Poly(ADPR)polymerase-1 signalling of the DNA damage induced by DNA topoisomerase I poison in D54p53wt and U251p53mut glioblastoma cell lines

Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to DNA topoisomerase I (TOPO I) inhibitor-mediated apoptosis.We investigated the effects of combined treatments with the DNA topoisomerase I inhibitor Topotecan and the poly(ADPR)polymerase-1 inhibitor NU1025 in D54p53wt and U251p53mut glioblastoma cell lines. Analysis of cell growth and cell cycle kinetics showed a synergistic anti-proliferative effect of 10 nM TPT and 10 μM NU1025 and a G2/M block of the cell cycle.We also evaluated, the influence of TPT+/−NU1025 treatment on PARP-1 and p53 activity. We got evidences of a TPT-dependent increase of PARP-1 auto-modification level in both the cells. Moreover, in the D54p53wt cells we found that in co-treatments NU1025 incremented the TPT-dependent stimulation of p53 transcriptional activity and increased the p21 nuclear amount. Conversely, in U251p53mut cells we found that NU1025 incremented the TPT-dependent apoptosis characterised by PARP-1 proteolysis.Our findings suggest that the modulation of PARP-1 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status.