期刊
MOLECULAR CANCER THERAPEUTICS
卷 4, 期 4, 页码 562-568出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-04-0229
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Microtubules are among the most successful targets for anticancer therapies and for the development of new anticancer drugs. A-432411 is a novel small molecule that destabilizes microtubules at high concentration and disrupts normal spindle formation at low concentration. A-432411 is an indolinone that is structurally different from other known synthetic microtubule inhibitors. This compound is efficacious against a variety of human cancer cell lines including drug-resistant HCT-15 that overexpresses Pgp170. Biochemical studies show that A-432411 competes with the colchicine-binding site on tubulin and inhibits microtubule polymerization. Fluorescence-activated cell sorting analysis indicates that A-432411 causes G(2)-M arrest and induces apoptosis. Cells treated with A-432411 have increased level of phospho-histone H3 at Ser(10) and decreased level of phospho-cdc2 at Tyr(15). Concurrently, securin and cyclin B1 expression levels remain the same, indicating the activation of the spindle checkpoint. Immunocytochemistry and fluorescence microscopy experiments reveal that. 1 mu mol/L A-432411 destabilizes microtubules in cells. At 0.1 mu mol/L, the compound disrupts normal spindle pole formation possibly through stabilization of microtubule dynamic. Both structural and cellular properties of A-432411 make it an attractive candidate for further development.
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