Apoptosis Induced by Topoisomerase Inhibitors
Curr Med Chem Anti-Canc Agents. 2003 Jul;3(4):271-90
Topoisomerase inhibitors are among the most efficient inducers of apoptosis. The
main pathways leading from topoisomerase-mediated DNA damage to cell death involve activation
of caspases in the cytoplasm by proapoptotic molecules released from mitochondria. In some
cells, apoptotic response also involves the death receptor Fas (APO-1/CD95). The engagement
of these apoptotic effector pathways is tightly controlled by upstream regulatory pathways
that respond to DNA lesions-induced by topoisomerase inhibitors in cells undergoing apoptosis.
These include the proapoptotic Chk2, c-Abl and SAPK/JNK pathways, the survival
PI(3)kinase-Akt-dependent pathway and the transcription factors p53 and NF-kappaB.
Initiation of cellular responses to DNA lesions-induced by topoisomerase inhibitors is
ensured by the protein kinases DNA-PK, ATM and ATR, which bind to DNA breaks. These kinases
commonly called "DNA sensors" mediate their effects (DNA repair, cell cycle arrest and/or
apoptosis) by phosphorylating a large number of substrates, including several downstream
kinases such as c-Abl and the checkpoint protein Chk2. c-Abl induces apoptosis by activating
cell death pathways (e.g., SAPK, p53 and p73) and inhibiting cell survival pathways [e.g.,
PI(3)kinase]. The DNA-damage regulating kinase Chk2, in addition to its role in cell cycle
arrest and/or DNA repair, can induce apoptosis by phosphorylation/activation of the promyelocytic
leukemia (PML) protein and p53. Finally, we will review the recent observations that support
a role for topoisomerases in chromatin fragmentation during the execution phase of apoptosis.