Small molecule antagonists for CXCR2 and CXCR1 inhibit human colon cancer liver metastases

Varney, Michelle L.; Singh, Seema; Li, Aihua; Mayer-Ezell, Rosemary; Bond, Richard; Singh, Rakesh K.

doi:10.1016/j.canlet.2010.10.004

Cited by 108 publications

(82 citation statements)

References 38 publications

(44 reference statements)

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“…A recent study has shown the potential of SCH-527123 in inhibiting human colon liver metastases using in vivo models (18). In our in vitro study, we showed that SCH-527123 treatment inhibited cell proliferation and induced apoptosis in both HCT116 and Caco2 parental and IL-8-overexpressing colorectal cancer cells.…”

Section: Discussionsupporting

confidence: 56%

“…SCH-527123, as a novel and selective antagonist of the CXCR2, has shown efficacy in the treatment of inflammatory diseases (17). Moreover, Singh and colleagues showed that SCH-527123 treatment inhibited human melanoma cancer growth and colorectal cancer liver metastases by decreasing tumor cell proliferation, angiogenesis, and enhancing the apoptosis of malignant cells (18,19).…”

Section: Introductionmentioning

confidence: 99%

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The CXCR2 Antagonist, SCH-527123, Shows Antitumor Activity and Sensitizes Cells to Oxaliplatin in Preclinical Colon Cancer Models

Ning

LaBonte

Zhang

et al. 2012

Molecular Cancer Therapeutics

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Colorectal cancer 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 showed that IL-8 overexpression in colorectal cancer cells triggers the upregulation of the CXCR2-mediated proliferative pathway. The aim of this study was to investigate whether the CXCR2 antagonist, SCH-527123, inhibits colorectal cancer proliferation and if it can sensitize colorectal cancer cells to oxaliplatin both in vitro and in vivo. SCH-527123 showed concentration-dependent antiproliferative effects in HCT116, Caco2, and their respective IL-8-overexpressing variants colorectal cancer cell lines. Moreover, SCH-527123 was able to suppress CXCR2-mediated signal transduction as shown through decreased phosphorylation of the NF-kB/mitogen-activated protein kinase (MAPK)/AKT pathway. These findings corresponded with decreased cell migration and invasion, while increased apoptosis in colorectal cancer cell lines. In vivo results verified that SCH-527123 treatment decreased tumor growth and microvessel density when compared with vehicle-treated tumors. Importantly, these preclinical studies showed 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 colorectal cancer to oxaliplatin treatment.

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Section: Discussionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

The CXCR2 Antagonist, SCH-527123, Shows Antitumor Activity and Sensitizes Cells to Oxaliplatin in Preclinical Colon Cancer Models

Ning

LaBonte

Zhang

et al. 2012

Molecular Cancer Therapeutics

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“…Thus, multiple small molecule inhibitors of the most important chemokine receptors, CXCR1 and CXCR2, have been generated. A few of these inhibitors showed efficacy in the treatment of experimental cancers (Bolitho et al 2010;Tazzyman et al 2011;Varney et al 2011). In this study, we determined the effects of our newly synthesized CXCR1/2 inhibitor G31P in prostate cancer cells.…”

Section: Discussionmentioning

confidence: 99%

G31P, an Antagonist against CXC Chemokine Receptors 1 and 2, Inhibits Growth of Human Prostate Cancer Cells in Nude Mice

Liu

Peng

Sun

et al. 2012

Tohoku J. Exp. Med.

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“…Several animal studies gave evidence that blocking CXCR1 and especially CXCR2 signaling, either by use of neutralizing antibodies or small-molecule inhibitors, inhibits colon cancer metastasis to liver (31,32). One earlier study showed similar results for a CXCR1/ CXCR2 blockade on lung metastasis development in a renal cell carcinoma model (33).…”

Section: Discussionmentioning

confidence: 90%

Norepinephrine Promotes the β1-Integrin–Mediated Adhesion of MDA-MB-231 Cells to Vascular Endothelium by the Induction of a GROα Release

Strell

Niggemann

Voss

et al. 2012

Molecular Cancer Research

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The migratory activity of tumor cells and their ability to extravasate from the blood stream through the vascular endothelium are important steps within the metastasis cascade. We have shown previously that norepinephrine is a potent inducer of the migration of MDA-MB-468 human breast carcinoma cells and therefore investigated herein, whether the interaction of these cells as well as MDA-MB-231 and MDA-MB-435S human breast carcinoma cells with the vascular endothelium is affected by this neurotransmitter as well. By means of a flow-through assay under physiologic flow conditions, we show that norepinephrine induces an increase of the adhesion of the MDA-MB-231 cells, but not of MDA-MB-468 and MDA-MB-435S cells to human pulmonary microvascular endothelial cells (HMVEC). The adhesion of MDA-MB-231 cells was based on a norepinephrine-mediated release of GROa from HMVECs. GROa caused a b1-integrin-mediated increase of the adhesion of MDA-MB-231 cells. Most interestingly, this effect of norepinephrine, similar to the aforementioned induction of migration in MDA-MB-468 cells, was mediated by b-adrenergic receptors and therefore abrogated by b-blockers. In conclusion, norepinephrine has cell line-specific effects with regard to certain steps of the metastasis cascade, which are conjointly inhibited by clinically established b-blockers. Therefore, these results may deliver a molecular explanation for our recently published retrospective data analysis of patients with breast cancer which shows that b-blockers significantly reduce the development of metastases. Mol Cancer Res; 10(2); 197-207. Ó2011 AACR.

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Small molecule antagonists for CXCR2 and CXCR1 inhibit human colon cancer liver metastases

Cited by 108 publications

References 38 publications

The CXCR2 Antagonist, SCH-527123, Shows Antitumor Activity and Sensitizes Cells to Oxaliplatin in Preclinical Colon Cancer Models

The CXCR2 Antagonist, SCH-527123, Shows Antitumor Activity and Sensitizes Cells to Oxaliplatin in Preclinical Colon Cancer Models

G31P, an Antagonist against CXC Chemokine Receptors 1 and 2, Inhibits Growth of Human Prostate Cancer Cells in Nude Mice

Norepinephrine Promotes the β1-Integrin–Mediated Adhesion of MDA-MB-231 Cells to Vascular Endothelium by the Induction of a GROα Release

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