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Cruentaren A, a highly cytotoxic benzolactone from Myxobacteria is a novel selective inhibitor of mitochondrial F 1 ‐ATPases
Author(s) -
Kunze Brigitte,
Sasse Florenz,
Wieczorek Helmut,
Huss Markus
Publication year - 2007
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2007.06.069
Subject(s) - cytotoxic t cell , myxobacteria , cell culture , mitochondrion , atpase , biology , apoptosis , cancer cell , biochemistry , microbiology and biotechnology , chemistry , in vitro , cancer , enzyme , genetics , bacteria
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.