Poly(ADP-ribose) polymerase-1 (PARP-1) is a sensitive sensor of DNA damage. This enzyme, which is strongly activated by DNA strand breaks, has important functions in DNA repair as well as in the maintenance of genome stability. PARP-1 also plays a key role in the initiation of cell death induced by different stimuli. The important role of PARP-1 in base excision repair and cell death led to the development of new highly specific strategies to inactivate PARP-1, which made it possible to test the effect of PARP-1 inhibition on the therapeutic effects of anticancer drugs. Recently, inhibition of PARP-1 activity by specific chemical inhibitors has been shown to potentiate the cytoxic effect of ionizing radiation, DNA methylating agents, oxidative damage, and topoisomerase I inhibitors. In line with that, several different PARP-1 inhibitors are being tested in clinical trials in combination with DNA damaging agents as a new strategy to sensitize tumor cells to conventional anitumor drugs.

Triazoloacridone C-1305 is a novel inhibitor of DNA topoisomerase II with unusual properties, which exhibits potent antitumor activity toward solid tumors. In our earlier studies, antiproliferative action of C-1305 was investigated in nontransformed mouse fibroblasts and two mutant cell lines in which the PARP-1 gene was specifically disrupted by homologous recombination in exon 2. Unexpectedly, C-1305 very strongly affected proliferation of cells lacking poly(ADPribose) polymerase-1 (PARP-1), whereas the action of another topoisomerase II inhibitor acridine m-AMSA as well as less biologically active triazoloacridone compound C-1533 toward normal and PARP-1-negative cells were comparable. The IC₅₀ concentration of C-1305 determined for PARP-1 knockout cells was about 150-fold lower than that determined for cells with functional PARP-1. Our data also suggested that the PARP-1 status might be essential for the maintenance of the G2 arrest induced by C-1305. In this study we determined the cytotoxic effect of compound C-1305 and m-AMSA to other mouse fibroblast cell line with inactivated PARP1 in exon 4. Interestingly, these cells were about 2-fold more sensitive to both drugs compared to cells with functional PARP1 gene.

We were also interested in clarifying whether we could reproduce the results obtained for compound C-1305 and cells with genetically inactivated PARP-1 with the effect of triazoloacridone toward tumor cells with functional PARP-1, in which this enzyme was inactivated by small-molecular weight inhibitors. We show here that human ovarian carcinoma HeLa S3 cells preincubated with specific inhibitor of PARP, compound NU1025, and treated with C-1305 were about 2-fold more sensitive to the drug than HeLa cells treated with C-1305 alone. We are currently elucidating the molecular mechanism responsible for this enhanced cytotoxic activity of C-1305 and m-AMSA toward tumor cells in which PARP-1 was inhibited by NU1025.

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