title: 2-deoxy-D-glucose causes cytotoxicity, oxidative stress, and radiosensitization in pancreatic cancer.
abstract: Glucose metabolism as assessed by (18)FDG PET imaging provides prognostic information in patients with pancreatic cancer but the implications of manipulating glucose metabolism for therapeutic purposes are unknown. Based on previous results with other cancer cell types, we hypothesized that inhibition of glucose metabolism in pancreatic cancer cells would cause cell killing via oxidative stress resulting from disruptions in thiol metabolism. 2-Deoxy-D-glucose (2DG), a chemical inhibitor of glucose metabolism, and glucose deprivation induced cytotoxicity in human pancreatic cancer cells in a time-and dose-dependent manner as well as causing significant increases in metabolic oxidative stress as measured by increased glutathione disulfide accumulation and NADP(+)/NADPH ratios. Simultaneous administration of the thiol antioxidant N-acetylcysteine protected pancreatic cancer cells against the c-ytotoxic effects of 2DG as well as reversing 2DG-induced glutathione disulfide accumulation and augmenting intracellular cysteine pools. In nude mice with heterotopic pancreatic tumors, the combination of 2DG and ionizing radiation resulted in greater inhibition of tumor growth and increased survival, relative to either agent alone. These results support the hypothesis that inhibiting glucose metabolism causes cytotoxicity in human pancreatic cancer cells via metabolic oxidative stress and disruptions in thiol metabolism. These results also support the speculation that inhibitors of glucose metabolism can be used in combination with classical oxidative stress-inducing agents (such as ionizing radiation) to enhance therapeutic responses in pancreatic cancer.
authors.affiliation: Department of Radiation Oncology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Mitchell C
authors.initials: MC
authors.lastname: Coleman
authors.forename: Carla R
authors.initials: CR
authors.lastname: Asbury
authors.forename: David
authors.initials: D
authors.lastname: Daniels
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Nukhet
authors.initials: N
authors.lastname: Aykin-Burns
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Smith
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Spitz
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Cullen
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005947:Glucose / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009249:NADP / Q000032:analysis; D018384:Oxidative Stress; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D011836:Radiation Tolerance / Q000187:drug effects*; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016166:Free Radical Scavengers; D011838:Radiation-Sensitizing Agents; D013438:Sulfhydryl Compounds; D009249:NADP; D003847:Deoxyglucose; D005947:Glucose; D000111:Acetylcysteine