Small-molecule antagonists for CXCR2 and CXCR1 inhibit human melanoma growth by decreasing tumor cell proliferation, survival, and angiogenesis.
OBJECTIVE
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.


METHODS
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-beta-cyclodextrin (20%) orally for 21 days 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.


CONCLUSIONS
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.
Singh
Seema
S
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5845, USA.
Sadanandam
Anguraj
A
Nannuru
Kalyan C
KC
Varney
Michelle L
ML
Mayer-Ezell
Rosemary
R
Bond
Richard
R
Singh
Rakesh K
RK
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival; D002633:Chemotaxis / Q000187:drug effects; D003503:Cyclobutanes / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D012878:Skin Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology
C516686:2-hydroxy-N,N-dimethyl-3-(2-((1-(5-methylfuran-2-yl)propyl)amino)-3,4-dioxocyclobut-1-enylamino)benzamide; D020533:Angiogenesis Inhibitors; D001549:Benzamides; D003503:Cyclobutanes; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; C544392:SCH 479833