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Increased Susceptibility of Poly(ADP-Ribose) Polymerase-1 Knockout Cells to Antitumor Triazoloacridone C-1305 Is Associated with Permanent G₂ Cell Cycle Arrest

Józefa Wsierska-Gdek¹, Daniela Schloffer¹, Marieta Gueorguieva¹, Maria Uhl² and Andrzej Skladanowski³

¹ Cell Cycle Regulation Group, Institute of Cancer Research and ² Environmental Toxicology Group, Institute of Cancer Research, Medical University of Vienna, Vienna, Austria, and ³ Laboratory of Molecular and Cellular Pharmacology, Department of Pharmaceutical Technology and Biochemistry; Gdask University of Technology, Gdask, Poland

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 IC₅₀ concentration of C-1305 determined for PARP-1 knockout cells was 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 G₂-M phase. However, the G₂-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 G₂ arrest induced by C-1305.

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