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

Seema Singh, Anguraj Sadanandam, Kalyan C. Nannuru, Michelle L. Varney, Rosemary Mayer-Ezell, Richard Bond, Rakesh K Singh

Research output: Contribution to journalArticle

93 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)2380-2386
Number of pages7
JournalClinical Cancer Research
Volume15
Issue number7
DOIs
StatePublished - Apr 1 2009

Fingerprint

Melanoma
Cell Survival
Cell Proliferation
Growth
Neoplasms
Skin Neoplasms
Nude Mice
Cyclodextrins
Chemotaxis
Therapeutics
Microvessels
Research Design
SCH 479833
2-hydroxy-N,N-dimethyl-3-(2-((1-(5-methylfuran-2-yl)propyl)amino)-3,4-dioxocyclobut-1-enylamino)benzamide
Apoptosis
In Vitro Techniques

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Small-molecule antagonists for CXCR2 and CXCR1 inhibit human melanoma growth by decreasing tumor cell proliferation, survival, and angiogenesis. / Singh, Seema; Sadanandam, Anguraj; Nannuru, Kalyan C.; Varney, Michelle L.; Mayer-Ezell, Rosemary; Bond, Richard; Singh, Rakesh K.

In: Clinical Cancer Research, Vol. 15, No. 7, 01.04.2009, p. 2380-2386.

Research output: Contribution to journalArticle

Singh, Seema ; Sadanandam, Anguraj ; Nannuru, Kalyan C. ; Varney, Michelle L. ; Mayer-Ezell, Rosemary ; Bond, Richard ; Singh, Rakesh K. / Small-molecule antagonists for CXCR2 and CXCR1 inhibit human melanoma growth by decreasing tumor cell proliferation, survival, and angiogenesis. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 7. pp. 2380-2386.
@article{1af7b63a8adc4101977b59de2218ae74,
title = "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 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.",
author = "Seema Singh and Anguraj Sadanandam and Nannuru, {Kalyan C.} and Varney, {Michelle L.} and Rosemary Mayer-Ezell and Richard Bond and Singh, {Rakesh K}",
year = "2009",
month = "4",
day = "1",
doi = "10.1158/1078-0432.CCR-08-2387",
language = "English (US)",
volume = "15",
pages = "2380--2386",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=65249183876&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65249183876&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-08-2387

DO - 10.1158/1078-0432.CCR-08-2387

M3 - Article

VL - 15

SP - 2380

EP - 2386

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 7

ER -