In vitro and In vivo Radiosensitization of Glioblastoma Cells by the Poly (ADP-Ribose) Polymerase Inhibitor E7016

Abstract

Purpose: Poly (ADP-ribose) polymerase (PARP) inhibitors are undergoing clinical evaluation for cancer therapy. Because PARP inhibition has been shown to enhance tumor cell sensitivity to radiation, we investigated the in vitro and in vivo effects of the novel PARP inhibitor E7016. Experimental Design:The effect of E7016 on the in vitro radiosensitivity of tumor cell lines was evaluated using clonogenic survival. DNA damage and repair were measured using gH2AX foci and neutral comet assay. Mitotic catastrophe was determined by immunostaining. Tumor growth delay was evaluated in mice for the effect of E7016 on in vivo (U251) tumor radiosensitivity. Results: Cell lines exposed to E7016 preirradiation yielded an increase in radiosensitivity with dose enhancement factors at a surviving fraction of 0.1 from 1.4 to 1.7. To assess DNA doublestrand breaks repair, gH2AX measured at 24 hours postirradiation had significantly more foci per cell in the E7016/irradiation group versus irradiation alone. Neutral comet assay further suggested unrepaired double-strand breaks with significantly greater DNA damage at 6 hours postirradiation in the combination group versus irradiation alone. Mitotic catastrophe staining revealed a significantly greater number of cells staining positive at 24 hours postirradiation in the combination group. In vivo, mice treated with E7016/irradiation/temozolomide had an additional growth delay of six days compared with the combination of temozolomide and irradiation. Conclusions: These results indicate that E7016 can enhance tumor cell radiosensitivity in vitro and in vivo through the inhibition of DNA repair. Moreover, enhanced growth delay with the addition of E7016 to temozolomide and radiotherapy in a glioma mouse model suggests a potential role for this drug in the treatment of glioblastoma multiforme.

TP53 induced glycolysis and apoptosis regulator (TIGAR) knockdown results in radiosensitization of glioma cells

“…One potential basis for radiosensitivity is through differences in ROS levels, which are involved in radiation-induced damage. A critical event in determining radiosensitivity is the repair of DNA double-strand breaks (DSB) [13]. Furthermore, several authors have described the importance of glycolytic metabolism and free radicals in chemo-and radiotherapies in glioma cells.…”

Selective radiosensitization of p53 mutant pancreatic cancer cells by combined inhibition of Chk1 and PARP1

“…PARP inhibitors have also been shown to sensitize to DNA damage in variety of cancer models, including those in which BRCA1 and BRCA2 are proficient. 18,19 Radiosensitization occurs p53 mutation would confer tumor cell selectivity for radiosensitization by Chk1 and PARP1 inhibition. To begin to test this hypothesis, we assessed radiosensitization in p53 mutant pancreatic cancers in response to the small molecule inhibitors of Chk1 and PARP1, AZD7762 and olaparib, respectively.…”

Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells

“…In vitro, inhibitors to PARP1 (often targeting both PARP1 and PARP2, and herein termed PARP inhibitors) radiosensitize cancer cells, including glioma cell lines, to drug and radiation treatment. [21][22][23][24][25][26][27] In vivo, PARP inhibitors enhance radiation therapy in syngeneic and xenograft models for colon, lung, head and neck, and cervical cancers. 21,[28][29][30][31][32] Olaparib (AZD2281), which targets PARP1 and PARP2, is currently in several phase I and phase II trials for solid tumors as a single agent or in combination with chemotherapy and/or radiotherapy.…”