The CXCR2 antagonist, SCH-527123, demonstrates antitumor activity and sensitizes cells to oxaliplatin in preclinical colon cancer models
Menée in vitro et in vivo, cette étude évalue l'intérêt d'un antagoniste du récepteur CXCR2, en combinaison avec l'oxaliplatine, pour le traitement d'un cancer colorectal
Colorectal cancer (CRC) 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 demonstrated that IL-8 overexpression in CRC cells triggers the upregulation of the CXCR2-mediated proliferative pathway. The aim of this study was to investigate if the CXCR2 antagonist, SCH-527123, inhibits CRC proliferation and if it can sensitize CRC cells to oxaliplatin both in vitro and in vivo. SCH-527123 demonstrated concentration dependent anti-proliferative effects in HCT116, Caco2 and their respective IL-8 overexpressing variants CRC cell lines. Moreover, SCH-527123 was able to suppress CXCR2 mediated signal transduction as demonstrated through decreased phosphorylation of the NFkappaB/MAPK/AKT pathway. These findings corresponded with decreased cell migration and invasion, while increased apoptosis in CRC cell lines. In vivo results verifed that SCH-527123 treatment decreased tumor growth and microvessel density when compared with vehicle treated tumors. Importantly, these preclinical studies demonstrated 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 CRC to oxaliplatin treatment.
http://mct.aacrjournals.org/content/early/2012/03/03/1535-7163.MCT-11-0915.abstract