The 5-aminosalicylic acid (5-ASA) anti-neoplastic effect in the intestine is mediated by PPARγ
Menée in vitro et à l'aide d'une xénogreffe sur deux modèles murins, cette étude montre que l'acide 5-aminosalicylique a un effet chimiopréventif sur la carcinogenèse colorectale par l'intermédiaire du récepteur PPARγ
BACKGROUND : Epidemiological evidences suggested that 5-ASA therapy may prevent the development of colorectal cancer in inflammatory bowel disease (IBD) patients. Our aim is to investigate whether PPARγ mediates the anti-neoplastic effects of 5-ASA.
METHODS : HT-29 and Caco-2 cells were treated by 5-ASA, rosiglitazone (PPARγ ligand), or etoposide (anti-carcinogenic drug, topoisomerase II inhibitor). Epithelial cell growth, proliferation and apoptosis were assessed by cell count, Ki-67 staining and TUNEL assay respectively. The anti-neoplastic 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 PPARγ was examined by administration of PPARγ antagonist, GW9662.
RESULTS : Compared to 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 a co-treatment with GW9662. In contrast with 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 to 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 administration of GW9662.
CONCLUSION : 5-ASA exerts potent anti-neoplastic effects which are mediated through PPARγ. These data provide new rational for further designing more effective and safe anti-neoplastic PPARγ ligands with topical effects.
http://carcin.oxfordjournals.org/content/early/2013/07/10/carcin.bgt245.abstract 2013