INDUCTION OF APOPTOSIS BY CRYPTOPHYCIN-1, A NEW ANTIMICROTUBULE AGENT

The ability of cryptophycin I, a new potent cytotoxic antimicrotubule agent, to initiate apoptosis was studied. Treatment of cells with cryp tophycin I (50 pM) rapidly caused morphological changes consistent wit h the induction of apoptosis. DNA strand breakage and fragmentation of the DNA into oligonucleosome-sized fragments was observed, and this c oincided with the loss of cellular DNA. Activation of the cysteine pro tease CPP32 (caspase 3, YAMA, apopain), a member of the ICE/CED-3-like protease family of apoptosis effecters, was consistent with the execu tion of cell death by a coordinated sequence of events. Low concentrat ions of cryptophycin I caused mitotic arrest with the formation of abn ormal mitotic spindles without affecting interphase microtubule struct ures. Unlike other microtubule active agents, cryptophycin-induced mit otic arrest persisted for only a brief period before the onset of apop tosis. There was no evidence of release from G(2)/M cell cycle arrest. Our results show that low concentrations of cryptophycin I (50 pM) in itiated cell death consistent with apoptosis. These data suggest that the cytotoxic effects of cryptophycin I are due in part to its ability to initiate apoptosis rapidly. (C) 1997 Wiley-Liss, Inc.