Promotion of Colon Tumors in C57BL/6J-APCmin/+ Mice by Thiazolidinedione PPARγ Agonists and a Structurally Unrelated PPARγ Agonist

Abstract

Thiazolidinedione PPARγ agonists (troglitazone and rosiglitazone) were previously shown to promote colon tumor formation in C57BL/6JAPC^min/+ mice, a model for human familial adenomatous polyposis. This study was conducted to determine if another thiazolidinedione PPARγ agonist, pioglitazone, and a PPARγ agonist structurally unrelated to the thiazolidinedione family, NID525, (a tetrazole-substituted phenoxymethylquinolone), would also promote colon tumors in this mouse model. Mice were treated in-feed with the thiazolidinediones troglitazone (150 mg/kg/day), rosiglitazone (20 mg/kg/day), or pioglitazone (150 mg/kg/day), or with NID525 (150 mg/kg/day) for 8 weeks. An increased incidence in colon tumors compared to controls was observed for all of the thiazolidinedione-treated groups as well as the NID525-treated group. These results indicate that the tumor-promoting effect of PPAR γ agonists in the colon of C57BL/6J-APC^min/+ mice is likely related to the pharmacological activity of this group of drugs and not the thiazolidinedione structure.

Keywords

Thiazolidinedione PPAR gamma agonist colon tumors APC min mouse adenomatous polyposis coli gene.

References

Bonnefoi, M.S. , M.F. Kelley , R.E. Wells , J.E. Sanders , Z. Jayyosi , E. Beys , D.J. Kornbrust , and J.M. Langloss (1995). “Subchronic Toxicity Studies with the Leukotriene D4 Antagonist RG 12525.” Fundam Appl Toxicol 28: 129—38.

Brun, R.P. and B.M. Speigelman (1997). “Obesity and the Adipocyte: PPAR Gamma and the Control of Adipogenesis.” J Endocrinol 155: 217— 8.

DuBois, R.N. , R. Gupta , J. Brockman , B.S. Reddy , S.L. Krakow , and M.A. Lazar (1998). “The Nuclear Eicosanoid Receptor, PPAR gamma, is Aberrantly Expressed in Colonic Cancers.” Carcinogenesis 19: 49—53.

Jacobs, L.R. and J.R. Lupton (1986). “Relationship Between Colonic Luminal pH, Cell Proliferation, and Colon Carcinogenesis in 1,2-dimethylhydrazine Treated Rats Fed High Fiber Diets.” Cancer Res 46: 1727—34.

Jayyosi, Z. , G. McGeehan , and M. Kelley (1999). Therapeutic uses of quinoline derivatives. Patent No. WO 99/20275.

Keller, H. and W. Wahli (1993). “Peroxisome Proliferator-Activated Receptors: A Link Between Endocrinology and Nutrition.” Trends Endocrinol Metab 4: 291—6.

Kitamura, S. , Y. Miyazaki , Y. Shinomura , S. Kondo , S. Kanayama , and Y. Matsuzawa (1999). “Peroxisome Proliferator-Activated Receptor Gamma Induces Growth Arrest and Differentiation Markers of Human Colon Cancer Cells.” Jpn J Cancer Res 90: 75—80.

Kubota, T. , K. Koshizuka , E.A. Williamson , H. Asou , J.W. Said , S. Holden , I. Miyoshi , and H.P. Koeffler (1998). “Ligand for Peroxisome Proliferator-Activated Receptor gamma (troglitazone) has Potent Antitumor Effect Against Human Prostate Cancer both in vitro and in vivo. Cancer Res 58: 3344—52.

Lefebvre, A. -M., I. Chen , P. Desreumaux , J. Najib , J.- C. Fruchart , K. Geboes , M. Briggs , R. Heyman , and J. Auwerx (1998). “Activation of the Peroxisome Proliferator-Activated Receptor gamma Promotes the Development of Colon Tumors in C57BL/6J-APCmin/+ Mice.” Nature Med 4: 1053—7.

10.

Lehmann, J.M. , L.B. Moore , T.A. Smith-Oliver , W.O. Wilkison , T.M. Willson , and S.A. Kliewer (1995). “An Antidiabetic Thiazolidinedione is a High Affinity Ligand for Peroxisome Proliferator-Activated Receptor gamma (PPAR gamma).” J Biol Chem 270: 12953—6.

11.

Mansen, A. , H. Guardiola-Diaz , J. Rafter , C. Branting , and J.A. Gustafsson (1996). Expression of the Peroxisome Proliferator-Activated Receptor (PPAR) in the Mouse Colonic Mucosa. Biochem Biophys Res Commun 222: 844—51.

12.

Moser, A.R. , H.C. Pitot , and W.F. Dove (1990). “A Dominant Mutation That Predisposes to Multiple Intestinal Neoplasia in the Mouse.” Science 247: 322—4.

13.

Mueller, E. , P. Sarraf , P. Tontonoz , R.M. Evans , K.J. Martin , M. Zhang , C. Fletcher , S. Singer , and B.M. Speigelman (1998). “Terminal Differentiation of Human Breast Cancer through PPAR gamma.” Molecular Cell 1: 465—70.

14.

Saez, E. , P. Tontonoz , M.C. Nelson , J.G.A. Alvarez , S.M. Baird , V.A. Thomazy , and R.M. Evans (1998). “Activators of the Nuclear Receptor PPAR gamma Enhance Colon Polyp Formation.” Nature Med 4: 1058—61.

15.

Sarraf, P. , E. Mueller , D. Jones , F.J. King , D.J. DeAngelo , J.B. Partridge , S.A. Holden , L.B. Chen , S. Singer , C. Fletcher , and B.M. Smegelman (1998). “Differentiation and Reversal of Malignant Changes in Colon Cancer Through PPAR gamma.” Nature Med 4: 1046—52.

16.

Sarraf, P. , E. Mueller , W.M. Smith , H.M. Wright , J.B. Kum , L.A. Aaltonen , A. Chapelle , B.M. Speigelman , and C. Eng (1999). “Loss-of-Function Mutations in PPAR gamma Associated with Human Colon Cancer.” Mol Cell 3: 799—804.

17.

Su, L.-K. , K.W. Kinzler , B. Vogelstein , A.C. Preisinger , A.R. Moser , C. Luongo , K.A. Gould , and W.F. Dove (1992). “Multiple Intestinal Neoplasia Caused by a Mutation in the Murine Homolog of the APC Gene.” Science 256: 668—70.

18.

Tontonoz, P. , L. Nagy , J.G. Alvarez , V.A. Thomazy , and R.M. Evans (1998). “PPAR gamma Promotes Monocyte/Macrophage Differentiation and Uptake of Oxidized LDL.” Cell 93: 241—52.

19.

Whitely, L.O. , M.R. Anver , S. Botts , and M.P. Jokinen (1996). Proliferative lesions of the intestine, salivary glands, oral cavity and esophagus in rats. Guides for Toxicologic Pathology. STP/ARP/AFIP, Washington, DC.

20.

Willson, T.M. , J.E. Cobb , D.J. Cowan , R.W. Wiethe , I.D. Correa , S.R. Prakash , K.D. Beck , L.B. Moore , S.A. Kliewer , and J.M. Lehmann (1996). “The Structure-Activity Relationship between Peroxisome Proliferator-Activated Receptor gamma Agonism and the Antihyperglycemic Activity of Thiazolidinediones.” J Med Chem 39: 665—8.

21.

Yu, C.F. , L. Whiteley , O. Carryl , and M.D. Basson (2001). “Differential and Dietary Effects on Colonic and Small Bowel Neoplasia in C57BL/6J and Apc Min/+ Mice. ” Dig Dis Sci 46: 1367—80.