Experimental Studies On NAMPT Inhibitor FK866 As A Potent Molecule To Promote Drug Sensitivity To Temozolomide In Glioma Cells

Background Glioma is a primary brain tumor with most prevalence and poor prognosis. Temozolomide (TMZ) is the first-line chemotherapy drug to treat glioma patients post surgery. However, the failure of chemotherapy is often seen due to the development of tumor cell resistance to the cytotoxic effects of TMZ. Clinical studies indicated that elevated expression and low promoter methylation of the repair protein O6-methylguanine-DNA methyltransferase (MGMT) associated with TMZ resistance. Recently, FK866 was reported to play important roles in tumorigenesis, metastasis and chemosesitivity in several cancer types, as a potent inhibitor of NAMPT (Nicotinamide phosphoribosyl transferase, the rate-limiting enzyme of salvage synthesis of NAD). But the study of NAMPT in glioma is less. The influence of the sensitivity to chemotherapy of FK866 in the treatment of glioma is unclear.Objective Explore NAMPT expressed in gliomas and its effect on the prognosis of patients; the effect of NAMPT inhibitor, FK866 in In the glioma cell lines; the influence of the combination of FK866 and the first-line chemotherapy TMZ on the sensitivity of chemotherapy. Thereby, it can open up a new vision for clinical treatment of glioma.Methods First of all, the author makes use of clinical data analysis to evaluate NAMPT high or low in gliomas and its influence on prognosis, and validation in the laboratory. Clinical data analysis is based on Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA); Used a variety of experiment methodS to validate On the cell lines through MTS method to detect medicines affect cell activity;through cell scratch test method of rough detect their effects on cell migration ability; The cell cycle and apoptosis were detected by Fluid cytology;TUNEL method to detect apoptosis;Protein immunoblot method (Western blot) to test the apoptosis and proliferation related proteins.Results1. NAMPT in high expression of glioma, and with the increase of the level increased2. In each grade glioma (Ⅱ Ⅲ Ⅳ) NAMPT low expression with good prognosis; High expression with poor prognosis.3. At level IV high MGMT methylation prognosis in patients with glioma, low methylation prognosis; High and low MGMT methylation group prompt NAMPT lower expression with better prognosis; High expression with poor prognosis.4. Postoperative radiotherapy and chemotherapy group also prompt NAMPT lower expression with better prognosis; High expression with poor prognosis.5. The combination of FK866 and TMZ can obviously inhibit the proliferation.and migration of glioma cells, and promote cell apoptosis.Conclusions1. Overexpression of NAMPT was observed in high-grade (WHO Ⅲ-Ⅳ) gliomas.2. NAMPT levels appeared to be a comparable index as the methylation of MGMT promoter for prognosis.3. FK866 was able to significantly increase TMZ-induced glioma cell death.4. Co-administration of FK866 with TMZ could be a new strategy to enhance chemosensitivity or overcome chemoresistance by down-express MGMT.