title: CXCR2 inhibition enhances sulindac-mediated suppression of colon cancer development.
abstract: Small chemical compound sulindac has been approved as a preventive approach against colon cancer for its effectiveness in treatment of precancerous adenoma. Due to its severe toxicities in the cardiovascular, gastrointestinal and renal systems, however, a combination of low-dose sulindac with other chemopreventive agents has been sought after as an alternative therapeutic strategy that could increase its effectiveness, while minimizing its adverse effects. To identify the promising alternative approach, we investigated the therapeutic potential of targeting the interleukin (IL)-8/CXCR2 pathway in colon cancer treatment using both loss-of-function (CXCR2 knockout) and gain-of-function (IL-8 overexpression) mouse models, as the IL-8/CXCR2 pathway has been shown to be activated in intestinal tumors of both human and experimental animals. We found that deletion of CXCR2 gene and ectopic expression of IL-8 suppresses and enhances, respectively, intestinal tumor development caused by a mutation in the APC gene. Moreover, a single copy deletion of CXCR2 gene resulted in abrogation of COX-2 and Gro-α upregulation in intestinal tumors caused by the APC mutation. Moreover, a single copy (heterozygote) deletion of CXCR2 gene was sufficient to synergize with a low-dose sulindac treatment in suppressing APCmin-induced intestinal polyposis. Together, our study provides a therapeutic justification of combined inhibition of CXCR2 and sulindac treatment in colon cancer prevention.
authors: Department of Surgery, University of Southern California, Los Angeles, CA; Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA; Department of Preventive Medicine, Division of Medical Oncology, University of Southern California, Los Angeles, CA.
authors: Yong Suk
authors: YS
authors: Lee
authors: Dongwon
authors: D
authors: Choi
authors: Nam Yoon
authors: NY
authors: Kim
authors: Sara
authors: S
authors: Yang
authors: Eunson
authors: E
authors: Jung
authors: Mingu
authors: M
authors: Hong
authors: Dongyun
authors: D
authors: Yang
authors: Heinz-Josef
authors: HJ
authors: Lenz
authors: Young-Kwon
authors: YK
authors: Hong
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000096:biosynthesis; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000517:prevention & control; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000235:genetics*; D013467:Sulindac / Q000008:administration & dosage*
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D023063:Receptors, Interleukin-8B; D013467:Sulindac; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
keywords: CXCR2; Interleukin-8; adenomatous polyposis coli; colon cancer; sulindac