2-Methoxyestradiol suppresses microtubule dynamics and arrests mitosis without depolymerizing microtubules.

2-Methoxyestradiol suppresses microtubule dynamics and arrests mitosis without depolymerizing microtubules. Research Abstract Details 

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2-Methoxyestradiol suppresses microtubule dynamics and arrests mitosis without depolymerizing microtubules. Abstract Text:

Kathy Kamath,Tatiana Okouneva,Gary Larson,Dulal Panda,Leslie Wilson,Mary Ann Jordan,

2-Methoxyestradiol (2ME2), a metabolite of estradiol-17beta, is a novel antimitotic and antiangiogenic drug candidate in phase I and II clinical trials for the treatment of a broad range of tumor types. 2ME2 binds to tubulin at or near the colchicine site and inhibits the polymerization of tubulin in vitro, suggesting that it may work by interfering with normal microtubule function. However, the role of microtubule depolymerization in its antitumor mechanism of action has been controversial. To determine the mechanism by which 2ME2 induces mitotic arrest, we analyzed its effects on microtubule polymerization in vitro and its effects on dynamic instability both in vitro and in living MCF7 cells. In vitro, 2ME2 (5-100 micromol/L) inhibited assembly of purified tubulin in a concentration-dependent manner, with maximal inhibition (60%) at 200 micromol/L 2ME2. However, with microtubule-associated protein-containing microtubules, significantly higher 2ME2 concentrations were required to depolymerize microtubules, and polymer mass was reduced by only 13% at 500 micromol/L 2ME2. In vitro, dynamic instability was inhibited at lower concentrations. Specifically, 4 micromol/L 2ME2 reduced the mean growth rate by 17% and dynamicity by 27%. In living interphase MCF7 cells at the IC50 for mitotic arrest (1.2 micromol/L), 2ME2 significantly suppressed the mean microtubule growth rate, duration and length, and the overall dynamicity, consistent with its effects in vitro, and without any observable depolymerization of microtubules. Taken together, the results suggest that the major mechanism of mitotic arrest at the lowest effective concentrations of 2ME2 is suppression of microtubule dynamics rather than microtubule depolymerization per se.

2-Methoxyestradiol suppresses microtubule dynamics and arrests mitosis without depolymerizing microtubules. Publishing Authors By Initials

K Kamath,T Okouneva,G Larson,D Panda,L Wilson,MA Jordan,

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2-Methoxyestradiol suppresses microtubule dynamics and arrests mitosis without depolymerizing microtubules. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Molecular cancer therapeutics

VOLUME: 5

Page Numbers: 2225-33

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ISSN: 1535-7163

DAY: 3

MONTH: Sep

YEAR: 2006

2-Methoxyestradiol suppresses microtubule dynamics and arrests mitosis without depolymerizing microtubules. Information

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LANGUAGE: eng

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Grant and Affiliation Information for 2-Methoxyestradiol suppresses microtubule dynamics and arrests mitosis without depolymerizing microtubules.

AFFILIATION: Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Bio II Room 3106, Santa Barbara, CA 93106, USA. kamath@lifesci.ucsb.edu

Country: United States

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MEDLINETA: Mol Cancer Ther

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