| First Author | Rousseaux C | Year | 2013 |
| Journal | Carcinogenesis | Volume | 34 |
| Issue | 11 | Pages | 2580-6 |
| PubMed ID | 23843037 | Mgi Jnum | J:202771 |
| Mgi Id | MGI:5521431 | Doi | 10.1093/carcin/bgt245 |
| Citation | Rousseaux C, et al. (2013) The 5-aminosalicylic acid antineoplastic effect in the intestine is mediated by PPARgamma. Carcinogenesis 34(11):2580-6 |
| abstractText | Epidemiological evidences suggested that 5-aminosalicylic acid (5-ASA) therapy may prevent the development of colorectal cancer in inflammatory bowel disease patients. Our aim is to investigate whether peroxisome proliferator-activated receptor-gamma (PPARgamma) mediates the antineoplastic effects of 5-ASA. HT-29 and Caco-2 cells were treated by 5-ASA, rosiglitazone (PPARgamma ligand) or etoposide (anticarcinogenic drug). Epithelial cell growth, proliferation and apoptosis were assessed by cell count, Ki-67 staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, respectively. The antineoplastic effect of 5-ASA was evaluated in a xenograft tumor model in SCID mice and in azoxymethane (AOM)-induced colon carcinogenesis in A/JOlaHsd mice. The role of PPARgamma was examined by administration of PPARgamma antagonist, GW9662 and in PPAR knockdown cells. Compared with untreated cells, treatment of HT-29 cells by 5-ASA inhibited significantly cell growth and cell proliferation (respectively, 60% and 63%) and induced apoptosis in 75% of cells. These effects were abolished by co-treatment with GW9662 and blunted in PPAR knockdown cells. Contrarily to etoposide, similar inhibitory effects of GW9662 were obtained in HT-29 cells treated with rosiglitazone. In the xenograft model, GW9662 abolished the therapeutic effect of 5-ASA, which decreased tumor weight and volume by 80% in SCID mice compared with untreated mice. In A/JOlaHsd mice, 5-ASA suppressed colon carcinogenesis by decreasing the number of aberrant crypt foci (75%) and aberrant crypts (22%) induced by AOM treatment with an absence of 5-ASA response after GW9662 administration. In conclusion, 5-ASA exerts potent antineoplastic effects that are mediated through PPARgamma. These data provide new rational for designing more effective and safe antineoplastic PPARgamma ligands with topical effects. |
