Mode of action of bullatacin, a potent antitumor acetogenin: inhibition of NADH oxidase activity of HeLa and HL-60, but not liver, plasma membranes.
Bullatacin, a potential antitumor substance isolated from plants of the Annonaceae, and analogs of bullatacin, known collectively as acetogenins, have been reported previously to show potent activity in the inhibition of growth of murine tumors and human tumor xenografts grown in athymic mice as well as an ability to inhibit mitochondrial electron transport. In this report, we show activity of bullatacin in inhibition of NADH oxidase activity of plasma membrane vesicles isolated from HeLa cells and HL-60 cells but not with plasma membrane vesicles isolated from rat livers which, unlike the inhibition of mitochondrial activity, correlated with the ability of the acetogenins to kill tumor cells. Additionally, bullatacin is active against HL-60 cells that are resistant to adriamycin which may suggest utility for bullatacin in management of drug-resistant cells and cell lines.
Morré
D J
DJ
Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907.
de Cabo
R
R
Farley
C
C
Oberlies
N H
NH
McLaughlin
J L
JL
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D005663:Furans / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000201:enzymology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D051379:Mice; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D005663:Furans; D009097:Multienzyme Complexes; C061022:bullatacin; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases