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Caspase Inhibition in Camptothecin-treated U-937 Cells Is Coupled with a Shift from Apoptosis to Transient G₁ Arrest Followed by Necrotic Cell Death¹

Research Centre of the University of Montreal, Notre-Dame Hospital, Montreal Cancer Institute, Montreal, Quebec, H2L 4M1 Canada

Leukemia U-937 cells rapidly undergo characteristic morphological changes, caspase activation, and DNA fragmentation typical of apoptosis on treatment with the DNA topoisomerase I inhibitor camptothecin (CPT). In a previous report (Sané, A. T., and Bertrand, R., Cancer Res., 58: 3066–3072, 1998), we showed that, after CPT treatment, caspase inhibition by the tripeptide derivative benzyloxycarbonyl-Val-Ala-Asp(Ome)-fluoromethyl ketone (zVAD-fmk) blocked apoptosis and slowed passage of the cells through S-G₂ and caused a transient accumulation of these cells at the G₁ phase of the cell cycle. Accumulation of these cells at G₁ is not associated with major changes in expression level of cyclin-dependent kinase (cdk)2, cdk4, and cdk6; cyclin D1 and cyclin E; or p16, p21, p27, and p57 after CPT treatment. Furthermore, cdk2, cdk4, and cdk6 kinase activities remain unaffected after CPT treatment. These results indicate that the G₁ arrest of these cells does not correlate with a classical driven cell cycle checkpoint but with the known effect of CPT in mediating inhibition of DNA replication and RNA transcription after stabilization of topoisomerase I-linked DNA strand breaks. However, persistent caspase inhibition after CPT treatment also results in cells falling into necrosis after the transient G₁ arrest. These results indicate that the enforced inhibition of caspase activities does not confer a survival advantage upon CPT-treated cells but is coupled with a shift from apoptosis to transient G₁ arrest followed by massive necrosis.

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