Small-Molecule Antagonists for CXCR2 and CXCR1 Inhibit Human Melanoma Growth by Decreasing Tumor Cell Proliferation, Survival, and Angiogenesis

Abstract

Purpose Melanoma, the most aggressive form of skin cancer, accounts for 75% of all skin cancer-related deaths and current therapeutic strategies are not effective in advanced disease. In the current study, we have investigated the efficacy of orally active small-molecule antagonist targeting CXCR2/CXCR1. Experimental Design Human A375SM melanoma cells were treated with SCH-479833 or SCH-527123, and their effect on proliferation, motility, and invasion was evaluated in vitro. We examined the downstream signaling events in the cells following treatment with antagonists. For in vivo studies, A375SM cells were implanted subcutaneously into athymic nude mice followed by administration of SCH-479833, SCH-527123, or hydroxypropyl-β-cyclodextrin (20%) orally for 21days and their effect on tumor growth and angiogenesis was evaluated. Results Our data show that SCH-479833 or SCH-527123 inhibited the melanoma cell proliferation, chemotaxis, and invasive potential in vitro.Treatment of melanoma cells with SCH-479833 or SCH-527123 also inhibited tumor growth. Histologic and histochemical analyses showed significant (P < 0.05) decreases in tumor cell proliferation and microvessel density in tumors. Moreover, we observed a significant increase in melanoma cell apoptosis in SCH-479833- or SCH-527123-treated animals compared with controls. Conclusion Together, these studies show that selectively targeting CXCR2/CXCR1 with orally active small-molecule inhibitors is a promising therapeutic approach for inhibiting melanoma growth and angiogenesis.

Enrichment of Foxp3+ CD4 Regulatory T Cells in Migrated T Cells to IL-6– and IL-8–Expressing Tumors through Predominant Induction of CXCR1 by IL-6

“…The findings in this study suggested that the IL-8 secretion was observed in some types of tumors (16). Expression of IL-8R CXCR1 and CXCR2 was also shown in tumors (20,21). IL-8 and its receptor interaction appeared to be involved in the behavior of such tumor cells via autocrine and paracrine mechanisms.…”

Targeting chemokine pathways in esophageal adenocarcinoma

“…SB332235 is a small molecule inhibitor that has been shown to be a specific inhibitor of CXCR2. 115 Esophageal adenocarcinoma derived OE33 cells were exposed to CXCR2 inhibitor and proliferation was assessed by a MTT assay. We observed that CXCR2 inhibition did not result in any significant effect on proliferation (Fig.…”

Inflammatory events in endometrial adenocarcinoma

“…The groups are known as C, C-C, C-X-C and C-X3-C (Murphy et al 2000). A number of C-X-C chemokines are angiogenic (Strieter et al 1995) and mitogenic (Wang et al 2006a, Singh et al 2009a. Their tumour-promoting properties have been demonstrated in mouse models of other cancer types such as melanoma, lung Sales et al (2008a,b) and prostate cancer (Haghnegahdar et al 2000, Keane et al 2004, Singh et al 2009b.…”