Increased susceptibility of poly(ADP-ribose) polymerase-1 knockout cells to antitumor triazoloacridone C-1305 is associated with permanent G2 cell cycle arrest.
Triazoloacridone C-1305 is a novel inhibitor of DNA topoisomerase II, which exhibits potent antitumor activity toward solid tumors. In this study, antiproliferative action of C-1305 and its close analog C-1533 was investigated in nontransformed mouse fibroblasts and two mutant cell lines in which the PARP-1 gene was specifically disrupted. Unexpectedly, C-1305 very strongly affected proliferation of cells lacking poly(ADP-ribose) polymerase-1 (PARP-1), whereas the action of less active compound C-1533 toward normal and PARP-1-negative cells was comparable. The IC(50) concentration of C-1305 determined for PARP-1 knockout cells was approximately 150-fold lower than that determined for cells with functional PARP-1. Both studied triazoloacridones exhibited very low direct cytotoxicity as evidenced by accumulation of 7-amino-actinomycin D, and only low levels of apoptosis were observed after a 24-h exposure to studied drugs. Analysis of DNA damage induced by C-1305 by the Comet assay showed that this drug induced very low levels of DNA strand breaks. C-1305 strongly affected cell cycle progression in normal and PARP-1 mutant cells and arrested both cell types in G(2)-M phase. However, the G(2)-M arrest induced by C-1305 was greatly prolonged in PARP-1-deficient cells as compared with normal fibroblasts. Together, these results show that mouse cells lacking PARP-1 are extremely sensitive to C-1305, a new topoisomerase II inhibitor. This is in striking contrast with previous reports in which PARP-1-deficient cells were shown to be resistant to classical topoisomerase II inhibitors. Our data also suggest that the PARP-1 status might be essential for the maintenance of the G(2) arrest induced by C-1305.
Wesierska-Gadek
Józefa
J
Cell Cycle Regulation Group, Institute of Cancer Research, Medical University of Vienna, Vienna, Austria. Jozefa.Gadek-Wesierski@meduniwien.ac.at
Schloffer
Daniela
D
Gueorguieva
Marieta
M
Uhl
Maria
M
Skladanowski
Andrzej
A
D000166:Acridines / Q000494:pharmacology*; D000677:Amsacrine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects; D019926:Cyclin B / Q000037:antagonists & inhibitors; D004249:DNA Damage; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D016195:G2 Phase / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency* / Q000235:genetics; D059005:Topoisomerase II Inhibitors; D014230:Triazoles / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D000166:Acridines; C488734:C 1305; D019926:Cyclin B; D059005:Topoisomerase II Inhibitors; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D000677:Amsacrine; D011065:Poly(ADP-ribose) Polymerases; D016203:CDC2 Protein Kinase