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 oligon...

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Bibliographic Details
Published in:International journal of cancer 1997-11, Vol.73 (3), p.440-448
Main Authors: Mooberry, Susan L., Busquets, Lizette, Tien, Georgia
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - pharmacology
Apoptosis - genetics
Biological and medical sciences
Caspase 3
Caspases
Cysteine Endopeptidases - metabolism
Depsipeptides
DNA Fragmentation
DNA, Neoplasm - drug effects
Enzyme Activation - drug effects
General aspects
Humans
Medical sciences
Microtubules - drug effects
Mitosis - drug effects
Peptides, Cyclic - pharmacology
Pharmacology. Drug treatments
Poly(ADP-ribose) Polymerases - metabolism
Tumor Cells, Cultured - drug effects
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Summary: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. Int. J. Cancer 73:440–448, 1997. © 1997 Wiley‐Liss, Inc.
ISSN:0020-7136
1097-0215
DOI:10.1002/(SICI)1097-0215(19971104)73:3<440::AID-IJC20>3.0.CO;2-F