Rosiglitazone synergizes anticancer activity of cisplatin and reduces its nephrotoxicity in 7, 12-dimethyl benz{a}anthracene (DMBA) induced breast cancer rats

Mammary tumours were induced in female Sprague-Dawley rats by feeding orally with dimethylbenz [a]anthracene (DMBA) (60 mg/kg). Cisplatin induced nephropathy was assessed by measurements of blood urea nitrogen, albumin and creatinine levels. Posttranslational modifications of histone H3, mitogen-activated protein (MAP) kinase p38 expression and PPAR-γ expression were examined by western blotting.Our data shows involvement of TNF-α in preventing cisplatin induced nephrotoxicity by rosiglitazone. Rosiglitazone pre-treatment to cisplatin increases the expression of p38, PPAR-γ in mammary tumours and shows maximum tumour reduction. Furthermore, cisplatin induced changes in histone acetylation, phosphorylation and methylation of histone H3 in mammary tumours was ameliorated by pre-treatment of rosiglitazone. Suggesting, PPAR-γ directly or indirectly alters aberrant gene expression in mammary tumours by changing histone modifications.To best of our knowledge this is the first report which shows that pre-treatment of rosiglitazone synergizes the anticancer activity of cisplatin and minimizes cisplatin induced nephrotoxicity in DMBA induced breast cancer.Breast cancer is a complex disease that results from a multi-stage process involving the deregulation of a number of different signalling cascades. About 212,930 new cases of breast cancer were diagnosed every year, of which 40,840 were related to deaths in the United States alone [1]. This continuing magnitude of the breast cancer problem with respect to incidence, morbidity and mortality requires further studies involving novel approach to prevent this disease [2]. Cisplatin, cis- [PtCl2(NHs)2], is a widely used anticancer drug, proved to be beneficial in the treatment of wide variety of solid tumours (head and neck, lung, bladder, colorectal and breast cancer) in various combination chemotherapy regimens [3]. Higher doses of cisplatin are considered to be more efficacious for cancer chemotherapy; however these therapies