NAD+ metabolic enzyme inhibitor as radiosensitizer for malignant meningioma and its modulation of P53 expression.

ABSTRACT

Surgical resection followed by radiotherapy (RT) is recommended for malignant meningioma but poor outcome is unavoidable. To improve the efficacy of RT in malignant meningioma, a targeted radiosensitizer could be added. Nicotinamide phosphoribosyltransferase (NAMPT), highly expressed in high-grade meningiomas may have a role in determining the radioresponse. Here, we evaluated the impact of NAMPT inhibition on radiosensitivity in malignant meningioma in vivo and in vitro. IOMM-Lee and TTMM705 cells were treated with NAMPT inhibition (FK866 or shRNA NAMPT) before irradiation. The subsequent clonogenic assay demonstrated significantly increased radiosensitivity. Combination treatment with FK866 and irradiation significantly increased the number of G2/M-phase cells, the percentage of apoptotic cells and the γ-H2A.X level compared to FK866 or RT alone. We examined the effect of NAMPT inhibition on NMI and p53 expression in IOMM-Lee and TTMM705 cells. NAMPT inhibition by FK866 and shRNA treatment increased NMI, p53, CDKN1A and BAX expression. Additionally, we assessed the efficacy of FK866/RT combination treatment in vivo. The combination treatment exhibited increased antitumor efficacy compared to either treatment alone. The Ki-67 level was significantly lower and the p53 and γ-H2A.X level was significantly higher in the combination treatment group than in any of the other three groups. In conclusion, these results indicate that FK866 improves radiosensitivity in malignant meningioma, an effect that may be attributed to the increase in p53 expression.