title: The 5-aminosalicylic acid antineoplastic effect in the intestine is mediated by PPARγ.
abstract: 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-γ (PPARγ) mediates the antineoplastic effects of 5-ASA. HT-29 and Caco-2 cells were treated by 5-ASA, rosiglitazone (PPARγ 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 PPARγ was examined by administration of PPARγ 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 PPARγ. These data provide new rational for designing more effective and safe antineoplastic PPARγ ligands with topical effects.
authors.affiliation: Department of Project Management, Intestinal Biotech Development, 59045 Lille, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Rousseaux
authors.forename: Noura
authors.initials: N
authors.lastname: El-Jamal
authors.forename: Mathurin
authors.initials: M
authors.lastname: Fumery
authors.forename: Caroline
authors.initials: C
authors.lastname: Dubuquoy
authors.forename: Olivier
authors.initials: O
authors.lastname: Romano
authors.forename: Denis
authors.initials: D
authors.lastname: Chatelain
authors.forename: Audrey
authors.initials: A
authors.lastname: Langlois
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bertin
authors.forename: David
authors.initials: D
authors.lastname: Buob
authors.forename: Jean Frederic
authors.initials: JF
authors.lastname: Colombel
authors.forename: Antoine
authors.initials: A
authors.lastname: Cortot
authors.forename: Pierre
authors.initials: P
authors.lastname: Desreumaux
authors.forename: Laurent
authors.initials: L
authors.lastname: Dubuquoy
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001397:Azoxymethane / Q000633:toxicity; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D008297:Male; D019804:Mesalamine / Q000494:pharmacology*; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D047495:PPAR gamma; D019804:Mesalamine; D001397:Azoxymethane