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Dipyridamole prevents triple-negative breast-cancer progression

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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.

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Abbreviations

AGP:

α1 Acid glycoprotein

BCRP/ABCG2:

Human breast cancer resistance protein

BLI:

Bioluminescence imaging

CI:

Cell index

DMEM:

Dulbecco’s modified Eagle’s medium

DMSO:

Dimethylsulfoxide

G-CSF:

Granulocyte colony-stimulating factor

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

IHC:

Immunohistochemistry

IL-1α:

Interleukin-1α

IL-1β:

Interleukin-1β

MCP-1:

Monocyte chemotactic protein 1

MDSCs:

Myeloid-derived suppressor cells

MIP-1a:

Macrophage inflammatory protein 1a

MMP9:

Matrix metalloproteinase 9

MTS:

(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)

PBS:

Phosphate-buffered saline

PEG:

Polyethylene glycol

PGK:

Phosphoglucokinase

RTCA:

Real-time cell analysis

RT-CES:

Real-time cell electronic sensor

SCF:

Stem cell factor

SE:

Standard error

SEM:

Standard error of the mean

TAMs:

Tumor-associated macrophages

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Acknowledgments

We would like to thank: Prof. Eugene Lukanidin for sharing the S100A4 antibodies used in this study, Prof. Luigi del Vecchio and Dr. Maddalena Raia for technical advice with the FACS analyses, Dr. Donatella Montanaro for technical advice with histological analyses, and Prof. Francesco Salvatore for supporting the project with the instrumentation required for in vivo imaging in mice. We also thank Viviana Vastolo for technical assistance in in vivo experiments. Associazione Italiana per la ricerca sul Cancro AIRC (MZ), Associazione Italiana per la lotta al Neuroblastoma (MZ). This study was also supported in part by the Intramural Research Program of the National Cancer Institute (PSS). DS was supported by the Dipartimento di Biochimica e Biotecnologie Mediche, ‘Federico II’ University of Naples; VDD was supported by the Fondazione San Paolo (IM) and Tumic; DMD was supported by a Dottorato in Medicina Molecolare, ‘Federico II’ University of Naples; GDV was supported by a Dottorato in Medicina Molecolare, ‘Federico II’ University of Naples; and CM was supported by a Dottorato in Produzione e Sanità degli Alimenti di Origine Animale, ‘Federico II’ University of Naples.

Conflict of interest

The authors declare that they have no competing interests as defined by Clinical & Experimental Metastasis, or other interests that might be perceived as influencing the results and discussion reported in this manuscript.

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Authors and Affiliations

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

    Daniela Spano, Natascia Marino, Daniela De Martino, Maria Nunzia Scoppettuolo, Anna Maria Bello, Valeria Di Dato, Luigi Navas, Gennaro De Vita, Chiara Medaglia & Massimo Zollo

  2. Dipartimento di Biochimica e Biotecnologie Mediche, ‘Federico II’ University of Naples, Via Sergio Pansini 5, 80131, Naples, Italy

    Daniela Spano, Daniela De Martino, Alessia Romano, Maria Nunzia Scoppettuolo, Anna Maria Bello, Valeria Di Dato, Gennaro De Vita, Chiara Medaglia & Massimo Zollo

  3. Women’s Cancers Section, Laboratory of Molecular Pharmacology, National Cancer Institute, 37 Convent Drive, Bethesda, MD, 20892, USA

    Jean-Claude Marshall, Natascia Marino & Patricia S. Steeg

  4. Dipartimento di Scienze Cliniche Veterinarie, Sezione di Clinica Chirurgica, ‘Federico II’ University of Naples, Via Delpino, 1, 80137, Naples, Italy

    Luigi Navas

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  1. Daniela Spano
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  2. Jean-Claude Marshall
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Correspondence to Massimo Zollo.

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Daniela De Martino, Alessia Romano and Maria Nunzia Scoppettuolo contributed equally to the work.

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10585_2012_9506_MOESM1_ESM.tif

Figure S1. Representative caspase-3 activity assay (of two experiments performed with similar results) in 4T1-Luc cells treated for 24 h with PBS-PEG or dipyridamole (as indicated). Data are means ±SE. * p = 0.03 (Students’ t-test). (TIFF 16188 kb)

10585_2012_9506_MOESM2_ESM.tif

Figure S2. Dipyridamole affects 4T1-Luc primary tumor growth in vivo. Time-course of bioluminescent signals from 4T1-Luc tumor cells implanted into the mouse mammary fat pad at day 0, followed by intraperitoneally administered treatments with PBS-PEG or 15 mg/kg/day (A) or 30 mg/kg/day (B) dipyridamole (as indicated). Data are total flux means ±SE. (A) * p = 0.0433; (B) * p = 0.0182 (ANOVA). (TIFF 16184 kb)

10585_2012_9506_MOESM3_ESM.tif

Figure S3. In vivo effects of dipyridamole. Statistical analyses on sections from 4T1-Luc primary tumors (A) and MDA-MB-231T lung metastases (B, C) stained for cleaved caspase-3 (A, C) and Ki67 (B). No significant differences were observed for all of the analyzed markers. (TIFF 16453 kb)

10585_2012_9506_MOESM4_ESM.tif

Figure S4. Dipyridamole toxicity in vivo. Time-course of mean weights of athymic nude mice injected with MDA-MB-231T cells via the tail vein and treated with vehicle or 30 mg/kg/day dipyridamole, delivery either by oral gavage or intraperitoneally (as indicated). There are no significant differences between the body weights of these three treatment groups. (TIFF 16194 kb)

10585_2012_9506_MOESM5_ESM.tif

Figure S5. In vitro effects of dipyridamole. (A) Immunoblotting for IkBα in 4T1-Luc cells treated for 4 h with PBS-PEG or dipyridamole (as indicated). β-actin used as control for equal loading. (B) Expression of PGK gene, a non-target of Wnt, ERK1/2-MAPK and NF-kB pathways, in 4T1-Luc cells treated for 24 h with PBS-PEG or dipyridamole (as indicated). Data are means ±SEM. (TIFF 16189 kb)

10585_2012_9506_MOESM6_ESM.tif

Figure S6. Dipyridamole affects in vivo the expression of known targets of Wnt pathway. Immunoblotting for cyclin D1 and c-Myc in tumors from mice implanted with 4T1-Luc cells in the mammary fat pad and treated with PBS-PEG or dipyridamole (as indicated). β-actin used as control for equal loading. (TIFF 16188 kb)

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Spano, D., Marshall, JC., Marino, N. et al. Dipyridamole prevents triple-negative breast-cancer progression. Clin Exp Metastasis 30, 47–68 (2013). https://doi.org/10.1007/s10585-012-9506-0

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