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Ansamitocin P3 Depolymerizes Microtubules and Induces Apoptosis by Binding to Tubulin at the Vinblastine Site

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Title Ansamitocin P3 Depolymerizes Microtubules and Induces Apoptosis by Binding to Tubulin at the Vinblastine Site
 
Creator VENGHATERI, JB
GUPTA, TK
VERMA, PJ
KUNWAR, A
PANDA, D
 
Subject PROTEIN-LIGAND COMPLEXES
KINETIC STABILIZATION
TUMOR INHIBITORS
DYNAMIC INSTABILITY
MAYTANSINE-BINDING
SULFHYDRYL-GROUPS
ANTITUMOR AGENTS
MITOTIC ARREST
BLIND DOCKING
HALOGEN BONDS
 
Description Maytansinoid conjugates are currently under different phases of clinical trials and have been showing promising activity for various types of cancers. In this study, we have elucidated the mechanism of action of ansamitocin P3, a structural analogue of maytansine for its anticancer activity. Ansamitocin P3 potently inhibited the proliferation of MCF-7, HeLa, EMT-6/AR1 and MDA-MB-231 cells in culture with a half-maximal inhibitory concentration of 20 +/- 3, 50 +/- 0.5, 140 +/- 17, and 150 +/- 1.1 pM, respectively. Ansamitocin P3 strongly depolymerized both interphase and mitotic microtubules and perturbed chromosome segregation at its proliferation inhibitory concentration range. Treatment of ansamitocin P3 activated spindle checkpoint surveillance proteins, Mad2 and BubR1 and blocked the cells in mitotic phase of the cell cycle. Subsequently, cells underwent apoptosis via p53 mediated apoptotic pathway. Further, ansamitocin P3 was found to bind to purified tubulin in vitro with a dissociation constant (K-d) of 1.3 +/- 0.7 mu M. The binding of ansamitocin P3 induced conformational changes in tubulin. A docking analysis suggested that ansamitocin P3 may bind partially to vinblastine binding site on tubulin in two different positions. The analysis indicated that the binding of ansamitocin P3 to tubulin is stabilized by hydrogen bonds. In addition, weak interactions such as halogen-oxygen interactions may also contribute to the binding of ansamitocin P3 to tubulin. The study provided a significant insight in understanding the antiproliferative mechanism of action of ansamitocin P3.
 
Publisher PUBLIC LIBRARY SCIENCE
 
Date 2014-10-14T13:06:25Z
2014-10-14T13:06:25Z
2013
 
Type Article
 
Identifier PLOS ONE, 8(10)
http://dx.doi.org/10.1371/journal.pone.0075182
http://dspace.library.iitb.ac.in/jspui/handle/100/14478
 
Language en