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Targeting monocyte chemotactic protein-1 synthesis with bindarit induces tumor regression in prostate and breast cancer animal models

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Abstract

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-β and AKT signaling, and it can impair the NF-κB signaling pathway through enhancing the expression of the NF-κB inhibitor IkB-α. 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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Acknowledgments

We thank the Core Services platforms of CEINGE Laboratories, and Prof. Luigi del Vecchio, Head of the Cell Sorter Facility, and its facility for helpful and critical discussions. This study was funded by Angelini Grants ACRAF 004FA09369, 004FA09383 (MZ) and the European GRANT-FP7-Tumic HEALTH-F2-2008-201662 (MZ). VDD was supported by Fondazione San Paolo (IM) and Tumic EU-FP7, DS was supported by the Dipartimento di Biochimica e Biotecnologie Mediche, ‘Federico II’ University of Naples, DMD was supported by Dottorato in Medicina Molecolare e Genetica, ‘Federico II’ University of Naples, and LL was supported by Scuola di Specializzazione in Genetica Medica, ‘Federico II’ University of Naples, Italy.

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Authors and Affiliations

  1. Centro di Ingegneria Genetica, Biotecnologie Avanzate (CEINGE), Via Gaetano Salvatore 486, 80145, Naples, Italy

    Massimo Zollo, Valeria Di Dato, Daniela Spano, Daniela De Martino, Lucia Liguori, Natascia Marino, Viviana Vastolo & Luigi Navas

  2. Dipartimento di Biochimica e Biotecnologie Mediche (DBBM), “Federico II” University of Naples, Naples, Italy

    Massimo Zollo, Valeria Di Dato, Daniela Spano, Daniela De Martino, Natascia Marino & Viviana Vastolo

  3. Angelini Research Centre, S. Palomba-Pomezia, Rome, Italy

    Beatrice Garrone, Giorgina Mangano, Giuseppe Biondi & Angelo Guglielmotti

  4. Dipartimento di Scienze Cliniche Veterinarie, Sez. di Clinica Chirurgica, “Federico II” University of Naples, Naples, Italy

    Luigi Navas

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  1. Massimo Zollo
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  2. Valeria Di Dato
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Correspondence to Massimo Zollo.

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Valeria Di Dato and Daniela Spano contributed equally to the work.

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Zollo, M., Di Dato, V., Spano, D. et al. Targeting monocyte chemotactic protein-1 synthesis with bindarit induces tumor regression in prostate and breast cancer animal models. Clin Exp Metastasis 29, 585–601 (2012). https://doi.org/10.1007/s10585-012-9473-5

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