BCL-2 PROTEIN INHIBITS ETOPOSIDE-INDUCED APOPTOSIS THROUGH ITS EFFECTS ON EVENTS SUBSEQUENT TO TOPOISOMERASE II-INDUCED DNA STRAND BREAKS AND THEIR REPAIR
S. Kamesaki et al., BCL-2 PROTEIN INHIBITS ETOPOSIDE-INDUCED APOPTOSIS THROUGH ITS EFFECTS ON EVENTS SUBSEQUENT TO TOPOISOMERASE II-INDUCED DNA STRAND BREAKS AND THEIR REPAIR, Cancer research, 53(18), 1993, pp. 4251-4256
Previous studies have shown that bcl-2 overexpression can inhibit apop
tosis induced by DNA-damaging agents widely used in cancer chemotherap
y, including X-irradiation, alkylating agents (hydroperoxycyclophospha
mide, etc.), and topoisomerase II inhibitors (etoposide, etc.). Howeve
r, little is known about the mechanism by which bcl-2 overexpression i
nhibits apoptosis triggered by these agents. In this study, we examine
d whether bcl-2 overexpression could have effects on etoposide-induced
DNA damage and its repair. For these experiments, we developed CH31 c
lones (mouse B-cells) stably transfected with human bcl-2 sense plasmi
ds and compared these clones with a parental CH31 clone or CH31 clones
with antisense plasmids. Overexpression of bcl-2 protein inhibited et
oposide-induced apoptosis and cytotoxicity. However, there was no or l
ittle difference in the production and repair of DNA-protein cross-lin
ks, DNA single-strand breaks, and double-strand breaks among a parenta
l CH31 clone and CH31 clones with human bcl-2 sense or antisense plasm
ids. These findings indicate that (a) apoptosis or cytotoxicity induce
d by etoposide can be separated into early events (formation of double
-strand breaks, DNA single-strand breaks, and double-strand breaks) an
d later events (secondary DNA fragmentation or cell death) and (b) bcl
-2 inhibits apoptosis and cytotoxicity induced by etoposide at some st
eps between these events.