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

DSpace/Manakin Repository

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

Show full item record

Title: Dicoumarol: A unique microtubule stabilizing natural product that is synergistic with Taxol
Author: MADARI, H; PANDA, D; WILSON, L; JACOBS, RS
Abstract: 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.
URI: http://dspace.library.iitb.ac.in/xmlui/handle/10054/3670
http://hdl.handle.net/10054/3670
Date: 2003


Files in this item

Files Size Format View

There are no files associated with this item.

This item appears in the following Collection(s)

Show full item record

Search DSpace


Advanced Search

Browse

My Account