Record Details

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

DSpace at IIT Bombay

View Archive Info
 
 
Field Value
 
Title 2-methoxyestradiol suppresses microtubule dynamics and arrests mitosis without depolymerizing microtubules
 
Creator KAMATH, K
OKOUNEVA, T
LARSON, G
PANDA, D
WILSON, L
JORDAN, MA
 
Subject endogenous mammalian metabolite
individual microtubules
kinetic stabilization
tubulin polymers
vinblastine
instability
binding
growth
cells
taxol
 
Description 2-Methoxyestradiol (2ME2), a metabolite of estradiol-17 beta, 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 mu mol/L) inhibited assembly of purified tubulin in a concentration-dependent manner, with maximal inhibition (60%) at 200 mu mol/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 mu mol/L 2ME2. In vitro, dynamic instability was inhibited at lower concentrations. Specifically, 4 mu mol/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 mu mol/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.
 
Publisher AMER ASSOC CANCER RESEARCH
 
Date 2011-07-13T11:55:37Z
2011-12-26T12:47:51Z
2011-12-27T05:41:04Z
2011-07-13T11:55:37Z
2011-12-26T12:47:51Z
2011-12-27T05:41:04Z
2006
 
Type Article
 
Identifier MOLECULAR CANCER THERAPEUTICS, 5(9), 2225-2233
1535-7163
http://dx.doi.org/10.1158/1535-7163.MCT-06-0113
http://dspace.library.iitb.ac.in/xmlui/handle/10054/3669
http://hdl.handle.net/10054/3669
 
Language en