title: Targeting monocyte chemotactic protein-1 synthesis with bindarit induces tumor regression in prostate and breast cancer animal models.
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.
authors.affiliation: Centro di Ingegneria Genetica, Biotecnologie Avanzate (CEINGE), Via Gaetano Salvatore 486, 80145, Naples, Italy. massimo.zollo@unina.it
authors.forename: Massimo
authors.initials: M
authors.lastname: Zollo
authors.forename: Valeria
authors.initials: V
authors.lastname: Di Dato
authors.forename: Daniela
authors.initials: D
authors.lastname: Spano
authors.forename: Daniela
authors.initials: D
authors.lastname: De Martino
authors.forename: Lucia
authors.initials: L
authors.lastname: Liguori
authors.forename: Natascia
authors.initials: N
authors.lastname: Marino
authors.forename: Viviana
authors.initials: V
authors.lastname: Vastolo
authors.forename: Luigi
authors.initials: L
authors.lastname: Navas
authors.forename: Beatrice
authors.initials: B
authors.lastname: Garrone
authors.forename: Giorgina
authors.initials: G
authors.lastname: Mangano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Biondi
authors.forename: Angelo
authors.initials: A
authors.lastname: Guglielmotti
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011422:Propionates / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D015398:Signal Transduction
chemical_list: D018932:Chemokine CCL2; D007191:Indazoles; D016328:NF-kappa B; D011422:Propionates; C079489:bindarit