Počet záznamů: 1  

Estradiol dimer inhibits tubulin polymerization and microtubule dynamics

  1. 1.
    SYSNO ASEP0494693
    Druh ASEPJ - Článek v odborném periodiku
    Zařazení RIVJ - Článek v odborném periodiku
    Poddruh JČlánek ve WOS
    NázevEstradiol 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) RID
    Celkový počet autorů17
    Zdroj.dok.Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier - ISSN 0960-0760
    Roč. 183, Říjen (2018), s. 68-79
    Poč.str.12 s.
    Jazyk dok.eng - angličtina
    Země vyd.GB - Velká Británie
    Klíč. slovaSteroid dimer ; Steroid receptor ; Luciferase reporter assay ; Microtubules ; Microtubule dynamics ; Tubulin assembly ; Molecular dynamics simulation ; Antimitotic activity
    Vědní obor RIVEB - Genetika a molekulární biologie
    Obor OECDCell biology
    CEPLO1220 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 podporaUMG-J - RVO:68378050
    UT WOS000445714300008
    DOI10.1016/j.jsbmb.2018.05.008
    AnotaceMicrotubule 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.
    PracovištěÚstav molekulární genetiky
    KontaktNikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217
    Rok sběru2019
Počet záznamů: 1  

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