The 5-aminosalicylic acid (5-ASA) anti-neoplasic effect in the intestine is mediated by PPAR gamma

Olivier Romano, Christel Rousseaux, Bruno Lefebvre, Gian Carlo Naccari, Antoine Cortot, Jean Frederic Colombel, Pierre Desreumaux

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2 Scopus citations

Abstract

Background: Epidemiologic evidence suggests that long-term 5-ASA therapy may prevent the development of colorectal cancer in inflammatory bowel diseases (IBD). The mechanism by which 5-ASA may exert this protective effect is unknown. We have recently shown that 5-ASA is a ligand for PPAR gamma, a nuclear receptor of epithelial cells with antineoplasic colonic properties (1). Aim: to evaluate if PPAR gamma mediates in vitro and in vivo the anti-neoplasic effects of 5-ASA. Methods: HT-29 cell line was treated either by clinically relevant concentrations of 5-ASA (1-5-30 mM), the PPAR gamma ligand rosiglitazone (10-5M) or etoposide (50 mM) used at optimal concentrations. Involvement of PPAR gamma was evaluated by administration of the specific PPAR gamma antagonist GW9662 (10-6M). Epithelial cell growth, proliferation and apoptosis were assessed respectively by nuclear protein Ki-67 staining and TUNEL assay. In vivo, the effect of 5-ASA (5mM daily) on tumor growth was evaluated in the human/mouse xenogtaft model system after engraftment of human colon cancers cells (107 HT29) into SCID mice treated or not with GW9662 (1 mg/kg/day). Results: Compared to untreated cells, incubation of HT-29 cells for 24, 48 and 72h with 5-ASA 5-30 mM resulted in a 60±8 % inhibition of cell growth (p<0.001). Similar results were obtained with the two positive controls rosiglitazone and etoposide. Growth inhibitory activities of 5-ASA and rosiglitazone were abolished by administration of the specific PPAR gamma antagonist GW9662. In comparison to untreated cells, 5-ASA 5-30 mM for 48h inhibited by 63% cell proliferation (35±4% vs 94±1% Ki-67 stained cells, p<0.001). This effect was blocked by GW9662 administration. Similarly, the pro-apoptotic capacity of 5-ASA induced in 75±5 % of cells was also abolished by the PPAR gamma antagonist GW9662 (6±2%, p<0.001). Similar results were obtained when using rosiglitazone as a control. Under daily 5-ASA treatment and compared to untreated mice, a 80% reduction of rumor weight and volume was observed in SCID mice after 3 weeks. This anti-tumorigenic effects of 5-ASA was completely abolished by simultaneous IP administration of GW9662. Conclusion: 5-ASA exerts in vitro and in vivo potent anti-neoplastic effects which are mediated by PPAR gamma. Them data reinforce the clinical interest of 5-ASA as a chemopreventive agent in patients with IBD.

Original languageEnglish
Pages (from-to)A-205
JournalGastroenterology
Volume128
Issue number4 SUPPL. 2
StatePublished - 2005
EventAnnual Meeting of the American-Gastroenterological-Association/ Digestive-Disease-Week - Chicago, IL, United States
Duration: 14 May 200519 May 2005

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