Dipyridamole prevents triple-negative breast-cancer progression

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.

Immediate Utility of Two Approved Agents to Target Both the Metabolic Mevalonate Pathway and Its Restorative Feedback Loop

“…Dipyridamole been shown to potentiate classical chemotherapeutic drugs mainly through P-gp modulation and by blocking nucleoside transport (47). Recently, it was shown that dipyridamole alone delays tumor growth in breast cancer xenografts (48), but in our hands, using low micromolar concentrations, dipyridamole did not have appreciable anticancer activity as a single agent. This is in line with the observation that dipyridamole's antiproliferative effects were only observed when tumor cells were simultaneously challenged with statin, thereby triggering the feedback loop that was suppressed by the addition of dipyridamole.…”

Tissue invasion and metastasis: Molecular, biological and clinical perspectives

“…dipyridamole and bindarit), or at interfering with their immunosuppressive functions (celocoxib), or killing MDSCs (5 fluorouracil-or 5FU). Interestingly, dipyridamole [118] and bindarit [119] decrease the infiltration not only of MDSCs but also of TAMs in breast and prostate cancer proof of concept animal model studies.…”

Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-cancer agent

“…The anticancer effects of aspirin may be related to anti-platelet effects via irreversible inhibition of COX-1 [172–173], and there is also some evidence that other anti-platelet agents, such as low molecular weight heparins and dipyridamole may also have anti-cancer or anti-metastatic activity [174–176]. Beta-adrenergic receptor antagonists are also known to have effects on platelet aggregation and a meta-analysis published in 2014 showed that they decreased platelet aggregation by 13% (95% CI = 8 - 17%, standardised mean difference=-0.54, 95% CI = -0.85 – -0.24, P < 0.0001) [177].…”