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
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Creator |
RAI, A
GUPTA, TK KINI, S KUNWAR, A SUROLIA, A PANDA, D |
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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 |
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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.
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Publisher |
PERGAMON-ELSEVIER SCIENCE LTD
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Date |
2014-10-15T12:28:58Z
2014-10-15T12:28:58Z 2013 |
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Type |
Article
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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 |
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Language |
en
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