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

Kulbhushan Tikoo,Parveen Kumar,Jeena Gupta

doi:10.1186/1471-2407-9-107

Abstract

BackgroundAntineoplastic drug cisplatin remains the drug of choice for various solid tumours including breast cancer. But dose dependent nephrotoxicity is the major drawback in majority of platinum based chemotherapy regimens. Recent reports have shown that inflammatory pathways are the main offender for cisplatin induced nephrotoxicity. The present study was undertaken to assess the effect of rosiglitazone, a PPARγ agonist and an anti-inflammatory agent, on cisplatin induced nephrotoxicity, and its anticancer activity in DMBA induced breast cancer rats.MethodsMammary 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.ResultsOur 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.ConclusionTo 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.

Highlights

Antineoplastic drug cisplatin remains the drug of choice for various solid tumours including breast cancer
After clearance of circulating blood, 4% paraformaldehyde in 0.1 M phosphate buffer was perfused for another 5 min
There was no significant change in Blood urea nitrogen (BUN), creatinine and albumin levels in rosiglitazone (8 mg/kg) treated rats (Table 1)

Summary

Introduction

Antineoplastic drug cisplatin remains the drug of choice for various solid tumours including breast cancer. 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]. Higher doses of cisplatin are considered to be more efficacious for cancer chemotherapy; these therapies manifest toxicities such as nephrotoxicity, despite its effectiveness which limits its use [4,5]. Recent reports have shown that cisplatin induced nephrotoxicity is characterized by activation of pro-inflammatory cytokines and chemokines. Blockade of either TNF-α production or its activity prevents the activation of cytokine network and provides protection against cisplatin-induced renal dysfunction and structural damage [8,9]

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