The novel brassinosteroid analog BR4848 inhibits angiogenesis in human endothelial cells and induces apoptosis in human cancer cells in vitro
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
29307714
DOI
10.1016/j.jsbmb.2018.01.005
PII: S0960-0760(18)30006-2
Knihovny.cz E-resources
- Keywords
- Angiogenesis, Apoptosis, Brassinosteroid analog, Cancer cell lines, HUVEC,
- MeSH
- Apoptosis drug effects MeSH
- Brassinosteroids chemistry pharmacology MeSH
- Human Umbilical Vein Endothelial Cells drug effects pathology MeSH
- Phosphorylation MeSH
- Angiogenesis Inhibitors chemistry pharmacology MeSH
- Cell Cycle Checkpoints drug effects MeSH
- Humans MeSH
- Tumor Cells, Cultured MeSH
- Neoplasms blood supply drug therapy pathology MeSH
- Neovascularization, Pathologic pathology prevention & control MeSH
- Cell Proliferation drug effects MeSH
- Signal Transduction MeSH
- In Vitro Techniques MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Brassinosteroids MeSH
- Angiogenesis Inhibitors MeSH
We report the synthesis and detailed biological study of the synthetic brassinosteroid analog 2α,3α-dihydroxy-6-oxo-5α-androstan-17β-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 subG1 cells, PARP-1 and caspase-7 fragmentation, downregulation of Bcl-2 and Mcl-1, an increase in caspase activity and G2/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 FAK, Erk 1/2, CDK5, VEGFR2, TNFα-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 (ERα, ERβ, 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.
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