The CXCR2 antagonist, SCH-527123, shows antitumor activity and sensitizes cells to oxaliplatin in preclinical colon cancer models
Document Type
Article
Publication Title
Molecular Cancer Therapeutics
Abstract
Colorectal cancer is the second most common cause of cancer-related death in the United States. Recent studies showed that interleukin-8 (IL-8) and its receptors (CXCR1 and CXCR2) are significantly upregulated in both the tumor anditsmicroenvironment, andact as keyregulators of proliferation, angiogenesis, andmetastasis. Our previous study showed that IL-8 overexpression in colorectal cancer cells triggers the upregulation of the CXCR2-mediated proliferative pathway. The aimof this studywas to investigatewhether theCXCR2 antagonist, SCH-527123, inhibits colorectal cancer proliferation and if it can sensitize colorectal cancer cells to oxaliplatin both in vitro and in vivo. SCH-527123 showed concentration-dependent antiproliferative effects in HCT116, Caco2, and their respective IL-8-overexpressing variants colorectal cancer cell lines.Moreover, SCH-527123 was able to suppress CXCR2-mediated signal transduction as shown through decreased phosphorylation of the NF-κB/mitogen-activated protein kinase (MAPK)/AKT pathway. These findings corresponded with decreased cell migration and invasion, while increased apoptosis in colorectal cancer cell lines. In vivo results verified that SCH-527123 treatment decreased tumor growth and microvessel density when compared with vehicle-treated tumors. Importantly, these preclinical studies showed that the combination of SCH-527123 and oxaliplatin resulted in a greater decrease in cell proliferation, tumor growth, apoptosis,andangiogenesis thatwas superior to single-agent treatment. Taken together, these findings suggest that targeting CXCR2 may block tumor proliferation, migration, invasion, and angiogenesis. In addition, CXCR2 blockade may further sensitize colorectal cancer to oxaliplatin treatment. ©2012 AACR.
First Page
1353
Last Page
1364
DOI
10.1158/1535-7163.MCT-11-0915
Publication Date
6-1-2012
Recommended Citation
Ning, Yan; Labonte, Melissa J.; Zhang, Wu; Bohanes, Pierre O.; Gerger, Armin; Yang, Dongyun; Benhaim, Leonor; Paez, David; Rosenberg, David O.; Nagulapalli Venkata, Kalyan C.; Louie, Stan G.; Petasis, Nicos A.; Ladner, Robert D.; and Lenz, Heinz Josef, "The CXCR2 antagonist, SCH-527123, shows antitumor activity and sensitizes cells to oxaliplatin in preclinical colon cancer models" (2012). Pharmaceutical and Administrative Sciences Faculty Publications. 124.
https://doi.org/10.1158/1535-7163.MCT-11-0915
https://collections.uhsp.edu/pharm-admin-sciences_pubs/124