Estradiol dimer inhibits tubulin polymerization and microtubule dynamics

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F18%3A00494693" target="_blank" >RIV/68378050:_____/18:00494693 - isvavai.cz</a>

Alternative codes found

RIV/61989592:15110/18:73590669 RIV/60461373:22330/18:43915839

Result on the web

<a href="http://dx.doi.org/10.1016/j.jsbmb.2018.05.008" target="_blank" >http://dx.doi.org/10.1016/j.jsbmb.2018.05.008</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.jsbmb.2018.05.008" target="_blank" >10.1016/j.jsbmb.2018.05.008</a>

Result language

angličtina

Original language name

Estradiol dimer inhibits tubulin polymerization and microtubule dynamics

Original language description

Microtubule dynamics is one of the major targets for new chemotherapeutic agents. This communication presents the synthesis and biological profiling of steroidal dimers based on estradiol, testosterone and pregnenolone bridged by 2,6-bis(azidomethyl)pyridine between D rings. The biological profiling revealed unique properties of the estradiol dimer including cytotoxic activities on a panel of 11 human cell lines, ability to arrest in the G2/M phase of the cell cycle accompanied with the attenuation of DNA/RNA synthesis. Thorough investigation precluded a genomic mechanism of action and revealed that the estradiol dimer acts at the cytoskeletal level by inhibiting tubulin polymerization. Further studies showed that estradiol dimer, but none of the other structurally related dimeric steroids, inhibited assembly of purified tubulin (IC50, 3.6 mu M). The estradiol dimer was more potent than 2-methoxyestradiol, an endogenous metabolite of 17 beta-estradiol and well-studied microtubule polymerization inhibitor with antitumor effects that was evaluated in clinical trials. Further, it was equipotent to nocodazole (IC50, 1.5 mu M), an antimitotic small molecule of natural origin. Both estradiol dimer and nocodazole completely and reversibly depolymerized microtubules in interphase U2OS cells at 2.5 mu M concentration. At lower concentrations (50 nM), estradiol dimer decreased the microtubule dynamics and growth life-time and produced comparable effect to nocodazole on the microtubule dynamicity. In silico modeling predicted that estradiol dimer binds to the colchicine-binding site in the tubulin dimer. Finally, dimerization of the steroids abolished their ability to induce transactivation by estrogen receptor a and androgen receptors. Although other steroids were reported to interact with microtubules, the estradiol dimer represents a new structural type of steroid inhibitor of tubulin polymerization and microtubule dynamics, bearing antimitotic and cytotoxic activity in cancer cell lines.

Czech name

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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

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OECD FORD branch

10601 - Cell biology

Project

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

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2018

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

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Volume of the periodical

183

Issue of the periodical within the volume

Říjen

Country of publishing house

GB - UNITED KINGDOM

Number of pages

12

Pages from-to

68-79

UT code for WoS article

000445714300008

EID of the result in the Scopus database

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