Recent studies have shown that interleukin-8 (IL-8) and its receptors CXCR1 and CXCR2 are significantly upregulated in colorectal cancer tumors and their microenvironment and act as regulators of proliferation, angiogenesis, and metastasis. Ning and colleagues from the University of Southern California, Los Angeles, have evaluated the in vitro and in vivo effects of inhibition of CXCR2 in colorectal cancer.
After showing that IL-8 overexpression in colorectal cancer cells induces upregulation of the CXCR2-mediated proliferative pathway, these investigators assessed whether a CXCR2 antagonist (SCH-527123) could inhibit colorectal cancer proliferation and sensitize colorectal cancer cells to oxaliplatin. The antagonist suppressed CXCR2-mediated signal transduction, as evidenced by decreased phosphorylation of the NF-κB/MAPK/AKT pathway.
Antagonist treatment of HCT116 and Caco2 colorectal cancer parental cell lines and their respective IL-8–overexpressing variants resulted in concentration-dependent antiproliferative effects, decreased cell migration and invasion, and increased apoptosis. Antagonist treatment in xenograft-bearing mice resulted in reduced tumor growth and microvessel density compared with vehicle-treated tumors. The combination of SCH-527123 and oxaliplatin resulted in greater reductions in cell proliferation, tumor growth, and angiogenesis and a greater increase in apoptosis compared with treatment with either agent alone.
As stated by the investigators, “Taken together, these findings suggest that targeting CXCR2 may block tumor proliferation, migration, invasion, and angiogenesis [and that] CXCR2 blockade may further sensitize [colorectal cancer] to oxaliplatin treatment.”■
Ning Y, et al: Mol Cancer Ther. March 5, 2012 (early release online).