Resveratrol analog (Z)-3,5,4'-trimethoxystilbene is a potent anti-mitotic drug inhibiting tubulin polymerization.
Resveratrol (3,5,4'-trihydroxystilbene) a natural polyphenol present in medicinal plants, grapes and wines, has potent chemopreventive properties on intestinal carcinogenesis. A methylated derivative (Z-3,5,4'-trimethoxystilbene: R3) was synthesized. R3 at 0.3 microM exerted a 80% growth inhibition of human colon cancer Caco-2 cells and arrested growth completely at 0.4 microM (R3 was 100-fold more active than resveratrol). The cis conformation of R3 was also 100-fold more potent than the trans isomer. R3 (0.3 microM) caused cell cycle arrest at the G2/M phase transition. The drug inhibited tubulin polymerization in a dose-dependent manner (IC50=4 microM), and it reduced also by 2-fold ornithine decarboxylase and s-adenosylmethionine decarboxylase activities. This caused the depletion of the polyamines, putrescine and spermidine, which are growth factors for cancer cells. R3 inhibited partially colchicine binding to its binding site on tubulin, indicating that R3 either partially overlaps with colchicine binding or that R3 binds to a specific site of tubulin that is not identical with the colchicine binding site modifying colchicine binding by allosteric influences. The resveratrol derivative (Z)-3,5,4'-trimethoxystilbene (R3) is an interesting anti-mitotic drug that exerts cytotoxic effects by depleting the intracellular pool of polyamines and by altering microtubule polymerization. Such a drug may be useful for the treatment of neoplastic diseases.
Schneider
Yann
Y
Laboratory of Nutritional Oncology, Inserm U392, IRCAD, Strasbourg, France.
Chabert
Philippe
P
Stutzmann
Jeanne
J
Coelho
David
D
Fougerousse
André
A
Gossé
Francine
F
Launay
Jean-François
JF
Brouillard
Raymond
R
Raul
Francis
F
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D018938:Caco-2 Cells / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003078:Colchicine / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006074:Gout Suppressants / Q000378:metabolism; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism; D011108:Polymers; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators; D014747:Vinblastine / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D006074:Gout Suppressants; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D011108:Polymers; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; D014747:Vinblastine; D009955:Ornithine Decarboxylase; D000077185:Resveratrol; D003078:Colchicine