title: Inhibitor of Nicotinamide Phosphoribosyltransferase Sensitizes Glioblastoma Cells to Temozolomide via Activating ROS/JNK Signaling Pathway.
abstract: Overcoming temozolomide (TMZ) resistance is a great challenge in glioblastoma (GBM) treatment. Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the biosynthesis of nicotinamide adenine dinucleotide and has a crucial role in cancer cell metabolism. In this study, we investigated whether FK866 and CHS828, two specific NAMPT inhibitors, could sensitize GBM cells to TMZ. Low doses of FK866 and CHS828 (5 nM and 10 nM, resp.) alone did not significantly decrease cell viability in U251-MG and T98 GBM cells. However, they significantly increased the antitumor action of TMZ in these cells. In U251-MG cells, administration of NAMPT inhibitors increased the TMZ (100μM)-induced apoptosis and LDH release from GBM cells. NAMPT inhibitors remarkably enhanced the activities of caspase-1, caspase-3, and caspase-9. Moreover, NAMPT inhibitors increased reactive oxygen species (ROS) production and superoxide anion level but reduced the SOD activity and total antioxidative capacity in GBM cells. Treatment of NAMPT inhibitors increased phosphorylation of c-Jun and JNK. Administration of JNK inhibitor SP600125 or ROS scavenger tocopherol with TMZ and NAMPT inhibitors substantially attenuated the sensitization of NAMPT inhibitor on TMZ antitumor action. Our data indicate a potential value of NAMPT inhibitors in combined use with TMZ for GBM treatment.
authors.affiliation: Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.affiliation: Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China.
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Yan
authors.affiliation: Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China.
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China.
authors.forename: Fang-Cheng
authors.initials: FC
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China.
authors.forename: Wo-Hua
authors.initials: WH
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China.
authors.forename: Min
authors.identifier: 0000-0001-7048-3915
authors.initials: M
authors.lastname: Feng
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage*; D000873:Anthracenes / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000235:genetics; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics; D010880:Piperidines / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077204:Temozolomide; D024505:Tocopherols / Q000008:administration & dosage
chemical_list: D000178:Acrylamides; D000873:Anthracenes; D016207:Cytokines; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D017382:Reactive Oxygen Species; C432165:pyrazolanthrone; D003606:Dacarbazine; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; D048055:Mitogen-Activated Protein Kinase 8; D048670:MAP Kinase Kinase 4; D020169:Caspases; D024505:Tocopherols; D000077204:Temozolomide