DNA topoisomerase (topo) II inhibitors either stabilize DNA-topo II complex
es by blocking DNA religation (e.g. etoposide) or block the enzyme's cataly
tic activity (e.g. dexrazoxane). The former class of drugs causes direct DN
A damage through topo II, while the latter class does not, but both classes
cause apoptosis. We cloned the Fas ligand (FasL) promoter and coupled it t
o the luciferase gene. Treatment of cells transfected with this construct r
evealed that complex-stabilizing (DNA-damaging) agents induce FasL expressi
on, but the catalytic inhibitors do not, suggesting that the FasL pathway m
ay not be involved in all cases of topoisomerase-mediated apoptosis. Some t
opo II inhibitors activate a pathway involving stress-activated protein kin
ases, which include c-Jun N-terminal kinase-1 (JNK-1). We will discuss the
effects of these agents on components of this pathway. Our earlier work rev
ealed that topo II alpha interacts with the cell cycle regulatory protein,
retinoblastoma protein (Rb). This interaction and the subcellular distribut
ion of these proteins are altered by topo II inhibitory drugs and lead to a
poptosis. In addition, agents that affect Rb, such as E1A and E2F1/DP-1, wh
en transfected into cells, also alter topo II alpha -Rb localization, activ
ate jun kinase pathways and cause apoptosis. This paper discusses current s
tudies that are designed to determine the contributions of these signalling
events to the alterations in subcellular protein distribution and apoptosi
s. We suggest that protein-protein interactions are important for mediation
of cytotoxic signalling by anticancer drugs.