title: Sulindac reversal of 15-PGDH-mediated resistance to colon tumor chemoprevention with NSAIDs.
abstract: Non-steroidal anti-inflammatory drugs prevent colorectal cancer by inhibiting cyclooxygenase (COX) enzymes that synthesize tumor-promoting prostaglandins. 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is a tumor suppressor that degrades tumor-promoting prostaglandins. Murine knockout of 15-PGDH increases susceptibility to azoxymethane-induced colon tumors. It also renders these mice resistant to celecoxib, a selective inhibitor of inducible COX-2 during colon neoplasia. Similarly, humans with low colonic 15-PGDH are also resistant to colon adenoma prevention with celecoxib. Here, we used aspirin and sulindac, which inhibit both COX-1 and COX-2, in order to determine if these broader COX inhibitors can prevent colon tumors in 15-PGDH knockout (KO) mice. Unlike celecoxib, sulindac proved highly effective in colon tumor prevention of 15-PGDH KO mice. Significantly, however, aspirin demonstrated no effect on colon tumor incidence in either 15-PGDH wild-type or KO mice, despite a comparable reduction in colonic mucosal Prostaglandin E₂ (PGE₂) levels by both sulindac and aspirin. Notably, colon tumor prevention activity by sulindac was accompanied by a marked induction of lymphoid aggregates and proximal colonic inflammatory mass lesions, a side effect seen to a lesser degree with celecoxib, but not with aspirin. These findings suggest that sulindac may be the most effective agent for colon cancer prevention in humans with low 15-PGDH, but its use may also be associated with inflammatory lesions in the colon.
authors.affiliation: Department of Medicine and Case Comprehensive Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Fink
authors.affiliation: Department of Pathology, Seidman Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Dawson
authors.affiliation: Department of Medicine and Case Comprehensive Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Yongyou
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA, Department of Pathology, Seidman Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Kresak
authors.affiliation: Department of Medicine and Case Comprehensive Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Earl G
authors.initials: EG
authors.lastname: Lawrence
authors.affiliation: Department of General Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA and.
authors.forename: Peiying
authors.initials: P
authors.lastname: Yang
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Jill S
authors.initials: JS
authors.lastname: Barnholtz-Sloan
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA, Department of Pathology, Seidman Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Willis
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.affiliation: Department of Medicine and Case Comprehensive Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA, sxm10@cwru.edu.
authors.forename: Sanford D
authors.initials: SD
authors.lastname: Markowitz
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D001397:Azoxymethane; D002273:Carcinogens; D000068579:Celecoxib; D018890:Chemoprevention; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control*; D051545:Cyclooxygenase 1 / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics*; D007249:Inflammation / Q000276:immunology; D007413:Intestinal Mucosa / Q000473:pathology; D008565:Membrane Proteins / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013467:Sulindac / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D002273:Carcinogens; D052246:Cyclooxygenase 2 Inhibitors; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D013467:Sulindac; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D000068579:Celecoxib; D015232:Dinoprostone; D001397:Azoxymethane; D001241:Aspirin