| Pyrrolo-1,5-benzoxazepines induce apoptosis in chronic myelogenous leukemia (CML) cells by bypassing the apoptotic suppressor bcr-abl. | |
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MedLine Citation:
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PMID: 11123359 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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M M Mc Gee; G Campiani; A Ramunno; C Fattorusso; V Nacci; M Lawler; D C Williams; D M Zisterer |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 296 ISSN: 0022-3565 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2001 Jan |
Date Detail:
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Created Date: 2001-02-02 Completed Date: 2001-02-02 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 31-40 Citation Subset: IM |
Affiliation:
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Department of Biochemistry, Trinity College, Dublin, Ireland. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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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 |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Fusion Proteins, bcr-abl; 0/Oncogene Proteins, Fusion; 0/Oxazepines; 0/PBOX-6; 0/Pyrroles; 0/Reactive Oxygen Species; 0/abl-bcr fusion protein, human; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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