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Kunze, B; Sasse, F; Wieczorek, H; Huss, M
FEBS letters, 07/2007, Letnik: 581, Številka: 18Journal Article
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 sub(0) sub(/) sub(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 sub(O)F sub(1)-ATPases with IC50 values of 15-30nM. Although the exact binding site of cruentaren remains undefined, inhibition was shown to occur by interaction with the catalytic F sub(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.
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