Apoptotic cell death induction by F 11782 a novel dual catalytic inhibitor of topoisomerases I and II.
F 11782 (2",3"-bis-pentafluorophenoxyacetyl-4",6"ethylidene-beta-D-glucoside of 4'-phosphate-4'-dimethylepipodophyllotoxin-2N-methyl glucamine salt), is a novel dual catalytic inhibitor of topoisomerases I and II characterised by marked in vivo antitumour activity, which also proved cytotoxic and exhibited DNA damaging properties in vitro. Mechanisms associated with this cell killing by F 11782 have been examined in P388 leukaemia cells. Treatment with F 11782 resulted in a dose-dependent DNA fragmentation coupled with the characteristic morphological features of apoptosis. Apoptosis-inducing concentrations of F 11782 induced caspases-3/7 activation accompanied by proteolytic cleavage of poly(ADP-ribose)-polymerase, which could be inhibited by the caspase inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde. In addition, F 11782-induced apoptosis in P388 cells was associated with an increased expression of the pro-apototic Bax protein, without significant changes in the level of the anti-apoptotic Bcl-2 protein, and with modification at the mitochondrial membrane function. These results indicate that F 11782 leads to apoptosis through a caspase-3/7 dependent mechanism and suggest that the so-called "mitochondrial pathway" is implicated in F 11782-induced apoptosis in P388 cells.
Etiévant
Chantal
C
Division de Cancérologie Expérimentale I, Centre de Recherche Pierre Fabre, 17 Avenue Jean Moulin, F-81106 Castres Cedex 06, France. chantal.etievant@pierre-fabre.com
Kruczynski
Anna
A
Barret
Jean-Marc
JM
Perrin
Dominique
D
Hill
Bridget T
BT
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D020134:Catalytic Domain; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D007941:Leukemia P388 / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009281:Naphthalenes / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011714:Pyrans / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D009281:Naphthalenes; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011714:Pyrans; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D051028:bcl-2-Associated X Protein; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; C405744:tafluposide