L. Cartee et al., Chronic exposure to bryostatin-1 increases the radiosensitivity of U937 leukaemia cells ectopically expressing Bcl-2 through a non-apoptotic mechanism, INT J RAD B, 76(10), 2000, pp. 1323-1333
Purpose: Ionizing radiation (IR) produced a dose-dependent increase in apop
tosis in U937/pCEP4 cells which was attenuated by the stable over expressio
n of Bcl-2 (U937/Bcl-2). A dose of 2 Gy IR was selected for further analyse
s to determine if subsequent exposure to 10 nM bryostatin-1 would overcome
the resistance to IR-induced apoptosis conferred by Bcl-2 over expression.
Methods and results: Although bryostatin-l did not increase IR-induced apop
tosis in U937/pCEP4 or U937/Bcl-2 cells, it impaired mitochondrial function
and increased the antiproliferative effects of IR in both cell lines. The
effects were more pronounced in U937/Bcl-2 cells. Bryostatin-l also exerted
differential effects on cell-cycle distributions of U937 transfectant cell
s, producing a significant G(0)/G(1) arrest in U937/Bcl-2 cells, while decr
easing IR-induced G(2)/M arrest in U937/pCEP4 cells. Although Bcl-2 over ex
pression attenuated IR-induced apoptosis, clonogenic survival was similar i
n U937/pCEP4 and U937/Bcl-2 cells following 2 Gy IR treatment. Treatment wi
th 10 nM bryostatin-l after 2 Gy IR further reduced clonogenic survival in
both cell lines. Moreover, U937/Bcl-2 cells were more susceptible to the gr
owth-inhibitory effects of IR/bryostatin-1 than U937/pCEP4 cells.
Conclusions: Bryostalin-1 increased the radiosensitivity of U937 transfecta
nt cell lines without enhancing apoptosis; furthermore, U937/Bcl-2 cells we
re more susceptible to IR/bryostatin-1-mediated antiproliferative effects t
han their empty-vector counterparts.