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

Some members of a series of novel pyrrolo-1,5-benzoxazepines (PBOXs) potent ly induce apoptosis in a number of human cancerous cell lines including HL- 60 cells and the drug-resistant chronic myelogenous leukaemia cell line, K5 62. The apoptotic induction seems to be independent of the mitochondrial pe ripheral-type benzodiazepine receptor (PBR), which binds these PBOXs with h igh affinity, due to a lack of correlation between their affinities for the receptor and their apoptotic potencies and their high apoptotic activity i n PBR-deficient cells. PBOX-6, a potent member of the series, induces a tra nsient activation of c-jun N-terminal kinase (JNK) in a dose-dependent mann er, which correlates with induction of apoptosis. Expression of a cytoplasm ic inhibitor of the JNK signal transduction pathway, Jip-1, prevents JNK ac tivity 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-fluoromet hylketone (z-DEVD-fmk), blocks caspase-3-like protease activity in both cel l types but only prevents PBOX-6-induced apoptosis in HL-60 cells, suggesti ng that the requirement for caspase-3-like proteases in the apoptotic pathw ay, is dependent on the cell type.