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Resveratrol analog ( Z )‐3,5,4′‐trimethoxystilbene is a potent anti‐mitotic drug inhibiting tubulin polymerization
Author(s) -
Schneider Yann,
Chabert Philippe,
Stutzmann Jeanne,
Coelho David,
Fougerousse André,
Gossé Francine,
Launay JeanFrançois,
Brouillard Raymond,
Raul Francis
Publication year - 2003
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.11344
Subject(s) - colchicine , tubulin , spermidine , resveratrol , putrescine , biochemistry , ornithine decarboxylase , polyamine , biology , mitosis , microtubule , allosteric regulation , chemistry , pharmacology , microbiology and biotechnology , enzyme , genetics
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 μM exerted a 80% growth inhibition of human colon cancer Caco‐2 cells and arrested growth completely at 0.4 μM (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 μM) caused cell cycle arrest at the G2/M phase transition. The drug inhibited tubulin polymerization in a dose‐dependent manner (IC 50 = 4 μM), 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. © 2003 Wiley‐Liss, Inc.