title: 15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors.
abstract: Pharmacologic inhibitors of the prostaglandin-synthesizing COX-2 oncogene prevent the development of premalignant human colon adenomas. However, resistance to treatment is common. In this study, we show that the adenoma prevention activity of the COX-2 inhibitor celecoxib requires the concomitant presence of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) tumor suppressor gene, and that loss of 15-PGDH expression imparts resistance to celecoxib's anti-tumor effects. We first demonstrate that the adenoma-preventive activity of celecoxib is abrogated in mice genetically lacking 15-PGDH. In FVB mice, celecoxib prevents 85% of azoxymethane-induced tumors >1 mm in size, but is essentially inactive in preventing tumor induction in 15-PGDH-null animals. Indeed, celecoxib treated 15-PGDH null animals develop more tumors than do celecoxib naive WT mice. In parallel with the loss of tumor prevention activity, celecoxib-mediated suppression of colonic PGE(2) levels is also markedly attenuated in 15-PGDH-null versus WT mice. Finally, as predicted by the murine models, humans with low colonic 15-PGDH levels also exhibit celecoxib resistance. Specifically, in a colon adenoma prevention trial, in all cases tested, individuals who developed new adenomas while receiving celecoxib treatment were also found as having low colonic 15-PGDH levels.
authors.affiliation: Department of Medicine and Pathology, Ireland Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Myung
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Fink
authors.forename: Earl
authors.initials: E
authors.lastname: Lawrence
authors.forename: James
authors.initials: J
authors.lastname: Lutterbaugh
authors.forename: Peiying
authors.initials: P
authors.lastname: Yang
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Zhou
authors.forename: Danielle
authors.initials: D
authors.lastname: Liu
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Rerko
authors.forename: Joseph
authors.initials: J
authors.lastname: Willis
authors.forename: Dawn
authors.initials: D
authors.lastname: Dawson
authors.forename: Hsin-Hsiung
authors.initials: HH
authors.lastname: Tai
authors.forename: Jill S
authors.initials: JS
authors.lastname: Barnholtz-Sloan
authors.forename: Robert A
authors.initials: RA
authors.lastname: Newman
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bertagnolli
authors.forename: Sanford D
authors.initials: SD
authors.lastname: Markowitz
mesh_terms: D000236:Adenoma / Q000517:prevention & control*; D000818:Animals; D000068579:Celecoxib; D003106:Colon / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000517:prevention & control*; D003113:Colonoscopy; D004335:Drug and Narcotic Control; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics* / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011720:Pyrazoles / Q000378:metabolism / Q000627:therapeutic use*; D013449:Sulfonamides / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D011720:Pyrazoles; D013449:Sulfonamides; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D000068579:Celecoxib