Poly (ADP-Ribose) polymerase-1 (PARP-1) inhibition increases the citotoxicity of DNA-damaging agents and ionizing radiation (IR) in several tumor models. We investigated the effects of combined treatment with the DNA-topoisomerase-1-inhibitor, topotecan (TPT), the PARP-1 inhibitor NU1025 and IR in both D54 p53wt and U251p53mut human glioblastoma cell lines. Cell growth studies showed that non-cytotoxic doses of NU 1025 (10μM) synergize with IR and TPT in both U251p53mut and D54 p53wt cells. In U251 p53mut cells, 10 nM of TPT induced 40% of cell growth inhibition after 96 hrs of treatment, than 2 Gy of IR about 20% only. The addiction of NU1025 synergize with both TPT (90% cell growth inhibition) and IR (45% of growth inhibition). The radiosensitive D54 p53wt cell line was strongly inhibited by 2Gy of IR (50% of growth inhibition) and about 30% by 10 nM of TPT. Even in this case, the addiction of NU1025 synergize with both IR (73% of growth inhibition) and TPT (62% of growth inhibition). DNA-flow cytometry did not show any specific perturbation of D54 p53wt cell cycle, than a G2/M block and apoptosis were evident in U251 p53mut cells. Our findings suggest that the inhibition of PARP-1 activity could be considered a strategy to increase the specific effects of TOPO-1 poisons and RT in human glioblastoma cells a part from the p53 status.

Inhibition of poly(ADP-Ribose)plymerase synergizes with the DNA-topoisomerase-1-inhibitor, topoteca, and radiation in human glioblastoma cell lines.

2008-01-01

Abstract

Poly (ADP-Ribose) polymerase-1 (PARP-1) inhibition increases the citotoxicity of DNA-damaging agents and ionizing radiation (IR) in several tumor models. We investigated the effects of combined treatment with the DNA-topoisomerase-1-inhibitor, topotecan (TPT), the PARP-1 inhibitor NU1025 and IR in both D54 p53wt and U251p53mut human glioblastoma cell lines. Cell growth studies showed that non-cytotoxic doses of NU 1025 (10μM) synergize with IR and TPT in both U251p53mut and D54 p53wt cells. In U251 p53mut cells, 10 nM of TPT induced 40% of cell growth inhibition after 96 hrs of treatment, than 2 Gy of IR about 20% only. The addiction of NU1025 synergize with both TPT (90% cell growth inhibition) and IR (45% of growth inhibition). The radiosensitive D54 p53wt cell line was strongly inhibited by 2Gy of IR (50% of growth inhibition) and about 30% by 10 nM of TPT. Even in this case, the addiction of NU1025 synergize with both IR (73% of growth inhibition) and TPT (62% of growth inhibition). DNA-flow cytometry did not show any specific perturbation of D54 p53wt cell cycle, than a G2/M block and apoptosis were evident in U251 p53mut cells. Our findings suggest that the inhibition of PARP-1 activity could be considered a strategy to increase the specific effects of TOPO-1 poisons and RT in human glioblastoma cells a part from the p53 status.
2008
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11386/3881464
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