Mechanism of action of iejimalide, a novel marine macrolide, in prostate and breast cancer cells

Abstract

Iejimalides are macrocyclic lactones (macrolides) composed of a 24‐member ring with two methoxy groups and an N‐formyl‐L‐serine side chain. We have tested iejimalide for biological activity in the NCI panel of 60 tumor cell lines and have established that the compound is active at low nanomolar concentrations. Using p53‐wild type or ‐null prostate tumor cell lines we have shown that iejimalide B induces apoptosis in LNCaP cells, which express wild type p53, and S‐phase arrest but not apoptosis in p53‐null PC‐3 cells. In p53‐wild type MCF‐7 breast cancer cells iejimalide B induces nuclear accumulation of p53, p21WAF1/CIP1, and AIF (apoptosis inducing factor). The signaling pathway responsible for the increase in nuclear p53 levels has not been fully elucidated; however, we have shown that iejimalide blocks the acidification of lysosomes, probably through the inhibition of the vacuolar H+‐ATPase (V‐ATPase) as early as 3 h after treatment. This precedes the depolarization of the mitochondrial membrane, cytochrome c release and DNA fragmentation, which occur after 24 h. Whether this delay is due to slow signaling from lysosomes to the nucleus and mitochondria or due to a second site of action of iejimalide, possibly through the inhibition of the mitochondrial F‐ATPase, remains to be determined. Nevertheless these data suggest that the macrolactone ring may be a useful pharmacophore for the development of new chemotherapeutic drugs for the treatment of some hormone dependent cancers. (Supported by the Walther Cancer Institute and the Coleman Foundation)