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

摘要

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