Cruentaren A, a highly cytotoxic benzolactone from Myxobacteria is a novel selective inhibitor of mitochondrial F1-ATPases

Abstract

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 G0/1 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 FOF1-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 F1 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.