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Thalidomide (5HPP-33) Suppresses Microtubule Dynamics and Depolymerizes the Microtubule Network by Binding at the Vinblastine Binding Site on Tubulin

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Title Thalidomide (5HPP-33) Suppresses Microtubule Dynamics and Depolymerizes the Microtubule Network by Binding at the Vinblastine Binding Site on Tubulin
 
Creator RASHID, A
KUPPA, A
KUNWAR, A
PANDA, D
 
Subject ENDOTHELIAL GROWTH-FACTOR
POLYMERIZATION INHIBITORS
INDIVIDUAL MICROTUBULES
KINETIC STABILIZATION
CELL-DIFFERENTIATION
COLCHICINE SITE
MCF-7 CELLS
ANGIOGENESIS
APOPTOSIS
MIGRATION
 
Description Thalidomides were initially thought to be broad-range drugs specifically for curing insomnia and relieving morning sickness in pregnant women. However, its use was discontinued because of a major drawback of causing teratogenicity. In this study, we found that a thalidomide derivative, 5-hydroxy-2-(2,6-diisopropylphenyl)-1H-isoindole-1,3-dione (5HPP-33), inhibited the proliferation of MCF-7 with a half-maximal inhibitory concentration of 4.5 +/- 0.4 mu M. 5HPP-33 depolymerized microtubules and inhibited the reassembly of cold-depolymerized microtubules in MCF-7 cells. Using time-lapse imaging, the effect of 5HPP-33 on the dynamics of individual microtubules in live MCF-7 cells was analyzed. 5HPP-33 (5 mu M) decreased the rates of growth and shortening excursions by 34 and 33%, respectively, and increased the time microtubules spent in the pause state by 92% as compared to that of the vehicle-treated MCF-7 cells. 5HPP-33 (5 mu M) reduced the dynamicity of microtubules by 62% compared to the control. 5HPP-33 treatment reduced the distance between the two poles of a bipolar spindle, induced multipolarity in some of the treated cells, and blocked cells at mitosis. In vitro, 5HPP-33 bound to tubulin with a weak affinity. Vinblastine inhibited the binding of 5HPP-33 to tubulin, and 5HPP-33 inhibited the binding of BODIPY FL-vinblastine to tubulin. Further, a molecular docking analysis suggested that 5HPP-33 shares its binding site on tubulin with vinblastine. The results provided significant insight into the antimitotic mechanism of action of 5HPP-33 and also suggest a possible mechanism for the teratogenicity of thalidomides.
 
Publisher AMER CHEMICAL SOC
 
Date 2016-01-15T06:21:02Z
2016-01-15T06:21:02Z
2015
 
Type Article
 
Identifier BIOCHEMISTRY, 54(12)2149-2159
0006-2960
http://dx.doi.org/10.1021/bi501429j
http://dspace.library.iitb.ac.in/jspui/handle/100/17918
 
Language en