Our previous studies have shown that murine fibroblast cells, in which PARP-1 gene was inactivated by gene disruption, are extremely sensitive to triazoloacridone compound
C-1305, an inhibitor of
DNA topoisomerase II with unusual properties. Here, we show that pharmacological inhibition of PARP-1 activity by its inhibitor compound
NU1025, sensitizes human cervical
carcinoma HeLa cells to compound
C-1305 compared to treatment with
drug alone. Cytotoxic effect of
drug/
NU1025 of other
topoisomerase II inhibitors varied depending on the dose of PARP-1 inhibitor. Increased cytotoxicity of
topoisomerase II inhibitor/
NU1025 combinations was attributable to the re-activation of the p53 pathway in
drug-treated HeLa cells. This lead to a more stringent cell cycle checkpoint control during G2 and M and enhanced cell death by mitotic catastrophe induced by
drug/
NU1025 combinations. Interestingly, treatment of HeLa cells with
NU1025 alone also increased p53 expression. This effect is, at least in part, related to the inhibition of
proteasome activity by
drug treatments. Together, our results show that concomitant inhibition of
topoisomerase II and PARP-1 leads to the synergistic cytotoxic effect toward
tumor cells that may be important for combination
therapies with
NU1025 and
topoisomerase II inhibitors. We also confirmed our earlier work and show the important role of PARP-1 activity in the maintenance of the G2 arrest induced by
DNA damaging drugs. Finally, based on our studies we propose that
NU1025 and possibly other inhibitors of PARP-1 may be used as non-genotoxic agents to activate p53 in
tumor cells with non-functional p53 pathways.