Pyrrolo-1,5-benzoxazepines: a new class of apoptotic agents.
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.
Zisterer
D M
DM
Biochemistry Department, Trinity College Dublin, Dublin 2, Ireland. dzistrer@tcd.ie
McGee
M M
MM
Campiani
G
G
Ramunno
A
A
Fattorusso
C
C
Nacci
V
V
Lawler
M
M
Williams
D C
DC
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D010077:Oxazepines / Q000494:pharmacology*; D010766:Phosphorylation; D011758:Pyrroles / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001552:Benzazepines; D004791:Enzyme Inhibitors; D010077:Oxazepines; D011758:Pyrroles