Dicoumarol: a unique microtubule stabilizing natural product that is synergistic with Taxol.
In studies on the antiproliferative actions of coumarin compounds, we discovered that dicoumarol (a coumarin anticoagulant; 3,3'-methylenebis[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 microM. 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 microM and that 0.1 microM 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.
Madari
Hamta
H
Departments of Ecology, Evolution, and Marine Biology, University of California, Santa Barbara, California 93106, USA.
Panda
Dulal
D
Wilson
Leslie
L
Jacobs
Robert S
RS
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D001728:Dicumarol / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D004357:Drug Synergism; D007700:Kinetics; D018715:Microscopy, Video; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D012617:Sea Urchins / Q000737:chemistry; D013050:Spectrometry, Fluorescence; D014404:Tubulin / Q000378:metabolism
D014404:Tubulin; D001728:Dicumarol; D017239:Paclitaxel