Carboxyamidotriazole-orotate inhibits the growth of Imatinib resistantchronic myeloid leukemia cells and modulates exosomes stimulated Angiogenesis

Chronic myeloid leukemia (CML) is characterized by the expression of Bcr–Abl oncoprotein with a constitutive tyrosine kinase that drives disease pathogenesis. Imatinib is the election therapy for CML, but some patients are resistant to this drug. Recently, attention is being focused on cell-cell communication that involves membrane vesicles called exosomes. A number of studies have described exosomes as new players in modulating the tumor microenvironment, promoting angiogenesis and tumor development; furthermore neovascularization is known to exert an important role in the progression of chronic myeloid leukaemia and may represent a valid alternative target for therapy. Little is known regarding the role of exosomes in CML biology. Our data indicate that LAMA84 R, an Imatinib resistant human CML cell line releases exosomes and that the addition of those microvesicles to human vascular endothelial cells affects in vitro and in vivo angiogenesis. Interestingly, in the last years some data have indicated that modulation of exosome release by pharmacological agents may affect malignant progression. We have tested the effects of the carboxyamidotriazole-orotate (CTO) on LAMA84 R, we observed the inhibitor effects of CTO on LAMA84 R cells proliferation and on CML tumor xenografts growth. CTO is able to decrease in vitro BCR/ABL level expression and its phosphorilation and consequently inhibition of the downstream signalling . Our data also show that treatment of endothelial cells with CTO may inhibit exosomes-dependent angiogenesis by interfering with signal transduction pathways activated in endothelial cells by interaction with the microvesicles.