title: Inhibition of NADPH Oxidase-4 Potentiates 2-Deoxy-D-Glucose-Induced Suppression of Glycolysis, Migration, and Invasion in Glioblastoma Cells: Role of the Akt/HIF1α/HK-2 Signaling Axis.
abstract: OBJECTIVE
  2-Deoxy-d-glucose (2-DG), a synthetic glycolytic inhibitor, is currently under clinical evaluation as a promising anticancer agent. However, 2-DG treatment in cancer cells activates prosurvival Akt signaling that might limit its clinical efficacy. The NADPH oxidase 4 (Nox-4)/reactive oxygen species/Akt signaling is known to regulate survival, proliferation, infiltration, and invasion in glioblastomas (GBMs). The enhanced motility, invasiveness, and therapy resistance in GBMs are attributed to metabolic adaptation through increased aerobic glycolysis. Therefore, we hypothesized that inhibition of the Nox-4 might enhance 2-DG-induced suppression of glycolysis, migration, and invasion in GBM cells.
  
  
  RESULTS
  We identified the natural naphthoquinone compound shikonin as a potent inhibitor of the Nox-4/Akt signaling pathway. The combined treatment of shikonin+2-DG suppressed the glycolytic phenotype, migration, and invasion through modulation of the Akt/HIF1α/hexokinase-2 signaling axis in GBM cells. The combination also exhibited enhanced antiproliferative and antiangiogenic effects in vivo.
  
  
  METHODS
  Our data for the first time demonstrate that inhibition of the Nox-4-associated prosurvival signaling pathway by shikonin enhances the antiproliferative and antiangiogenic potential of 2-DG in GBM cells.
  
  
  CONCLUSIONS
  In summary, the combined inhibition of Nox-4 and glycolysis may have therapeutic implications for the management of GBMs.
authors.affiliation: 1 Endocrinology Division, Cell Death Research Laboratory, CSIR-Central Drug Research Institute , Lucknow, India .
authors.forename: Priyanka
authors.initials: P
authors.lastname: Gupta
authors.affiliation: 2 Pharmacology Division, CSIR-Central Drug Research Institute , Lucknow, India .
authors.forename: Kumaravelu
authors.initials: K
authors.lastname: Jagavelu
authors.affiliation: 1 Endocrinology Division, Cell Death Research Laboratory, CSIR-Central Drug Research Institute , Lucknow, India .
authors.forename: Durga Prasad
authors.initials: DP
authors.lastname: Mishra
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D003847:Deoxyglucose / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D019255:NADPH Oxidases / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D009285:Naphthoquinones; C016101:shikonin; D003847:Deoxyglucose; D019255:NADPH Oxidases; D051057:Proto-Oncogene Proteins c-akt