De Martino, Daniela (2013) An attempt to define the therapeutic use of Dipyridamole in triple-negative breast-cancer patients-a proof of concept in animal model-. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: An attempt to define the therapeutic use of Dipyridamole in triple-negative breast-cancer patients-a proof of concept in animal model-
Creators:
CreatorsEmail
De Martino, Danielademartinod@ceinge.unina.it
Date: 28 March 2013
Number of Pages: 85
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Scuola di dottorato: Medicina molecolare
Dottorato: Genetica e medicina molecolare
Ciclo di dottorato: 25
Coordinatore del Corso di dottorato:
nomeemail
Nitsch, Lucionitsch@unina.it
Tutor:
nomeemail
Zollo, Massimomassimo.zollo@unina.it
Date: 28 March 2013
Number of Pages: 85
Uncontrolled Keywords: Triple-negative breast-cancer; Metastatic process; Dipyridamole;The tumor microenvironment;Tumor-associated macrophages:Myeloid-derived suppressor cells; Wnt pathway;ERK1/2-MAPK pathway;NF-kB pathway.
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/11 - Biologia molecolare
Area 05 - Scienze biologiche > BIO/13 - Biologia applicata
Date Deposited: 12 Apr 2013 12:31
Last Modified: 22 Jul 2014 08:52
URI: http://www.fedoa.unina.it/id/eprint/9200
DOI: 10.6092/UNINA/FEDOA/9200

Abstract

Dipyridamole belongs to the category of antiplatelet drugs commonly used in cardiovascular disease, here we want test its effectiveness in the treatment of triple-negative breast-cancer. In-vitro assays were used to analyze the perturbations induced by dipyridamole on the cell cycle, on cell growth and motility. We also want to assess the dipyridamole action on Wnt, NF-kB and ERK1/2-MAPK signaling pathways that are overactive in such tumors. Here we provide the evidence that dipyridamole is able to perturb also in vivo the activation of these important pathways and inhibit the infiltration of immune cells within the tumor mass that may control the tumor growth and propagation of metastasis. Xenograft mice bearing triple-negative breast-cancer 4T1-Luc cells were generated to investigate the primary tumor growth, metastasis formation and serum inflammatory cytokines levels. In vivo, dipyridamole significantly reduced primary tumor growth and metastasis formation, indeed treatment with 60 mg/kg/day dipyridamole reduced mean primary tumor size by 76.7% (p = 0.0429), while treatment with 30 mg/kg/day dipyridamole resulted in an almost a total reduction in metastasis formation (p = 0.0292). Immunohistochemical analyses reveal significant effects of dipyridamole on the Wnt, ERK1/2-MAPK and NF-kB pathways in primary tumor animal models. In vivo dipyridamole decreased activated β-catenin by 38.64 % (p <0.0001), phospho-ERK1/2 by 25.05 % (p =0.0129), phospho-p65 by 67.82 % (p <0.0001) and doubled the expression of IkBa (p = 0.0019), thus revealing significant effects on Wnt, ERK1/2-MAPK and NF-kB pathways in 4T1-Luc xenograft animal model. Moreover dipyridamole significantly decreased the infiltration of tumor-associated macrophages and myeloid-derived suppressor cells in primary tumors (p <0.005), and the inflammatory cytokines levels in the sera of the treated mice. We suggest that when used at appropriate doses and with the correct mode of administration, dipyridamole is a promising agent for breast-cancer treatment, thus also implying its potential use in other cancers that show highly activated Wnt, ERK1/2-MAPK and NF-kB pathways.

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