Vanadium(III)-L-cysteine protects cisplatin-induced nephropathy through activation of Nrf2/HO-1 pathway

Abstract

Cisplatin (CDDP) is one of the first-line anticancer drugs; however, the major limitation of CDDP therapy is development of nephrotoxicity (25–35% cases), whose precise mechanism mainly involves oxidative stress, inflammation and cell death. Therefore, in search of a potential chemoprotectant, an organovanadium complex, viz., vanadium(III)-L-cysteine (VC-III) was evaluated against CDDP-induced nephropathy in mice. CDDP was administered intraperitoneally (5 mg/kg b.w.) and VC-III was given by oral gavage (1 mg/kg b.w.) in concomitant and pre-treatment schedule. The results showed that VC-III administration reduced (p < 0.001) serum creatinine and blood urea nitrogen levels, suggesting amelioration of renal dysfunction. VC-III treatment also significantly (p < 0.001) prevented CDDP-induced generation of reactive oxygen species, reactive nitrogen species, and onset of lipid peroxidation in kidney tissues of the experimental mice. In addition, VC-III also substantially (p < 0.001) restored CDDP-induced depleted activities of the renal antioxidant enzymes such as, superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, and glutathione (reduced) level. Furthermore, histopathological study also confirmed the renoprotective efficacy of VC-III. Western blotting analysis appended by immunohistochemical data showed that VC-III treatment quite effectively reduced the expression of proinflammatory mediators such as, NFκβ, COX-2 and IL-6. VC-III administration also stimulated Nrf2-mediated antioxidant defense system by promotion of downstream antioxidant enzymes, such as HO-1. Moreover, treatment with VC-III significantly (p < 0.001) enhanced CDDP-mediated cytotoxicity in MCF-7 and NCI-H520 human cancer cell lines. Thus, VC-III can serve as a suitable chemoprotectant and increase the therapeutic window of CDDP in cancer patients.

Keywords:

• Antioxidant
• ARE pathway
• chemotherapy
• free radicals
• inflammation

Acknowledgements

This work was supported by Grant from Indian Council of Medical Research (ICMR), New Delhi, India. Abhishek Basu gratefully acknowledges ICMR for Senior Research Fellowship (no. 3/2/2/58/2011/NCD-III). Arin Bhattacharjee also gratefully acknowledges ICMR for Senior Research Fellowship (no. 45/36/2008/PHA-BMS). Somnath Singha Roy also acknowledges Council of Scientific and Industrial Research (CSIR), New Delhi for Research Associateship [02(0141)/13/EMRII]. The authors are thankful to Ms. Soumita De, Senior Research Fellow, Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata for her help during the immunohistochemistry study. The authors are also thankful to Mr. Jyotirmoy Adhikari and Mr. Sumanta Adhikari, Department of Translational Research, Chittaranjan National Cancer Institute for their help during atomic absorption spectroscopic analysis.

Declaration of interest

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