期刊
CLINICAL & EXPERIMENTAL METASTASIS
卷 29, 期 6, 页码 585-601出版社
SPRINGER
DOI: 10.1007/s10585-012-9473-5
关键词
Prostate; Breast; Tumor-associated macrophages; Myeloid-derived suppressor cells; MCP-1/CCL2; Xenograft
类别
资金
- Angelini [ACRAF 004FA09369, ACRAF 004FA09383]
- European GRANT-FP7-Tumic [HEALTH-F2-2008-201662]
- Fondazione San Paolo
- EU
- Dipartimento di Biochimica e Biotecnologie Mediche, 'Federico II' University of Naples
- Dottorato in Medicina Molecolare e Genetica, 'Federico II' University of Naples
- Scuola di Specializzazione in Genetica Medica, 'Federico II' University of Naples, Italy
Prostate and breast cancer are major causes of death worldwide, mainly due to patient relapse upon disease recurrence through formation of metastases. Chemokines are small proteins with crucial roles in the immune system, and their regulation is finely tuned in early inflammatory responses. They are key molecules during inflammatory processes, and many studies are focusing on their regulatory functions in tumor growth and angiogenesis during metastatic cell seeding and spreading. Bindarit is an anti-inflammatory indazolic derivative that can inhibit the synthesis of MCP-1/CCL2, with a potential inhibitory function in tumor progression and metastasis formation. We show here that in vitro, bindarit can modulate cancer-cell proliferation and migration, mainly through negative regulation of TGF-beta and AKT signaling, and it can impair the NF-kappa B signaling pathway through enhancing the expression of the NF-kappa B inhibitor IkB-alpha. In vivo administration of bindarit results in impaired metastatic disease in prostate cancer xenograft mice (PC-3M-Luc2 cells injected intra-cardially) and impairment of local tumorigenesis in syngeneic Balb/c mice injected under the mammary gland with murine breast cancer cells (4T1-Luc cells). In addition, bindarit treatment significantly decreases the infiltration of tumor-associated macrophages and myeloid-derived suppressor cells in 4T1-Luc primary tumors. Overall, our data indicate that bindarit is a good candidate for new therapies against prostate and breast tumorigenesis, with an action through impairment of inflammatory cell responses during formation of the tumor-stroma niche microenvironment.
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