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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.While sulindac has been approved as a preventive approach against colon cancer, low-dose alternatives are being sought due to its severe toxicity. Using mouse models, here the authors defined the contribution of IL-8 and CXCR2 to intestinal adenoma development induced by an APC gene mutation and showed that adenoma formation was suppressed by a single copy deletion of CXCR2 gene but promoted by ectopic expression of IL-8. Moreover, CXCR2 inhibition enhanced the efficacy of sulindac. Together, this study provided an in vivo therapeutic validation for inhibiting the IL-8/CXCR2 pathway in combination with sulindac for treatment and prevention of colorectal cancer.