TY - JOUR
T1 - Small-molecule antagonists for CXCR2 and CXCR1 inhibit human melanoma growth by decreasing tumor cell proliferation, survival, and angiogenesis
AU - Singh, Seema
AU - Sadanandam, Anguraj
AU - Nannuru, Kalyan C.
AU - Varney, Michelle L.
AU - Mayer-Ezell, Rosemary
AU - Bond, Richard
AU - Singh, Rakesh K.
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2009/4/1
Y1 - 2009/4/1
N2 - 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 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. 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.
AB - 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 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. 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.
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U2 - 10.1158/1078-0432.CCR-08-2387
DO - 10.1158/1078-0432.CCR-08-2387
M3 - Article
C2 - 19293256
AN - SCOPUS:65249183876
VL - 15
SP - 2380
EP - 2386
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 7
ER -