Induction of apoptosis by cryptophycin 1, a new antimicrotubule agent.
The ability of cryptophycin 1, a new potent cytotoxic antimicrotubule agent, to initiate apoptosis was studied. Treatment of cells with cryptophycin 1 (50 pM) rapidly caused morphological changes consistent with the induction of apoptosis. DNA strand breakage and fragmentation of the DNA into oligonucleosome-sized fragments was observed, and this coincided with the loss of cellular DNA. Activation of the cysteine protease CPP32 (caspase 3, YAMA, apopain), a member of the ICE/CED-3-like protease family of apoptosis effectors, was consistent with the execution of cell death by a coordinated sequence of events. Low concentrations of cryptophycin 1 caused mitotic arrest with the formation of abnormal mitotic spindles without affecting interphase microtubule structures. Unlike other microtubule active agents, cryptophycin-induced mitotic arrest persisted for only a brief period before the onset of apoptosis. There was no evidence of release from G2/M cell cycle arrest. Our results show that low concentrations of cryptophycin 1 (50 pM) initiated cell death consistent with apoptosis. These data suggest that the cytotoxic effects of cryptophycin 1 are due in part to its ability to initiate apoptosis rapidly.
Mooberry
S L
SL
Natural Products Program, Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu 96813, USA. sue@crch.hawaii.edu
Busquets
L
L
Tien
G
G
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D053938:DNA Fragmentation; D004273:DNA, Neoplasm / Q000187:drug effects*; D047630:Depsipeptides; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D047630:Depsipeptides; D010456:Peptides, Cyclic; C088419:cryptophycin; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases