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Vol. 293, Issue 1, 48-59, April 2000
Department of Biochemistry, Trinity College, Ireland (D.M.Z.,
D.C.W.); and Dipartimento Farmaco Chimico Tecnologico, Universita'
Degli Studi di Siena, Siena, Italy (G.C., V.N.)
Some, but not all, of a series of novel pyrrolo-1,5-benzoxazepines
(PBOXs) induce apoptosis as shown by cell shrinkage, chromatin condensation, and DNA fragmentation in three human cell lines, HL-60
promyelocytic, Jurkat T lymphoma, and Hut-78 s.c. lymphoma cells. This
chemical selectivity, together with the lack of apoptotic activity
against rat Leydig cells, argues against a general cell poisoning
effect. PBOX-6, a potent member of the series, caused activation of a
member of the caspase-3 family of proteases. In addition, the
caspase-3-like inhibitor z-DEVD-fmk, but not the caspase-1-like
inhibitor z-YVAD-fmk prevented PBOX-6-induced apoptosis, suggesting
that caspase 3-like proteases are involved in the mechanism by which
PBOX compounds induce apoptosis. The release of cytochrome c into the cytosol in HL-60 cells in response to PBOX-6
suggests that this cellular response may be important in the mechanism by which PBOX-6 induces apoptosis. However, reactive oxygen
intermediates do not play a key role in PBOX-6-induced apoptosis
because neither the free radical scavenger TEMPO nor the antioxidant
N-acetylcysteine had any effect on PBOX-6-induced
apoptosis. The apoptotic induction seems independent of the
mitochondrial peripheral-type benzodiazepine receptor (PBR) that binds
these pyrrolobenzoxazepines with high affinity, due to the lack of
correlation between their affinities for the receptor and their
apoptotic potencies, their high apoptotic activity in PBR-deficient
cells such as Jurkats, and their lack of apoptotic induction in
PBR-rich rat Leydig cells. These PBOXs also can overcome nuclear
factor-
B-mediated resistance to apoptosis. This suggests an
important potential use of these compounds in drug-resistant cancers.
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