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

Rai, Ankit and Gupta, Tilak Kumar and Kini, Sudarshan and Kunwar, Ambarish and Surolia, Avadhesha and Panda, Dulal (2013) CXI-benzo-84 reversibly binds to tubulin at colchicine site and induces apoptosis in cancer cells. In: BIOCHEMICAL PHARMACOLOGY, 86 (3). pp. 378-391.

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Abstract

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.

Item Type:	Journal Article
Publication:	BIOCHEMICAL PHARMACOLOGY
Publisher:	PERGAMON-ELSEVIER SCIENCE LTD
Additional Information:	Copyright for this article belongs to PERGAMON-ELSEVIER SCIENCE LTD, ENGLAND.
Keywords:	Apoptosis; Anticancer drug; Benzimidazole Cell cycle; Checkpoint proteins; Microtubule assembly dynamics
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	23 Sep 2013 12:16
Last Modified:	23 Sep 2013 12:16
URI:	http://eprints.iisc.ac.in/id/eprint/47289

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