MODE OF ACTION OF THE ANTICANCER QUASSINOIDS - INHIBITION OF THE PLASMA-MEMBRANE NADH OXIDASE

A plasma membrane-associated NADH oxidase of transformed cells was sho wn to be inhibited by nanomolar and subnanomolar concentrations of the antitumor quassinoid, glaucarubolone. The inhibition was seen with pl asma membrane vesicles of HeLa cells at two log orders less glaucarubo lone than with plasma membrane vesicles of rat liver. Assignment of a drug-binding site to the external surface of the HeLa cell plasma memb rane was supported by findings where full activity of the glaucarubolo ne in the inhibition of NADH oxidase activity of isolated plasma membr ane vesicles and of growth of HeLa cells was given on a molar glaucaru bolone basis by an impermeant conjugate of glaucarubolone in which the glaucarubolone moiety was linked via the C-15 hydroxyl to amino polye thyleneglycol (ave Mr 5,000). The activity of the conjugate, and to a lesser extent, of free glaucarubolone was modulated by the redox envir onment of the cells and of the plasma membrane vesicles. Activity, bot h in the inhibition of NADH oxidase activity and in the inhibition of growth, was enhanced by oxidizing conditions in the presence of oxidiz ed glutathione compared to reducing conditions in the presence of redu ced glutathione.