Microtubule effects of welwistatin, a cyanobacterial indolinone that circumvents multiple drug resistance.
Welwitindolinones are a family of novel alkaloids recently isolated from the blue-green alga Hapalosiphon welwitschii. We demonstrate that incubation of SK-OV-3 human ovarian carcinoma cells and A-10 vascular smooth muscle cells with welwitindolinone C isothiocyanate, now termed welwistatin, results in dose-dependent inhibition of cell proliferation, which is correlated with increases in the percentage of cells in mitosis. Treatment of A-10 cells with welwistatin resulted in reversible depletion of cellular microtubules but did not affect microfilaments. Pretreatment of A-10 cells with paclitaxel prevented microtubule depolymerization in response to welwistatin. Welwistatin inhibited the polymerization of purified tubulin in vitro but did not alter the ability of tubulin to bind [3H]colchicine or to hydrolyze GTP. Also, welwistatin did not induce the formation of topoisomerase/DNA complexes. Results of the present study indicate that welwistatin is a new antimicrotubule compound that circumvents multiple drug resistance and so may be useful in the treatment of drug-resistant tumors.
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Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Smith
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D000470:Alkaloids / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000633:toxicity; D002166:Camptothecin / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003078:Colchicine / Q000378:metabolism; D000458:Cyanobacteria; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D018432:Drug Resistance, Multiple; D005047:Etoposide / Q000633:toxicity; D005260:Female; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D026121:Indole Alkaloids; D007700:Kinetics; D008870:Microtubules / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure; D010051:Ovarian Neoplasms; D014404:Tubulin / Q000378:metabolism
D000470:Alkaloids; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D026121:Indole Alkaloids; D014404:Tubulin; C092270:welwitindolinone C isothiocyanate; D005047:Etoposide; D020558:GTP Phosphohydrolases; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D003078:Colchicine; D002166:Camptothecin