefully acknowledge University Grant Commission (UGC), New Delhi, India, for Junior Research Fellowship (18-12/2011(ii) EU-V).