Abstract
In a recent study, several new derivatives of antimycin A (AMA) were produced by means
of a novel transacylation reaction, and these were shown to mediate selective toxicity
toward cultured A549 human lung epithelial adenocarcinoma cells, as compared with
WI-38 normal human lung fibroblasts. The purpose of our study was to investigate whether
the analogues all expressed their cytotoxicity by the same mechanism. This was done
by studying the effects of the compounds in several types of cell lines. In comparison
with 2-O-methylantimycin, which acts at the locus of Bcl-2, none of the new derivatives exhibited
a difference in cytotoxicity toward cells expressing different levels of Bcl-2. In
cell lines that over- or underexpress estrogen or Her2 receptors, AMA analogue 2 exhibited Her2 receptor dependency at low concentration. Three compounds (1, 4, and 6) exhibited concentration-dependent increases in reactive oxygen species, with 6 being especially potent. Compounds 5 and 6 diminished mitochondrial membrane potential more potently than AMA, and 1 also displayed enhanced activity relative to 2–4. Interestingly, only 1 and AMA displayed strong inhibition of the respiratory chain, as measured by monitoring
NADH (reduced nicotinamide adenine dinucleotide) oxidase. Because four of the analogues
have positively charged substituents, two of these (4 and 6) were studied to see whether the observed effects were due to much higher level of
accumulation within the mitochondria. Their presence in the mitochondria was not dramatically
enhanced. Neither of the two presently characterized mechanisms of cell killing by
AMA can fully account for the observed results.
Key words
antimycin A - cytotoxicity - Bcl-2 expression - NADH oxidase inhibition - reactive
oxygen species - mitochondrial membrane potential
