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CXI-benzo-84 reversibly binds to tubulin at colchicine site and induces apoptosis in cancer cells

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Title CXI-benzo-84 reversibly binds to tubulin at colchicine site and induces apoptosis in cancer cells
 
Creator RAI, A
GUPTA, TK
KINI, S
KUNWAR, A
SUROLIA, A
PANDA, D
 
Subject Apoptosis
Anticancer drug
Benzimidazole Cell cycle
Checkpoint proteins
Microtubule assembly dynamics
MICROTUBULE DYNAMIC INSTABILITY
KINETIC STABILIZATION
INHIBITS MIGRATION
ANTICANCER AGENTS
HYDROGEN-BOND
PROTEIN
BENZIMIDAZOLE
DOMAIN
MECHANISM
IDENTIFICATION
 
Description Here, we have discovered CXI-benzo-84 as a potential anticancer agent from a library of benzimidazole derivatives using cell based screening strategy. CXI-benzo-84 inhibited cell cycle progression in metaphase stage of mitosis and accumulated spindle assembly checkpoint proteins Mad2 and BubR1 on kinetochores, which subsequently activated apoptotic cell death in cancer cells. CXI-benzo-84 depolymerized both interphase and mitotic microtubules, perturbed EB1 binding to microtubules and inhibited the assembly and GTPase activity of tubulin in vitro. CXI-benzo-84 bound to tubulin at a single binding site with a dissociation constant of 1.2 +/- 0.2 mu M. Competition experiments and molecular docking suggested that CXI-benzo-84 binds to tubulin at the colchicine-site. Further, computational analysis provided a significant insight on the binding site of CXI-benzo-84 on tubulin. In addition to its potential use in cancer chemotherapy, CXI-benzo-84 may also be useful to screen colchicine-site agents and to understand the colchicine binding site on tubulin. (C) 2013 Elsevier Inc. All rights reserved.
 
Publisher PERGAMON-ELSEVIER SCIENCE LTD
 
Date 2014-10-15T12:28:58Z
2014-10-15T12:28:58Z
2013
 
Type Article
 
Identifier BIOCHEMICAL PHARMACOLOGY, 86(3)378-391
http://dx.doi.org/10.1016/j.bcp.2013.05.024
http://dspace.library.iitb.ac.in/jspui/handle/100/14906
 
Language en