Biological Evaluation of a New Brassinosteroid: Antiproliferative Effects and Targeting Estrogen Receptor α Pathways.

Abstract

Brassinosteroids (BS), a class of plant-specific steroid hormones, are considered as new potential anticancer agents for the treatment of tumors of different origin, including hormone-dependent cancers. Effects of a synthetic brassinosteroid BS4 ((22R,23R,24R)-22,23-dihydroxy-24-methyl-B-homo-7-oxa-5α-cholest-2-en-6-one ((3aS,7aR,7bS,9aS,10R,12aS,12bS)-10-[(2S,3R,4R,5R)-3,4-dihydroxy-5,6-dimethylheptan-2-yl]-7a,9a-dimethyl-1,3a,4,7,7a,7b,8,9,9a,10,11,12,12a,12b-tetradecahydro-3H-benzo[c]indeno[5,4-e]oxepin-3-one)) on hormone-dependent breast cancer cells and normal epithelial cells and its impact on the estrogen receptor signaling were evaluated. Cytotoxicity was assessed by MTT-test; expression of estrogen receptor α and survivin was measured by immunoblotting. Transactivation analysis of luciferase reporter gene was performed for ERα and AP-1 factors after the brassinosteroid treatment. Dock6 and Autodock Vina were used for molecular docking. BS4 revealed a significant antiproliferative effect towards the hormone-dependent breast cancer cells and was not active against normal epithelial cells. BS4 action on MCF-7 breast cancer cells was found to be complex: a decrease in ERα expression as well as in its transcription activity was accompanied by inhibition of ERα-related signaling pathways (AP-1 complex and survivin). BS4 binding mode to ERα ligand-binding domain was analyzed by molecular docking. The obtained results show that antiproliferative and antiestrogenic properties of the brassinosteroid BS4, as well as its ability to inhibit the anti-apoptotic protein survivin may be of interest for further development of anticancer agents.

• Authors: Alexander M Scherbakov, Vladimir N Zhabinskii, Vladimir A Khripach, Dmitrii S Shcherbinin, Arif R Mekhtiev, Yuri Yu Shchegolev, Aleh P Savochka, Olga E Andreeva
• Journal: Chemistry & biodiversity (Chem Biodivers) Vol. 16 Issue 9 Pg. e1900332 (Sep 2019) ISSN: 1612-1880 [Electronic] Switzerland
• PMID: 31381816 (Publication Type: Journal Article)
• Copyright: © 2019 Wiley-VHCA AG, Zurich, Switzerland.

Chemical References

• Antineoplastic Agents, Phytogenic
• Brassinosteroids
• ESR1 protein, human
• Estrogen Receptor alpha

Topics

• Antineoplastic Agents, Phytogenic (chemistry, isolation & purification, pharmacology)
• Brassinosteroids (chemistry, isolation & purification, pharmacology)
• Cell Line
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Estrogen Receptor alpha (antagonists & inhibitors, metabolism)
• Humans
• MCF-7 Cells
• Molecular Conformation
• Molecular Dynamics Simulation
• Structure-Activity Relationship