title: The anti-tumor efficacy of 2-deoxyglucose and D-allose are enhanced with p38 inhibition in pancreatic and ovarian cell lines.
abstract: OBJECTIVE
  The anti-tumor activity of glucose analogs 2-deoxy-glucose (2-DG) and D-allose was investigated alone or in combination with p38 mitogen-activated protein kinase (MAPK) inhibitor SB202190 or platinum analogs as a strategy to pharmacologically target glycolytic tumor phenotypes.
  
  
  METHODS
  Hypoxia inducible factor-1 alpha (HIF-1α) protein accumulation in pancreatic cell lines treated with SB202190 alone and in combination with glucose analogs was analyzed by Western blot. HIF-1α transcriptional activity was measured in MIA PaCa-2 cells stably transfected with a hypoxia response element luciferase reporter following treatment with glucose analogs alone, and in combination with SB202190. Induction of cleaved poly(ADP-ribose) polymerase (PARP) was measured by Western blot in the MIA PaCa-2 cells. In vitro anti-proliferative activity of 2-DG and D-allose alone, or in combination with oxaliplatin (pancreatic cell lines), cisplatin (ovarian cell lines), or with SB202190 were investigated using the MTT assay.
  
  
  RESULTS
  SB202190 decreased HIF-1α protein accumulation and transcriptional activity. 2-DG demonstrated greater anti-proliferative activity than D-allose. Pre-treatment with SB202190 enhanced activity of both 2-DG and D-allose in MIA PaCa-2, BxPC-3, ASPC-1, and SK-OV-3 cells. The combination of D-allose and platinum agents was additive to moderately synergistic in all but the OVCAR-3 and HEY cells. SB202190 pre-treatment further enhanced activity of D-allose and 2-DG with platinum agents in most cell lines investigated.
  
  
  CONCLUSIONS
  SB202190 induced sensitization of tumor cells to 2-DG and D-allose may be partially mediated by inhibition of HIF-1α activity. Combining glucose analogs and p38 MAPK inhibitors with chemotherapy may be an effective approach to target glycolytic tumor phenotypes.
authors.affiliation: College of Pharmacy, University of Arizona, Tucson, Arizona, USA. malm@pharmacy.arizona.edu.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Malm
authors.affiliation: College of Medicine, University of Arizona Cancer Center, Tucson, Arizona, USA. nhanke@email.arizona.edu.
authors.forename: Neale T
authors.initials: NT
authors.lastname: Hanke
authors.affiliation: College of Medicine, University of Arizona Cancer Center, Tucson, Arizona, USA. alex2@email.arizona.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Gill
authors.affiliation: College of Medicine, University of Arizona Cancer Center, Tucson, Arizona, USA. lili.carbajal@gmail.com.
authors.forename: Liliana
authors.initials: L
authors.lastname: Carbajal
authors.affiliation: College of Medicine, University of Arizona Cancer Center, Tucson, Arizona, USA. abaker@uacc.arizona.edu.
authors.forename: Amanda F
authors.initials: AF
authors.lastname: Baker
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D017930:Genes, Reporter; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D019344:Lactic Acid / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007093:Imidazoles; D011725:Pyridines; D019344:Lactic Acid; C002055:allose; D003847:Deoxyglucose; D011065:Poly(ADP-ribose) Polymerases; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole