Mode of action of the anticancer quassinoids--inhibition of the plasma membrane NADH oxidase.
A plasma membrane-associated NADH oxidase of transformed cells was shown to be inhibited by nanomolar and subnanomolar concentrations of the antitumor quassinoid, glaucarubolone. The inhibition was seen with plasma membrane vesicles of HeLa cells at two log orders less glaucarubolone than with plasma membrane vesicles of rat liver. Assignment of a drug-binding site to the external surface of the HeLa cell plasma membrane was supported by findings where full activity of the glaucarubolone in the inhibition of NADH oxidase activity of isolated plasma membrane vesicles and of growth of HeLa cells was given on a molar glaucarubolone basis by an impermeant conjugate of glaucarubolone in which the glaucarubolone moiety was linked via the C-15 hydroxyl to amino polyethyleneglycol (ave Mr 5,000). The activity of the conjugate, and to a lesser extent, of free glaucarubolone was modulated by the redox environment of the cells and of the plasma membrane vesicles. Activity, both in the inhibition of NADH oxidase activity and in the inhibition of growth, was enhanced by oxidizing conditions in the presence of oxidized glutathione compared to reducing conditions in the presence of reduced glutathione.
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, USA.
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Morré
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Grieco
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Morré
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002462:Cell Membrane / Q000201:enzymology; D005900:Glaucarubin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008970:Molecular Weight; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D051381:Rats; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D009097:Multienzyme Complexes; C024967:glaucarubolone; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D005900:Glaucarubin