Iejimalide A and iejimalide B induce S‐phase arrest or apoptosis through a potentially p53‐independent pathway

Macrolide compounds have long been used as antibiotics, but recently some macrolides have been proposed as cancer chemotherapeutics. Initial results from the NCI cancer cell screen suggested that two similar forms of a novel macrolide, iejimalide (Iej), had different effects on cells. Our objective was to elucidate and compare the mechanisms of action of IejA and IejB in tumor cells. Flow cytometry was used to determine the effects of Iejs on apoptosis and cell cycle dynamics. Western and real‐time PCR analyses were used to test protein and mRNA levels of potential targets of Iejs. Iejs induced apoptosis in MCF‐7 (p53 +/+ ) breast cancer cells and CHO‐A8 (p53‐mutated) cells, while they arrested PC‐3 (p53 null) prostate cancer cells in S‐phase. In our investigations, no qualitative difference between the two chemical forms was observed. Taken together, our results suggest that IejA and IejB may differ in potency but probably not in mode of action and that Iejs may act through a p53‐independent pathway to induce apoptosis and cell cycle arrest. (Supported by the Coleman Foundation and the Walther Cancer Institute)