title: 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.
authors.affiliation: a Department of Cancer Chemoprevention , Chittaranjan National Cancer Institute , West Bengal , India.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Basu
authors.affiliation: a Department of Cancer Chemoprevention , Chittaranjan National Cancer Institute , West Bengal , India.
authors.forename: Somnath
authors.initials: S
authors.lastname: Singha Roy
authors.affiliation: a Department of Cancer Chemoprevention , Chittaranjan National Cancer Institute , West Bengal , India.
authors.forename: Arin
authors.initials: A
authors.lastname: Bhattacharjee
authors.affiliation: b Department of Immunoregulation and Immunodiagnostics , Chittaranjan National Cancer Institute , West Bengal , India.
authors.forename: Avishek
authors.initials: A
authors.lastname: Bhuniya
authors.affiliation: b Department of Immunoregulation and Immunodiagnostics , Chittaranjan National Cancer Institute , West Bengal , India.
authors.forename: Rathindranath
authors.initials: R
authors.lastname: Baral
authors.affiliation: c Department of Translational Research , Chittaranjan National Cancer Institute , West Bengal , India.
authors.forename: Jaydip
authors.initials: J
authors.lastname: Biswas
authors.affiliation: a Department of Cancer Chemoprevention , Chittaranjan National Cancer Institute , West Bengal , India.
authors.forename: Sudin
authors.initials: S
authors.lastname: Bhattacharya
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D000975:Antioxidants / Q000378:metabolism; D001806:Blood Urea Nitrogen; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000633:toxicity*; D056831:Coordination Complexes / Q000737:chemistry / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D056831:Coordination Complexes; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D020011:Protective Agents; C000611675:vanadium(III)-cysteine; D003404:Creatinine; D051547:Heme Oxygenase-1; D003545:Cysteine; D002945:Cisplatin
keywords: ARE pathway; Antioxidant; chemotherapy; free radicals; inflammation