S. Harvey et al., Interactions between 2-fluoroadenine 9-beta-d-arabinofuranoside and the kinase inhibitor UCN-01 in human leukemia and lymphoma cells, CLIN CANC R, 7(2), 2001, pp. 320-330
Interactions between the purine analogue 2-fluoroadenine 9-beta -D-arabinof
uranoside (F-ara-A) and the kinase inhibitor UCN-01 have been examined in h
uman leukemia cells (U937 and HL-60) with respect to induction of mitochond
rial damage, caspase activation, apoptosis, and loss of clonogenic survival
, Simultaneous or subsequent exposure of F-ara-A-treated cells (2 muM) to U
CN-01 (100 nM) resulted in a marked potentiation of apoptosis, manifested b
y loss of mitochondrial membrane potential (Delta psi (m)), cleavage/activa
tion of procaspase-9 and procaspase-3, DNA fragmentation, and degradation o
f poly-ADP(ribosyl) polymerase, Coadministration of UCN-01 with F-ara-PL wa
s also associated with diminished phosphorylation of the cdc25 phosphatase.
In contrast, exposure of cells to the sequence UCN-01, followed by F-ara-A
, resulted in only a modest increase in apoptotic cells, The ability of UCN
-01 to potentiate F-ara-A-mediated lethality was not mimicked by the select
ive PKC inhibitor bisindolylmaleimide nor did treatment of cells with UCN-0
1 enhance formation of F-ara-ATP or increase incorporation of [H-3]F-ara-A
into DNA. Enhanced apoptosis in cells exposed sequentially or simultaneousl
y to F-ara-A and UCN-01 was accompanied by a substantial reduction in colon
y formation (e.g., to 0.01% of control values). Cotreatment with UCN-01 als
o increased F-ara-A-mediated apoptosis and loss of Delta psi (m) in U937 ce
lls ectopically expressing Bcl-2, although not to the same extent as that o
bserved in empty-vector controls, Finally, simultaneous exposure (24 h) of
malignant B lymphocytes from the pleural effusion of a patient with indolen
t non-Hodgkin's lymphoma to F-ara-A and UCN-01 ex vivo resulted in a striki
ng increase in apoptosis, as determined by terminal deoxynucleotidyltrans-f
erase-mediated nick end labeling assay. These findings indicate that UCN-01
increases F-ara-A-induced mitochondrial damage and apoptosis in human leuk
emia cells in a sequence-dependent manner, and that these events occur in a
t least some primary human lymphoma cells.