Pyrrolo-1,5-benzoxazepines induce apoptosis in chronic myelogenous leukemia (CML) cells by bypassing the apoptotic suppressor bcr-abl.

Abstract

Expression of the transforming oncogene bcr-abl in chronic myelogenous leukemia (CML) cells is reported to confer resistance against apoptosis induced by many chemotherapeutic agents such as etoposide, ara-C, and staurosporine. In the present study some members of a series of novel pyrrolo-1,5-benzoxazepines potently induce apoptosis, as shown by cell shrinkage, chromatin condensation, DNA fragmentation, and poly(ADP-ribose) polymerase (PARP) cleavage, in three CML cell lines, K562, KYO.1, and LAMA 84. Induction of apoptosis by a representative member of this series, PBOX-6, was not accompanied by either the down-regulation of Bcr-Abl or by the attenuation of its protein tyrosine kinase activity up to 24 h after treatment, when approximately 50% of the cells had undergone apoptosis. These results suggest that down-regulation of Bcr-Abl is not part of the upstream apoptotic death program activated by PBOX-6. By characterizing the mechanism in which this novel agent executes apoptosis, this study has revealed that PBOX-6 caused activation of caspase 3-like proteases in only two of the three CML cell lines. In addition, inhibition of caspase 3-like protease activity using the inhibitor z-DEVD-fmk blocked caspase 3-like protease activity but did not prevent the induction of apoptosis, suggesting that caspase 3-like proteases are not essential in the mechanism by which PBOX-6 induces apoptosis in CML cells. In conclusion, this study demonstrates that PBOX-6 can bypass Bcr-Abl-mediated suppression of apoptosis, suggesting an important potential use of these compounds in the treatment of CML.

• Authors: M M Mc Gee, G Campiani, A Ramunno, C Fattorusso, V Nacci, M Lawler, D C Williams, D M Zisterer
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 296 Issue 1 Pg. 31-40 (Jan 2001) ISSN: 0022-3565 [Print] United States
• PMID: 11123359 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Oncogene Proteins, Fusion
• Oxazepines
• Pyrroles
• Reactive Oxygen Species
• abl-bcr fusion protein, human
• Poly(ADP-ribose) Polymerases
• Protein-Tyrosine Kinases
• Fusion Proteins, bcr-abl
• CASP3 protein, human
• Caspase 3
• Caspases
• PBOX-6

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis
• Blotting, Western
• Caspase 3
• Caspases (metabolism)
• Down-Regulation
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Fusion Proteins, bcr-abl
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (pathology)
• Oncogene Proteins, Fusion (genetics, physiology)
• Oxazepines (pharmacology)
• Phosphorylation
• Poly(ADP-ribose) Polymerases (metabolism)
• Protein-Tyrosine Kinases (metabolism)
• Pyrroles (pharmacology)
• Reactive Oxygen Species (metabolism)
• Tumor Cells, Cultured