Cruentaren A, a highly cytotoxic benzolactone from Myxobacteria is a novel selective inhibitor of mitochondrial F1-ATPases.
Cruentaren A, a new antifungal benzolactone produced by the myxobacterium Byssovorax cruenta, proved to be highly cytotoxic against various human cell lines. It inhibited the proliferation of different cancer cell lines including a multidrug-resistant KB line at low nanomolar levels. It arrested human histocytic lymphoma cells (U-937) in G(0/1) phase, but did not trigger an apoptotic process. Studies to uncover the molecular target of cruentaren A showed that the novel compound, despite its structural similarity to the benzolactone enamides apicularen and salicylihalamide, was no V-ATPase inhibitor. In contrast, cruentaren specifically inhibited mitochondrial F(O)F(1)-ATPases with IC50 values of 15-30 nM. Although the exact binding site of cruentaren remains undefined, inhibition was shown to occur by interaction with the catalytic F(1) domain. Since mitochondrial ATPases play a crucial role in the pathophysiology of several human disorders including cancer, cruentaren or synthetic derivatives thereof could form the basis of future therapeutic strategies.
Kunze
Brigitte
B
Arbeitsgruppe Mikrobielle Kommunikation, Helmholtz Zentrum für Infektionsforschung, 38124 Braunschweig, Germany. brigitte.kunze@helmholtz-hzi.de
Sasse
Florenz
F
Wieczorek
Helmut
H
Huss
Markus
M
D000818:Animals; D001554:Benzene / Q000737:chemistry*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000633:toxicity; D002417:Cattle; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000633:toxicity*; D006321:Heart / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D018942:Macrolides / Q000737:chemistry* / Q000145:classification / Q000633:toxicity*; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015394:Molecular Structure; D009206:Myocardium / Q000201:enzymology; D009231:Myxococcales / Q000737:chemistry*; D012995:Solubility
D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D018942:Macrolides; C117813:apicularen A; C516694:cruentaren A; D025261:Mitochondrial Proton-Translocating ATPases; D001554:Benzene