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Rarova, Lucie; Sedlak, David; Oklestkova, Jana; Steigerova, Jana; Liebl, Johanna; Zahler, Stefan; Bartunek, Petr; Kolar, Zdenek; Kohout, Ladislav; Kvasnica, Miroslav; Strnad, Miroslav (2018): The novel brassinosteroid analog BR4848 inhibits angiogenesis in human endothelial cells and induces apoptosis in human cancer cells in vitro. In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 178: pp. 263-271
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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.