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Antimitotic sulfonamides inhibit microtubule assembly dynamics and cancer cell proliferation

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Title Antimitotic sulfonamides inhibit microtubule assembly dynamics and cancer cell proliferation
 
Creator MOHAN, R
BANERJEE, M
RAY, A
MANNA, T
WILSON, L
OWA, T
BHATTACHARYYA, B
PANDA, D
 
Subject cycle progression
colchicine site
g1 phase
kinetic stabilization
protease inhibitors
in-vitro
anticancer
tubulin
binding
phosphorylation
 
Description Several sulfonamides have antitumor activities and are currently undergoing clinical evaluation for the treatment of cancer. In this study, we have elucidated the antiproliferative mechanism of action of five indole sulfonamides. The indole sulfonamides inhibited the polymerization of microtubule protein into microtubules in vitro. In addition, three representative derivatives, ER-68378 (2), ER-68384 (4) and ER-68394 (5), suppressed the dynamic instability behavior at the plus ends of individual steady-state microtubules in vitro. The analogues inhibited HeLa cell proliferation with half-maximal inhibitory concentrations in the range of 6-17 mu M. The compounds blocked cell cycle progression at mitosis. At their lowest effective antimitotic concentrations, they depolymerized the spindle microtubules and disorganized the chromosomes but did not affect the microtubules in interphase cells. However, at relatively high concentrations, interphase microtubules were also depolymerized by these sulfonamides. Furthermore, all five compounds were found to induce apoptosis in the cells in association with the phosphorylation of bcl-2. The results suggest that the indole sulfonamides inhibit cell proliferation at mitosis by perturbing the assembly dynamics of spindle microtubules and that they can kill cancer cells by inducing apoptosis through the bcl-2-dependent pathway.
 
Publisher AMER CHEMICAL SOC
 
Date 2011-07-13T17:14:32Z
2011-12-26T12:47:59Z
2011-12-27T05:42:53Z
2011-07-13T17:14:32Z
2011-12-26T12:47:59Z
2011-12-27T05:42:53Z
2006
 
Type Article
 
Identifier BIOCHEMISTRY, 45(17), 5440-5449
0006-2960
http://dx.doi.org/10.1021/bi0523409
http://dspace.library.iitb.ac.in/xmlui/handle/10054/3725
http://hdl.handle.net/10054/3725
 
Language en