Pyrrolo-1,5-benzoxazepines: a new class of apoptotic agents

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

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Some members of a series of novel pyrrolo-1,5-benzoxazepines (PBOXs) potently induce apoptosis in a number of human cancerous cell lines including HL-60 cells and the drug-resistant chronic myelogenous leukaemia cell line, K562. The apoptotic induction seems to be independent of the mitochondrial peripheral-type benzodiazepine receptor (PBR), which binds these PBOXs with high affinity, due to a lack of correlation between their affinities for the receptor and their apoptotic potencies and their high apoptotic activity in PBR-deficient cells. PBOX-6, a potent member of the series, induces a transient activation of c-Jun N-terminal kinase (JNK) in a dose-dependent manner, which correlates with induction of apoptosis. Expression of a cytoplasmic inhibitor of the JNK signal transduction pathway, Jip-1, prevents JNK activity and significantly reduces the extent of apoptosis induced by PBOX-6. This demonstrates the requirement for JNK in the cellular response to this apoptotic agent. In addition, PBOX-6 activates caspase-3-like proteases in K562 and HL-60 cells. The caspase-3 inhibitor, Z-Asp-Glu-Val-Asp-fluoromethylketone (z-DEVD-fmk), blocks caspase-3-like protease activity in both cell types but only prevents PBOX-6-induced apoptosis in HL-60 cells, suggesting that the requirement for caspase-3-like proteases in the apoptotic pathway is dependent on the cell type.

Original languageEnglish
Pages (from-to)704-6
Number of pages3
JournalBiochemical society transactions
Volume29
Issue numberPt 6
Publication statusPublished - Nov 2001

Keywords

  • Antineoplastic Agents
  • Apoptosis
  • Benzazepines
  • Enzyme Inhibitors
  • HL-60 Cells
  • Humans
  • K562 Cells
  • Oxazepines
  • Phosphorylation
  • Pyrroles

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