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

M M Mc Gee, G Campiani, A Ramunno, C Fattorusso, V Nacci, M Lawler, D C Williams, D M Zisterer, Mark Lawler

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25 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)31-40
Number of pages10
JournalThe Journal of pharmacology and experimental therapeutics
Volume296
Issue number1
Publication statusPublished - Jan 2001

Keywords

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

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