The effect of iodine-131 beta-particles in combination with A-966492 and Topotecan on radio-sensitization of glioblastoma: An in-vitro study

Glioblastoma tumors are resistant to radiotherapy, and the need for drugs to induce radio-sensitization in tumor cells has always been a challenge. Besides, radiotherapy using targeted radionuclide would be effective even for resistant tumors. It has been shown topoisomerase I and poly (ADP-ribose) polymerase (PARP) enzymes have critical roles in the repair process of DNA injury in cells. Therefore, the inhibition of the activity of these enzymes can halt this process and result in the accumulation of damaged DNA in cells and the induction of cell death in tumors. In the present research, the impact of beta-particles of iodine-131 in combination with Topotecan (TPT), as the inhibitor of topoisomerase I, and A-966492, as the inhibitor of the PARP enzyme on the possible increase of radio-sensitivity of glioblastoma cells was assessed. For this purpose, a human glioblastoma cell line, U87MG, was cultured in flasks coated with Poly-Hema to achieve 300 mu m-diameter spheroids. Then, nontoxic concentrations of A-966492 and TPT were applied in the cell culture media. The viability of the cells treated with iodine131 in combination with A-966492 and TPT was determined by the clonogenic assay. The expression rate of gamma-H2AX, as a biomarker of DNA double-strand breaks, was analyzed using immunofluorescence microscopy to unravel the effect of TPT, A-966492 (1 mu M), and radiation on the cell death induction. The combination of each TPT or A-966492 with radiation resulted in the increased rate of cell death, and the ratios of sensitizer enhancement at 50% survival (SER50) were elevated by 1.45 and 1.25, respectively. Chemoand radio-sensitization were promoted when iodine-131 was combined with A-966492 and TPT, with the SER50 of 1.68. Also, the expression of gamma-H2AX was significantly increased in cells treated with A-966492 and TPT combined with radiation. The results demonstrated that iodine-131, in combination with A-966492 and TPT, had marked effects on radio-sensitizing and can be used as a targeted radionuclide for targeting radiotherapy in combination with topoisomerase I and PARP inhibitors to enhance radiotherapy in clinics.

Automated summary

The combination of iodine-131 with topotecan and A-966492 shows marked effects in radio-sensitizing glioblastoma cells, enhancing the efficacy of radiotherapy.