Dipyridamole prevents triple-negative breast-cancer progression

Daniela Spano, Jean Claude Marshall, Natascia Marino, Daniela De Martino, Alessia Romano, Maria Nunzia Scoppettuolo, Anna Maria Bello, Valeria Di Dato, Luigi Navas, Gennaro De Vita, Chiara Medaglia, Patricia S. Steeg, Massimo Zollo

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Dipyridamole is a widely prescribed drug in ischemic disorders, and it is here investigated for potential clinical use as a new treatment for breast cancer. Xenograft mice bearing triple-negative breast cancer 4T1-Luc or MDA-MB-231T cells were generated. In these in vivo models, dipyridamole effects were investigated for primary tumor growth, metastasis formation, cell cycle, apoptosis, signaling pathways, immune cell infiltration, and serum inflammatory cytokines levels. Dipyridamole significantly reduced primary tumor growth and metastasis formation by intraperitoneal administration. Treatment with 15 mg/kg/day dipyridamole reduced mean primary tumor size by 67.5 % (p = 0.0433), while treatment with 30 mg/kg/day dipyridamole resulted in an almost a total reduction in primary tumors (p = 0.0182). Experimental metastasis assays show dipyridamole reduces metastasis formation by 47.5 % in the MDA-MB-231T xenograft model (p = 0.0122), and by 50.26 % in the 4T1-Luc xenograft model (p = 0.0292). 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 IkBα (p = 0.0019), thus revealing significant effects on Wnt, ERK1/2-MAPK and NF-kB pathways in both animal models. 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 those highly activated pathways.

Original languageEnglish
Pages (from-to)47-68
Number of pages22
JournalClinical & Experimental Metastasis
Volume30
Issue number1
DOIs
Publication statusPublished - Jan 2013

Fingerprint

Triple Negative Breast Neoplasms
Dipyridamole
Neoplasms
Heterografts
Neoplasm Metastasis
Breast Neoplasms
Cytokines
Catenins
NF-kappa B
Growth
Serum
Cell Cycle
Animal Models
Macrophages
Apoptosis

Keywords

  • Dipyridamole
  • ERK1/2-MAPK
  • Immune cell infiltration
  • Metastasis
  • NF-kB
  • Tumor microenvironment
  • Wnt

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Spano, D., Marshall, J. C., Marino, N., De Martino, D., Romano, A., Scoppettuolo, M. N., ... Zollo, M. (2013). Dipyridamole prevents triple-negative breast-cancer progression. Clinical & Experimental Metastasis, 30(1), 47-68. https://doi.org/10.1007/s10585-012-9506-0

Dipyridamole prevents triple-negative breast-cancer progression. / Spano, Daniela; Marshall, Jean Claude; Marino, Natascia; De Martino, Daniela; Romano, Alessia; Scoppettuolo, Maria Nunzia; Bello, Anna Maria; Di Dato, Valeria; Navas, Luigi; De Vita, Gennaro; Medaglia, Chiara; Steeg, Patricia S.; Zollo, Massimo.

In: Clinical & Experimental Metastasis, Vol. 30, No. 1, 01.2013, p. 47-68.

Research output: Contribution to journalArticle

Spano, D, Marshall, JC, Marino, N, De Martino, D, Romano, A, Scoppettuolo, MN, Bello, AM, Di Dato, V, Navas, L, De Vita, G, Medaglia, C, Steeg, PS & Zollo, M 2013, 'Dipyridamole prevents triple-negative breast-cancer progression', Clinical & Experimental Metastasis, vol. 30, no. 1, pp. 47-68. https://doi.org/10.1007/s10585-012-9506-0
Spano D, Marshall JC, Marino N, De Martino D, Romano A, Scoppettuolo MN et al. Dipyridamole prevents triple-negative breast-cancer progression. Clinical & Experimental Metastasis. 2013 Jan;30(1):47-68. https://doi.org/10.1007/s10585-012-9506-0
Spano, Daniela ; Marshall, Jean Claude ; Marino, Natascia ; De Martino, Daniela ; Romano, Alessia ; Scoppettuolo, Maria Nunzia ; Bello, Anna Maria ; Di Dato, Valeria ; Navas, Luigi ; De Vita, Gennaro ; Medaglia, Chiara ; Steeg, Patricia S. ; Zollo, Massimo. / Dipyridamole prevents triple-negative breast-cancer progression. In: Clinical & Experimental Metastasis. 2013 ; Vol. 30, No. 1. pp. 47-68.
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