Relationships between DNA strand breakage and apoptotic progression upon treatment of HL-60 leukemia cells with tafluposide or etoposide.
Tafluposide (F11782), an epipodophyllotoxin derivative currently undergoing phase I clinical trials, is structurally close to the established anti-cancer drug etoposide, but mechanistically distinct. It is a dual inhibitor of topoisomerases I and II which impairs the binding of the enzyme to DNA, but does not stabilize the cleavage complex. Nevertheless, both etoposide and tafluposide induce DNA strand breaks and are potent pro-apoptotic agents. In this study, we have compared the cellular response of HL-60 human promyelocytic leukemia cells treated with etoposide and tafluposide. We show that tafluposide induces delayed, but extensive, DNA strand breaks, whereas etoposide provokes rapid and massive DNA damage. The two drugs trigger similar types of alterations at the mitochondrial and cell cycle levels, and lead to the generation of comparable levels of reactive oxygen species, but with different kinetics. Our data suggest that modification of the mitochondrial mass plays an important role in apoptosis induced by DNA-damaging anti-cancer agents, at least in the epipodophyllotoxin series. We suggest that drug-induced mitochondrial alterations can be divided into three successive steps: (i) hyperpolarization, (ii) depolarization and (iii) increase of the mitochondrial mass.
Kluza
Jérôme
J
INSERM U524, Institut de Recherche sur le Cancer de Lille, Lille, France.
Mazinghien
Romain
R
Irwin
Helen
H
Hartley
John A
JA
Bailly
Christian
C
D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects*; D005047:Etoposide / Q000627:therapeutic use*; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D009281:Naphthalenes / Q000627:therapeutic use*; D011714:Pyrans / Q000627:therapeutic use*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D009281:Naphthalenes; D011714:Pyrans; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; C405744:tafluposide