Small change – big consequence: The impact of C15-C16 double bond in a D‑ring of estrone on estrogen receptor activity

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61389030%3A_____%2F23%3A00575940" target="_blank" >RIV/61389030:_____/23:00575940 - isvavai.cz</a>

Alternative codes found

RIV/61388963:_____/23:00575940 RIV/00209805:_____/23:00079344 RIV/61989592:15310/23:73622582

Result on the web

<a href="https://doi.org/10.1016/j.jsbmb.2023.106365" target="_blank" >https://doi.org/10.1016/j.jsbmb.2023.106365</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.jsbmb.2023.106365" target="_blank" >10.1016/j.jsbmb.2023.106365</a>

Result language

angličtina

Original language name

Small change – big consequence: The impact of C15-C16 double bond in a D‑ring of estrone on estrogen receptor activity

Original language description

Estrogen receptor alpha (ER) is a key biomarker for breast cancer, and the presence or absence of ER in breast and other hormone-dependent cancers decides treatment regimens and patient prognosis. ER is activated after ligand binding typically by steroid. 2682 steroid compounds were used in a molecular docking study to identify novel ligands for ER and to predict compounds that may show anticancer activity. The effect of the most promising compounds was determined by a novel luciferase reporter assay. Two compounds, 7 and 12, showing ER inhibitory activity comparable to clinical inhibitors such as tamoxifen or fulvestrant were selected. We propose that the inhibitory effect of compounds 7 and 12 on ER is related to the presence of a double bond in their D-ring, which may protect against ER activation by reducing the electron density of the keto group, or may undergo metabolism leading to an active compound. Western blotting revealed that compound 12 decreased the level of ER in the breast cancer cell line MCF7, which was associated with reduced expression of both isoforms of the progesterone receptor, a well-known downstream target of ER. However, compound 12 has a different mechanism of action from fulvestrant. Furthermore, we found that compound 12 interferes with mitochondrial functions, probably by disrupting the electron transport chain, leading to induction of the intrinsic apoptotic pathway even in ER-negative breast cancer cells. In conclusion, the combination of computational and experimental methods shown here represents a rapid approach to determine the activity of compounds towards ER. Our data will not only contribute to research focused on the regulation of ER activity but may also be useful for the further development of novel steroid receptor-targeted drugs applicable in clinical practice.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10608 - Biochemistry and molecular biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal of Steroid Biochemistry and Molecular Biology

ISSN

0960-0760

e-ISSN

—

Volume of the periodical

233

Issue of the periodical within the volume

OCT

Country of publishing house

GB - UNITED KINGDOM

Number of pages

13

Pages from-to

106365

UT code for WoS article

001048999000001

EID of the result in the Scopus database

2-s2.0-85165571434