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Research Articles: Therapeutics

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

¹ Department of Molecular, Cellular, and Developmental Biology and the Neuroscience Research Institute, University of California, Santa Barbara, California and ² Indian Institute of Technology Bombay, Mumbai, India

Requests for reprints: Kathy Kamath, Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Bio II Room 3106, Santa Barbara, CA 93106. Phone: 805-893-8057. E-mail: kamath{at}lifesci.ucsb.edu

2-Methoxyestradiol (2ME2), a metabolite of estradiol-17ß, 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 µmol/L) inhibited assembly of purified tubulin in a concentration-dependent manner, with maximal inhibition (60%) at 200 µmol/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 µmol/L 2ME2. In vitro, dynamic instability was inhibited at lower concentrations. Specifically, 4 µmol/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 µmol/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. [Mol Cancer Ther 2006;5(9):2225–33]

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³ K. Kamath, L. Wilson, and M.A. Jordan, unpublished results.

⁴ T. LaVallee, EntreMed, Inc., personal communication.

Received 2/28/06; revised 7/14/06; accepted 7/26/06.

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