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

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.

[1]  M. Sporn,et al.  A new ligand for the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), GW7845, inhibits rat mammary carcinogenesis. , 1999, Cancer research.

[2]  Rajnish A. Gupta,et al.  Controversy: PPARγ as a target for treatment of colorectal cancer , 2002 .

[3]  I. Ellis,et al.  Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. , 2002, Histopathology.

[4]  N. Patel,et al.  Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute inflammation. , 2004, European journal of pharmacology.

[5]  J. Lord,et al.  Serine/threonine protein kinases and apoptosis. , 2000, Experimental cell research.

[6]  Y. Surh,et al.  Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands as bifunctional regulators of cell proliferation. , 2003, Biochemical pharmacology.

[7]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[8]  T. Rosol,et al.  Dietary (n-3) polyunsaturated fatty acids inhibit HER-2/neu-induced breast cancer in mice independently of the PPARgamma ligand rosiglitazone. , 2005, The Journal of nutrition.

[9]  K. Umesono,et al.  The nuclear receptor superfamily: The second decade , 1995, Cell.

[10]  D. Kabra,et al.  Differential effects of tannic acid on cisplatin induced nephrotoxicity in rats , 2007, FEBS letters.

[11]  S. Safe,et al.  Peroxisome Proliferator-activated Receptor γ Agonists Induce Proteasome-dependent Degradation of Cyclin D1 and Estrogen Receptor α in MCF-7 Breast Cancer Cells , 2003 .

[12]  K. Umesono,et al.  Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors , 1992, Nature.

[13]  Y. Surh,et al.  Peroxisome proliferator-activated receptor γ (PPARγ) ligands as bifunctional regulators of cell proliferation , 2003 .

[14]  M. Carpenter,et al.  Resveratrol, but not EGCG, in the diet suppresses DMBA-induced mammary cancer in rats , 2006, Journal of carcinogenesis.

[15]  K. Chien,et al.  PPARγ Is Required for Placental, Cardiac, and Adipose Tissue Development , 1999 .

[16]  S. Safe,et al.  Peroxisome proliferator-activated receptor gamma agonists induce proteasome-dependent degradation of cyclin D1 and estrogen receptor alpha in MCF-7 breast cancer cells. , 2003, Cancer research.

[17]  Lawrence A. Donehower,et al.  Cyclin D1 Repression of Peroxisome Proliferator-Activated Receptor γ Expression and Transactivation , 2003, Molecular and Cellular Biology.

[18]  D. Tripathi,et al.  Intermittent fasting prevents the progression of type I diabetic nephropathy in rats and changes the expression of Sir2 and p53 , 2007, FEBS letters.

[19]  K. Jang,et al.  Rosiglitazone ameliorates cisplatin-induced renal injury in mice. , 2006, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[20]  B. Spiegelman,et al.  PPARγ: a Nuclear Regulator of Metabolism, Differentiation, and Cell Growth* , 2001, The Journal of Biological Chemistry.

[21]  R. Evans,et al.  PPAR gamma is required for placental, cardiac, and adipose tissue development. , 1999, Molecular cell.

[22]  T. Kundu,et al.  Implications of small molecule activators and inhibitors of histone acetyltransferases in chromatin therapy. , 2004, Biochemical pharmacology.

[23]  G. Ramesh,et al.  TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. , 2002, The Journal of clinical investigation.

[24]  O. Straume,et al.  Hyperbaric oxygen alone or combined with 5-FU attenuates growth of DMBA-induced rat mammary tumors. , 2004, Cancer letters.

[25]  E. Wagner,et al.  p38alpha: a suppressor of cell proliferation and tumorigenesis. , 2007, Cell cycle.

[26]  Sudhir V. Shah,et al.  Cisplatin nephrotoxicity is mediated by deoxyribonuclease I. , 2005, Journal of the American Society of Nephrology : JASN.

[27]  M. Musri,et al.  Histone H3 Lysine 4 Dimethylation Signals the Transcriptional Competence of the Adiponectin Promoter in Preadipocytes* , 2006, Journal of Biological Chemistry.

[28]  M. Lisanti,et al.  Acetylation in hormone signaling and the cell cycle. , 2002, Cytokine & growth factor reviews.

[29]  M. Sporn,et al.  A New Ligand for the Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ), GW7845, Inhibits Rat Mammary Carcinogenesis , 1999 .

[30]  C. Edelstein,et al.  Cisplatin-Induced Acute Renal Failure Is Associated with an Increase in the Cytokines Interleukin (IL)-1β, IL-18, IL-6, and Neutrophil Infiltration in the Kidney , 2007, Journal of Pharmacology and Experimental Therapeutics.

[31]  E. Simpson,et al.  Peroxisome proliferator-activated receptor gamma ligands inhibit estrogen biosynthesis in human breast adipose tissue: possible implications for breast cancer therapy. , 2000, Cancer research.

[32]  T. Rosol,et al.  Dietary (n-3) polyunsaturated fatty acids inhibit HER-2/neu-induced breast cancer in mice independently of the PPARgamma ligand rosiglitazone. , 2005, The Journal of nutrition.

[33]  S. Kurdistani.  Histone modifications as markers of cancer prognosis: a cellular view , 2007, British Journal of Cancer.

[34]  B. Spiegelman,et al.  Terminal differentiation of human breast cancer through PPAR gamma. , 1998, Molecular cell.

[35]  A. Baranova,et al.  PPARγ activation by thiazolidinediones (TZDs) may modulate breast carcinoma outcome: the importance of interplay with TGFβ signalling , 2007, Journal of cellular and molecular medicine.

[36]  B. Seed,et al.  PPAR-γ agonists inhibit production of monocyte inflammatory cytokines , 1998, Nature.

[37]  E. Simpson,et al.  Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Estrogen Biosynthesis in Human Breast Adipose Tissue: Possible Implications for Breast Cancer Therapy , 2000 .

[38]  D. Portilla,et al.  Anti-inflammatory effect of fibrate protects from cisplatin-induced ARF. , 2005, American journal of physiology. Renal physiology.

[39]  Rajnish A. Gupta,et al.  Controversy: PPARgamma as a target for treatment of colorectal cancer. , 2002, American journal of physiology. Gastrointestinal and liver physiology.

[40]  G. D. De Zutter,et al.  Pro-apoptotic gene expression mediated by the p38 mitogen-activated protein kinase signal transduction pathway , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[41]  D. Kabra,et al.  Change in histone H3 phosphorylation, MAP kinase p38, SIR 2 and p53 expression by resveratrol in preventing streptozotocin induced type I diabetic nephropathy , 2008, Free radical research.

[42]  M. Hung,et al.  Regulation of the Activity of p38 Mitogen-Activated Protein Kinase by Akt in Cancer and Adenoviral Protein E1A-Mediated Sensitization to Apoptosis , 2003, Molecular and Cellular Biology.

[43]  Chenguang Wang,et al.  Acetylation of nuclear receptors in cellular growth and apoptosis. , 2004, Biochemical pharmacology.

[44]  B. Seed,et al.  PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. , 1998, Nature.

[45]  E. Wagner,et al.  p38α: A Suppressor of Cell Proliferation and Tumorigenesis , 2007 .

[46]  Sandip K. Mishra,et al.  Dynamic chromatin remodeling on the HER2 promoter in human breast cancer cells , 2001, FEBS letters.

[47]  B. Spiegelman,et al.  15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. , 1995, Cell.

[48]  Seong-ho Lee,et al.  A novel peroxisome proliferator–activated receptor γ ligand, MCC-555, induces apoptosis via posttranscriptional regulation of NAG-1 in colorectal cancer cells , 2006, Molecular Cancer Therapeutics.

[49]  G. Ramesh,et al.  TNF-α mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity , 2002 .

[50]  B. Ali,et al.  Agents ameliorating or augmenting the nephrotoxicity of cisplatin and other platinum compounds: a review of some recent research. , 2006, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[51]  S. Nakagawa,et al.  Effect of pre-treatment with St John's Wort on nephrotoxicity of cisplatin in rats. , 2007, Life sciences.

[52]  B. Spiegelman,et al.  PPARgamma : a nuclear regulator of metabolism, differentiation, and cell growth. , 2001, The Journal of biological chemistry.

[53]  Béatrice Desvergne,et al.  Peroxisome-proliferator-activated receptors and cancers: complex stories , 2004, Nature Reviews Cancer.

[54]  I. Ellis,et al.  Pathological prognostic factors in breast cancer. , 1999, Critical reviews in oncology/hematology.