The CXCR2 antagonist, SCH-527123, shows antitumor activity and sensitizes cells to oxaliplatin in preclinical colon cancer models.

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 and its microenvironment, and act as key regulators of proliferation, angiogenesis, and metastasis. Our previous study showed that IL-8 overexpression in colorectal cancer cells triggers the upregulation of the CXCR2-mediated proliferative pathway. The aim of this study was to investigate whether the CXCR2 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, and angiogenesis that was 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.

• Authors: Yan Ning, Melissa J Labonte, Wu Zhang, Pierre O Bohanes, Armin Gerger, Dongyun Yang, Leonor Benhaim, David Paez, David O Rosenberg, Kalyan C Nagulapalli Venkata, Stan G Louie, Nicos A Petasis, Robert D Ladner, Heinz-Josef Lenz
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 6 Pg. 1353-64 (Jun 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22391039 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR

Chemical References

• 2-hydroxy-N,N-dimethyl-3-(2-((1-(5-methylfuran-2-yl)propyl)amino)-3,4-dioxocyclobut-1-enylamino)benzamide
• Angiogenesis Inhibitors
• Antineoplastic Agents
• Benzamides
• Cyclobutanes
• Interleukin-8
• Organoplatinum Compounds
• Receptors, Interleukin-8B
• Oxaliplatin

Topics

• Angiogenesis Inhibitors (pharmacology, therapeutic use)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Benzamides (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation
• Colonic Neoplasms (blood supply, drug therapy, pathology)
• Cyclobutanes (pharmacology, therapeutic use)
• Drug Synergism
• Drug Therapy, Combination
• HCT116 Cells
• Humans
• Interleukin-8 (antagonists & inhibitors, metabolism)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Organoplatinum Compounds (pharmacology, therapeutic use)
• Oxaliplatin
• Receptors, Interleukin-8B (antagonists & inhibitors, genetics, metabolism)
• Xenograft Model Antitumor Assays