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A Synthetic Dolastatin 10 Analogue Suppresses Microtubule Dynamics, Inhibits Cell Proliferation, and Induces Apoptotic Cell Death

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Title A Synthetic Dolastatin 10 Analogue Suppresses Microtubule Dynamics, Inhibits Cell Proliferation, and Induces Apoptotic Cell Death
 
Creator GAJULA, PK
ASTHANA, J
PANDA, D
CHAKRABORTY, TK
 
Subject SUGAR AMINO-ACIDS
TUBULIN BINDING
CANCER-CELLS
COMBINATORIAL SYNTHESIS
KINETIC STABILIZATION
QUANTITATIVE-ANALYSIS
ANTICANCER DRUGS
MITOTIC ARREST
BETA-TUBULIN
PHASE-I
 
Description We have synthesized eight analogues (D1-D8) of dolastatin 10 containing several unique amino acid subunits. Of these agents, D5 was found to be most effective in inhibiting both He La cell proliferation and microtubule assembly in vitro. At low nanomolar concentrations, 135 inhibited the proliferation of several types of cancer cells in culture. D5 bound to tubulin with a dissociation constant of 29.4 +/- 6 mu M. D5 depolymerized microtubules in cultured cells and produced mulitpolar spindles. At its half-maximal inhibitory concentration (15 nM), DS strongly suppressed the dynamics of individual microtubules in live MCF-7 cells. DS increased the accumulation of checkpoint proteins BubR1 and Mad2 at the kinetochoric region and caused G2/M block in these cells. The blocked cells underwent apoptosis with the activation of Jun N-terminal kinase. The results suggested that DS exerts its antiproliferative action by dampening microtubule dynamics.
 
Publisher AMER CHEMICAL SOC
 
Date 2014-10-16T13:56:44Z
2014-10-16T13:56:44Z
2013
 
Type Article
 
Identifier JOURNAL OF MEDICINAL CHEMISTRY, 56(6)2235-2245
0022-2623
1520-4804
http://dx.doi.org/10.1021/jm3009629
http://dspace.library.iitb.ac.in/jspui/handle/100/15722
 
Language en