Homoharringtonine (omacetaxine mepesuccinate) limits the angiogenic capacity of endothelial cells and reorganises filamentous actin

Le résumé fourni par la source

Homoharringtonine (HHT), an alkaloid from the plant genus Cephalotaxus , disrupts the first elongation phase of protein synthesis by interacting with the 60S ribosomal subunit, making it effective in treating diseases such as myeloid leukaemia. Semi-synthetically produced as omacetaxine mepesuccinate, HHT has been approved in Europe and in the US for patients resistant to two or more tyrosine kinase inhibitors. Although recent studies assume an anti-angiogenic capacity, the actions of HHT have not yet been characterised in primary endothelial cells, the major cell type driving angiogenesis. Therefore, this study addresses this issue by investigating the anti-angiogenic effect of HHT ex vivo and in vitro . A concentration-dependent decrease in sprouting was observed in a mouse aortic ring assay and in spheroids generated from human umbilical vein endothelial cells (HUVECs). Other angiogenic key features such as migration, proliferation and tube formation were similarly decreased by HHT. Interestingly, we observed an accumulation of F-actin. Inhibition of the ROCK pathway restored the angiogenic effects. A specific inhibition of typical upstream or downstream proteins of the ROCK pathway like Rho, MLC-2 or LIMK only marginally restored the angiogenic capability. Further analyses revealed that the alteration of the actin network might relate to the p38 MAPK/HSP27 axis: A significant prolongation of p38 phosphorylation induced by HHT treatment resulted in a partial restoration of endothelial spheroid sprouting. This study demonstrates the anti-angiogenic capabilities of HHT in endothelial cells and opens a promising further research field for an already approved drug. • HHT concentration-dependently decreases angiogenic sprouting ex vivo and in vitro. • Key features as migration, proliferation and tube formation were reduced by HHT. • Accumulation of F-actin due to HHT was reversed by an inhibition of ROCK. • Inhibition of specific ROCK proteins partly restored the angiogenic capability. • Alteration of the F-actin network may relate to the p38 MAPK/HSP27 axis.

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