Dasatinib induces endothelial-to-mesenchymal transition in human vascular-endothelial cells: counteracted by cotreatment with bosutinib.

Dasatinib induces endothelial-to-mesenchymal transition in human vascular-endothelial cells: counteracted by cotreatment with bosutinib.
Int J Hematol. 2021 Jan 03;:
Authors: Alkebsi L, Wang X, Ohkawara H, Fukatsu M, Mori H, Ikezoe T
Abstract
Adverse vascular events have become a serious clinical problem in chronic myeloid leukemia (CML) patients who receive certain BCR/ABL1 tyrosine kinase inhibitors (TKIs). Studies have shown that endothelial-to-mesenchymal transition (EndMT) can contribute to various vascular diseases. We investigated the effects of TKIs on the development of EndMT in human vascular-endothelial cells (VECs). Exposure of VECs to dasatinib, but not to other TKIs, produced a significant increase in the formation of spindle-shaped cells. This effect was accompanied by a significant increase in expression of the EndMT inducer transforming growth factor-β (TGF-β) and mesenchymal markers vimentin, smooth muscle alpha-actin, and fibronectin, as well as a significant decrease in expression of vascular-endothelial markers CD31 and VE-cadherin attributable at least in part to activation of ERK signaling. Inhibitors of TGF-β and ERK partially attenuated dasatinib-induced EndMT. Interestingly, bosutinib efficiently counteracted dasatinib-induced EndMT and attenuated dasatinib-induced phosphorylation of ERK. Taken together, these results show that dasatinib induces EndMT, which might contribute to the development of vascular...

Source: International Journal of Hematology - January 3, 2021 Category: Hematology Authors: Alkebsi L, Wang X, Ohkawara H, Fukatsu M, Mori H, Ikezoe T Tags: Int J Hematol Source Type: research