DNA topoisomerase (topo) II inhibitors either stabilize DNA–topo II complexes by blocking DNA religation (e.g. etoposide) or block the enzyme's catalytic activity (e.g. dexrazoxane). The former class of drugs causes direct DNA 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 to the luciferase gene. Treatment of cells transfected with this construct revealed that complex-stabilizing (DNA-damaging) agents induce FasL expression, but the catalytic inhibitors do not, suggesting that the FasL pathway may not be involved in all cases of topoisomerase-mediated apoptosis. Some topo II inhibitors activate a pathway involving stress-activated protein kinases, 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 revealed that topo IIα interacts with the cell cycle regulatory protein, retinoblastoma protein (Rb). This interaction and the subcellular distribution of these proteins are altered by topo II inhibitory drugs and lead to apoptosis. In addition, agents that affect Rb, such as E1A and E2F1/DP-1, when transfected into cells, also alter topo IIα-Rb localization, activate jun kinase pathways and cause apoptosis. This paper discusses current studies that are designed to determine the contributions of these signalling events to the alterations in subcellular protein distribution and apoptosis. We suggest that protein-protein interactions are important for mediation of cytotoxic signalling by anticancer drugs.
Skip Nav Destination
Conference Article| November 01 2001
Cytotoxic signalling by inhibitors of DNA topoisomerase II
W. T. Beck ;
W. T. Beck 1
*Department of Molecular Genetics, The University of Illinois at Chicago, Chicago, IL, U.S.A.
†Department of Pharmaceutics and Pharmacodynamics, The University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612–7231, U.SA
1To whom correspondence should be addressed (e-mail firstname.lastname@example.org).
Search for other works by this author on:
Y.-Y. Mo ;
- Views Icon Views
- Share Icon Share
W. T. Beck, Y.-Y. Mo, U. G. Bhat; Cytotoxic signalling by inhibitors of DNA topoisomerase II. Biochem Soc Trans 1 November 2001; 29 (6): 702–703. doi: https://doi.org/10.1042/bst0290702
Download citation file:
Don't already have an account? Register
Get Access To This Article
Buy This Article