DDIS-27. COMBINED INHIBITION OF NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE (NAMPT) AND POLY (ADP-RIBOSE) POLYMERASE (PARP) IMPAIRS GLIOBLASTOMA CELL GROWTH. (5th November 2018)

• Record Type: Journal Article
• Authors: Hwang, Lee; Su, Yu-Ting; Vogelbaum, Michael; Gilbert, Mark; Wu, Jing
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi74
• Page End: vi75
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.306
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: BACKGROUND: Glioblastoma is aggressive with poor prognosis. Nicotinamide phosphoribosyltransferase (NAMPT) is essential to maintain nicotinamide adenine dinucleotide metabolism during rapid proliferation and regulates poly (ADP-ribose) polymerase (PARP), which is crucial for DNA repair. Targeting both NAMPT and PARP may represent a treatment strategy in glioblastoma. We hypothesize that the combined inhibition of NAMPT and PARP can induce synergistic cell death in tumor, while sparing significant cytotoxicity in normal astrocytes. METHODS: NAMPT expression was determined in a group of six human glioblastoma cell lines and normal human astrocytes (NHA) by Western blotting. To analyze the cytotoxic effects of the treatments in tumor and normal cells, U251 and NHA cells were selected to receive FK866 (NAMPT inhibitor), Olaparib (PARP inhibitor), or both drugs for 72 hours prior to the cell viability test. RESULTS: Various levels of NAMPT expression were demonstrated in a group of glioblastoma cell lines and NHA, where U251 showed the strongest expression. We demonstrated a significant decrease of cell viability in U251 cells that were treated with FK866 in a dose-dependent manner. A 32% reduction of cell viability was demonstrated at a dose as low as 10 nM. However, a 28% reduction of cell viability was found in NHA at the EC50 concentration for U251 cells. When tumor cells were treated with a combination of FK866 and Olaparib at their EC50 concentrations (28nM and 406nM), 72% and 50% reductions of cell viability occurred in tumor cells and NHA, respectively. CONCLUSION: The combined treatment with FK866 and Olaparib enhances cytotoxicity in glioblastoma cells compared to the single-agent therapy, representing a promising therapeutic strategy. However, the toxic effects on NHA are concerning and warrant further investigations to determine a precise therapeutic window in preclinical models before the treatment is considered for clinical trials.