Carboxyamidotriazole-orotate inhibits the growth of imatinib-resistant chronic myeloid leukemia cells and modulates exosomes-stimulated angiogenesis

The Bcr/Abl kinase has been targeted for the treatment of chronic myelogenous leukaemia (CML) by imatinib mesylate.While imatinib has been extremely effective for chronic phase CML, blast crisis CML are often resistant. New therapeuticoptions are therefore needed for this fatal disease. Although more common in solid tumors, increased microvessel densitywas also reported in chronic myelogenous leukaemia and was associated with a significant increase of angiogenic factors,suggesting that vascularity in hematologic malignancies is a controlled process and may play a role in the leukaemogenicprocess thus representing an alternative therapeutic target. Carboxyamidotriazole-orotate (CTO) is the orotate salt form ofcarboxyamidotriazole (CAI), an orally bioavailable signal transduction inhibitor that in vitro has been shown to possessantileukaemic activities. CTO, which has a reduced toxicity, increased oral bioavailability and stronger efficacy whencompared to the parental compound, was tested in this study for its ability to affect imatinib-resistant CML tumor growth ina xenograft model. The active cross talk between endothelial cells and leukemic cells in the bone marrow involvingexosomes plays an important role in modulating the process of neovascularization in CML. We have thus investigated theeffects of CTO on exosome-stimulated angiogenesis. Our results indicate that CTO may be effective in targeting both cancercell growth and the tumor microenvironment, thus suggesting a potential therapeutic utility for CTO in leukaemia patients.