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Dicoumarol: A unique microtubule stabilizing natural product that is synergistic with Taxol

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Title Dicoumarol: A unique microtubule stabilizing natural product that is synergistic with Taxol
 
Creator MADARI, H
PANDA, D
WILSON, L
JACOBS, RS
 
Subject dynamic instability
transition frequencies
estramustine phosphate
kinetic stabilization
coumarin derivatives
malignant-melanoma
antitumor-activity
prostate-cancer
breast-cancer
in-vitro
 
Description In studies on the antiproliferative actions of coumarin compounds, we discovered that dicoumarol (a coumarin anticoagulant; 3,3'-methyl-enebis[4-hydroxycoumarin]) inhibits the first cleavage of Strongylocentrotus purpuratus (sea urchin) embryos in a concentration-dependent manner with 50% inhibition occurring at a concentration of 10 muM. Because first cleavage in sea urchin embryos is highly selective for microtubule-targeted agents, we thought that the active compounds might inhibit cell division by interacting with tubulin or microtubules. We found that dicoumarol binds to bovine brain tubulin with a K-d of 22 muM and that 0.1 muM dicoumarol strongly stabilizes the growing and shortening dynamics at the plus ends of the microtubules in vitro. Dicoumarol reduces the rate and extent of shortening, it increases the percentage of time the microtubules spend in an attenuated (paused) state, and it reduces the overall dynamicity of the microtubules. The antimitotic effects of the widely used cancer chemotherapeutic agent Taxol (paclitaxel) are also mediated by suppressing microtubule dynamics. We demonstrate that exposure to combinations of Taxol and dicoumarol results in a synergistic inhibition of cell division of sea urchin embryos. The results suggest that the antiproliferative mechanism of action of dicoumarol and possibly related pharmacophores may be mediated by tubulin binding and the stabilization of spindle microtubule dynamics. Because of its low toxicity and simple chemical structure, there is potential interest to explore combinations of antimitotic coumarins with other chemotherapeutic agents to improve efficacy and lower toxicity.
 
Publisher AMER ASSOC CANCER RESEARCH
 
Date 2011-07-13T12:01:14Z
2011-12-26T12:47:52Z
2011-12-27T05:41:07Z
2011-07-13T12:01:14Z
2011-12-26T12:47:52Z
2011-12-27T05:41:07Z
2003
 
Type Article
 
Identifier CANCER RESEARCH, 63(6), 1214-1220
0008-5472
http://dspace.library.iitb.ac.in/xmlui/handle/10054/3670
http://hdl.handle.net/10054/3670
 
Language en