Zoledronic acid repolarizes tumor-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway

ABSTRACT It is unknown whether zoledronic acid at clinically relevant doses is active against tumors not located in bone. Mice transgenic for the activated ErbB-2 oncogene were treated with a cumulative number of doses equivalent to that recommended in humans. A significant increase in tumor-free and overall survival was observed in mice treated with zoledronic acid. At clinically compatible concentrations, zoledronic acid modulated the mevalonate pathway and affected protein prenylation in both tumor cells and macrophages. A marked reduction in the number of tumor associated macrophages was paralleled by a significant decrease in tumor vascularization. The local production of vascular endothelial growth factor and interleukin-10 was drastically downregulated in favour of interferon-gamma production. Peritoneal macrophages and tumor associated macrophages of zoledronic acid-treated mice recovered a full M1 antitumoral phenotype, as shown by nuclear translocation of nuclear factor kB, inducible nitric oxide synthase expression, and nitric oxide production. These data indicate that clinically achievable doses of zoledronic acid inhibit spontaneous mammary cancerogenesis by targeting the local microenvironment, as shown by a decreased tumor vascularization, a reduced number of tumor associated macrophages and their reverted polarization from M2 to M1 phenotype.