Antitumor agents. XXXV: Effects of brusatol, bruceoside A, and bruceantin on P-388 lymphocytic leukemia cell respiration.

Brusatol, a quassinoid with potent antineoplastic activity against P-388 lymphocytic leukemia cell proliferation, significantly inhibited P-388 cell hexokinase, phosphofructokinase, malic dehydrogenase, and succinic dehydrogenase. Mitochondrial oxidative phosphorylation, basal, and adenosine diphosphate-stimulated respiration, utilizing succinate and alpha-ketoglutarate as the substrate, was suppressed significantly by in vivo treatment with brusatol. However, brusatol treatment had no effect on liver oxidative phosphorylation. Brusatol greatly increased P-388 cyclic AMP levels but had no effect on liver cyclic nucleotides. Similar inhibitory effects on P-388 cell oxidative phosphorylation were found in vitro with brusatol, bruceoside A, and bruceantin. Brusatol had no effect on adenosine triphosphatase activity or on uncoupling of oxidative phosphorylation. Rather, brusatol appeared to increase the concentration of reduced mitochondrial electron-transport cofactors, thereby blocking aerobic respiration. A proposed mechanism of action is discussed.