Počet záznamů: 1
Estradiol dimer inhibits tubulin polymerization and microtubule dynamics
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SYSNO ASEP 0494693 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Estradiol dimer inhibits tubulin polymerization and microtubule dynamics Tvůrce(i) Jurasek, M. (CZ)
Černohorská, Markéta (UMG-J)
Řehulka, J. (CZ)
Spiwok, V. (CZ)
Sulimenko, Tetyana (UMG-J)
Dráberová, Eduarda (UMG-J) RID, ORCID
Darmostuk, M. (CZ)
Gurska, S. (CZ)
Frydrych, I. (CZ)
Burianova, R. (CZ)
Ruml, T. (CZ)
Hajduch, M. (CZ)
Bartůněk, Petr (UMG-J) RID
Dráber, Pavel (UMG-J) RID, ORCID
Dzubak, P. (CZ)
Drašar, P. B. (CZ)
Sedlák, David (UMG-J) RIDCelkový počet autorů 17 Zdroj.dok. Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier - ISSN 0960-0760
Roč. 183, Říjen (2018), s. 68-79Poč.str. 12 s. Jazyk dok. eng - angličtina Země vyd. GB - Velká Británie Klíč. slova Steroid dimer ; Steroid receptor ; Luciferase reporter assay ; Microtubules ; Microtubule dynamics ; Tubulin assembly ; Molecular dynamics simulation ; Antimitotic activity Vědní obor RIV EB - Genetika a molekulární biologie Obor OECD Cell biology CEP LO1220 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy LO1304 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy LM2015063 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy GA15-22194S GA ČR - Grantová agentura ČR GA16-25159S GA ČR - Grantová agentura ČR Institucionální podpora UMG-J - RVO:68378050 UT WOS 000445714300008 DOI 10.1016/j.jsbmb.2018.05.008 Anotace 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. Pracoviště Ústav molekulární genetiky Kontakt Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Rok sběru 2019
Počet záznamů: 1