The novel brassinosteroid analog BR4848 inhibits angiogenesis in human endothelial cells and induces apoptosis in human cancer cells in vitro

0489630 - ÚMG 2019 RIV GB eng J - Journal Article
Rárová, L. - Sedlák, David - Oklešťková, Jana - Steigerová, J. - Liebl, J. - Zahler, S. - Bartůněk, Petr - Kolář, Z. - Kohout, Ladislav - Kvasnica, Miroslav - Strnad, Miroslav
The novel brassinosteroid analog BR4848 inhibits angiogenesis in human endothelial cells and induces apoptosis in human cancer cells in vitro.
Journal of Steroid Biochemistry and Molecular Biology. Roč. 178, April (2018), s. 263-271. ISSN 0960-0760
R&D Projects: GA MŠMT(CZ) LO1204; GA MŠMT LO1220; GA MŠMT LM2015063
Institutional support: RVO:68378050 ; RVO:61389030
Keywords : Brassinosteroid analog * Cancer cell lines * Apoptosis * HUVEC * Angiogenesis
OECD category: Organic chemistry
Impact factor: 3.785, year: 2018

We report the synthesis and detailed biological study of the synthetic brassinosteroid analog 2 alpha,3 alpha-dihydroxy-6-oxo-5 alpha-androstan-17 beta-yl N-(tert-butoxycarbonyl)-D,L-valinate (BR4848). The panel of cancer cell lines was used for characterization of its antiproliferative activity, yet had no adverse effects in normal human fibroblasts. In HeLa cells, BR4848-induced apoptosis was accompanied by increase of apoptotic subG(1) cells, PARP-1 and caspase-7 fragmentation, downregulation of Bcl-2 and Mcl-1, an increase in caspase activity and G(2)/M phase cell cycle arrest. Antiproliferative properties of BR4848 were exhibited by inhibition of phosphorylation of Akt, Erk1/2 and FAK. Furthermore, the developed analog exhibited in vitro antiangiogenic activity in human umbilical vein endothelial cells (HUVECs). BR4848-induced apoptosis accompanied with G2/M arrest was detected in endothelial cells. BR4848 also inhibited adhesion, tube formation and migration of endothelial cells by inhibition of FAY, Erk 1/2, CDK5, VEGFR2, TNF alpha-stimulated production of IL-6, angiopoietin-2 and Jagged1. Finally, BR4848 did not modulate the activity nor nuclear translocation of any of the steroid receptors (ER alpha, ER beta, AR, MR and PR) included in reporter cell-based assays, which excludes the genomic activity of steroid receptors as a contributing factor to the observed biological activities of BR4848.
Permanent Link: http://hdl.handle.net/11104/0284010