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 1) 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 D54(p53wt) and U251(p53mut) glioblastoma cell lines. Analysis of cell growth and cell cycle kinetics showed a synergistic anti-proliferative effect of 10 nM TPT and 10 mu M NU1025 and a G(2)/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 D54(p53wt) 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 U251(p53mut) cells we found that NU1025 incremented the TPT-dependent apoptosis characterised by PARP-I 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. (c) 2006 Elsevier Ltd. All rights reserved.