15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors.

Hdl Handle:
http://hdl.handle.net/10147/94497
Title:
15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors.
Authors:
Yan, Min; Myung, Seung-Jae; Fink, Stephen P; Lawrence, Earl; Lutterbaugh, James; Yang, Peiying; Zhou, Xiaohua; Liu, Danielle; Rerko, Ronald M; Willis, Joseph; Dawson, Dawn; Tai, Hsin-Hsiung; Barnholtz-Sloan, Jill S; Newman, Robert A; Bertagnolli, Monica M; Markowitz, Sanford D
Affiliation:
Department of Medicine and Pathology, Ireland Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA.
Citation:
15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors. 2009, 106 (23):9409-13 Proc. Natl. Acad. Sci. U.S.A.
Journal:
Proceedings of the National Academy of Sciences of the United States of America
Issue Date:
9-Jun-2009
URI:
http://hdl.handle.net/10147/94497
DOI:
10.1073/pnas.0902367106
PubMed ID:
19470469
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.
Language:
en
Local subject classification:
COLORECTAL CANCER
MeSH:
Adenoma; Animals; Colon; Colonic Neoplasms; Colonoscopy; Drug and Narcotic Control; Humans; Hydroxyprostaglandin Dehydrogenases; Intestinal Mucosa; Mice; Mice, Knockout; Pyrazoles; Sulfonamides
ISSN:
1091-6490

Full metadata record

DC FieldValue Language
dc.contributor.authorYan, Minen
dc.contributor.authorMyung, Seung-Jaeen
dc.contributor.authorFink, Stephen Pen
dc.contributor.authorLawrence, Earlen
dc.contributor.authorLutterbaugh, Jamesen
dc.contributor.authorYang, Peiyingen
dc.contributor.authorZhou, Xiaohuaen
dc.contributor.authorLiu, Danielleen
dc.contributor.authorRerko, Ronald Men
dc.contributor.authorWillis, Josephen
dc.contributor.authorDawson, Dawnen
dc.contributor.authorTai, Hsin-Hsiungen
dc.contributor.authorBarnholtz-Sloan, Jill Sen
dc.contributor.authorNewman, Robert Aen
dc.contributor.authorBertagnolli, Monica Men
dc.contributor.authorMarkowitz, Sanford Den
dc.date.accessioned2010-03-18T11:16:46Z-
dc.date.available2010-03-18T11:16:46Z-
dc.date.issued2009-06-09-
dc.identifier.citation15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors. 2009, 106 (23):9409-13 Proc. Natl. Acad. Sci. U.S.A.en
dc.identifier.issn1091-6490-
dc.identifier.pmid19470469-
dc.identifier.doi10.1073/pnas.0902367106-
dc.identifier.urihttp://hdl.handle.net/10147/94497-
dc.description.abstractPharmacologic 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.-
dc.language.isoenen
dc.subject.meshAdenoma-
dc.subject.meshAnimals-
dc.subject.meshColon-
dc.subject.meshColonic Neoplasms-
dc.subject.meshColonoscopy-
dc.subject.meshDrug and Narcotic Control-
dc.subject.meshHumans-
dc.subject.meshHydroxyprostaglandin Dehydrogenases-
dc.subject.meshIntestinal Mucosa-
dc.subject.meshMice-
dc.subject.meshMice, Knockout-
dc.subject.meshPyrazoles-
dc.subject.meshSulfonamides-
dc.subject.otherCOLORECTAL CANCERen
dc.title15-Hydroxyprostaglandin dehydrogenase inactivation as a mechanism of resistance to celecoxib chemoprevention of colon tumors.en
dc.contributor.departmentDepartment of Medicine and Pathology, Ireland Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA.en
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaen

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