FR901228 causes mitotic arrest but does not alter microtubule polymerization

FR901228, a natural cyclic depsipeptide, shows high cytotoxicity against hu man cancer cell lines (low nM IC50 values). Cells exposed to FR901228 arres t with G(1) or G(2)/M DNA content; S phase is depleted. G(2)/M cells includ e cells arrested in mitosis. We wished to understand the mitotic arrest by this compound. Mitotic arrest is often due to interference with microtubule s and COMPARE testing in the NCI drug screen indicated a possible taxane-li ke mechanism, Testing of FR901228 for tubulin binding or alteration of in v itro MT assembly failed to reveal any effect. Likewise, examination of cell ular microtubules following exposure to FR901228 did not reveal any change, Similar G(2)/M accumulation was observed in MCF7, MCF10 and PC3 cells. Abo ut 50% of G(2)/M cells were mitotic and contained microtubule spindles. Mit otic cells peaked at about 14-16 h drug exposure and declined to near 0% by 24-30 h. The block was at prometaphase, with numerous chromosomes unattach ed to the spindle. We conclude that FR901228 induces formation of aberrant spindles probably by Interfering with chromosome attachment, causing mitoti c accumulation without affecting mitotic microtubules.