Rosiglitazone synergizes anticancer activity of cisplatin and reduces its nephrotoxicity in 7, 12-dimethyl benz{a}anthracene (DMBA) induced breast cancer rats.
BACKGROUND
Antineoplastic 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 PPARgamma agonist and an anti-inflammatory agent, on cisplatin induced nephrotoxicity, and its anticancer activity in DMBA induced breast cancer rats.


METHODS
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-gamma expression were examined by western blotting.


RESULTS
Our data shows involvement of TNF-alpha in preventing cisplatin induced nephrotoxicity by rosiglitazone. Rosiglitazone pre-treatment to cisplatin increases the expression of p38, PPAR-gamma 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-gamma directly or indirectly alters aberrant gene expression in mammary tumours by changing histone modifications.


CONCLUSIONS
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.
Laboratory of Chromatin Biology, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Punjab, India. tikoo.k@gmail.com
Kulbhushan
K
Tikoo
Parveen
P
Kumar
Jeena
J
Gupta
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001806:Blood Urea Nitrogen; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D006657:Histones / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D012709:Serum Albumin / Q000378:metabolism; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D006657:Histones; D047495:PPAR gamma; D012709:Serum Albumin; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D015127:9,10-Dimethyl-1,2-benzanthracene; D003404:Creatinine; D048051:p38 Mitogen-Activated Protein Kinases; D002945:Cisplatin