title: A bioactive probe of the oxidative pentose phosphate cycle: novel strategy to reverse radioresistance in glucose deprived human colon cancer cells.
abstract: The specific effects of glucose deprivation on oxidative pentose phosphate cycle (OPPC) function, thiol homeostasis, protein function and cell survival remain unclear due to lack of a glucose-sensitive chemical probe. Using p53 wild type and mutant human colon cells, we determined the effects of hydroxyethyl disulfide (HEDS) on NADPH, GSH, GSSG, total glutathione, total non-protein and protein thiol levels, the function of the DNA repair protein Ku, and the susceptibility to radiation-induced free radicals under normal glucose or glucose-deprived conditions. HEDS is rapidly detoxified in normal glucose but triggered a p53-independent metabolic stress in glucose depleted state that caused loss of NADPH, protein and non-protein thiol homeostasis and Ku function, and enhanced sensitivity of both p53 wild type and mutant cells to radiation induced oxidative stress. Additionally, high concentration of HEDS alone induced cell death in p53 wild type cells without significant effect on p53 mutant cells. HEDS offers a useful tool to gain insights into how glucose metabolism affects OPPC dependent stress-induced cellular functions and injury, including in tumor cells, where our findings imply a novel therapeutic approach to target glucose deprived tumor. Our work introduces a novel probe to address cancer metabolism and ischemic pathology.
authors.affiliation: Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Ward
authors.forename: Donglan
authors.initials: D
authors.lastname: Zhang
authors.forename: Eswarkumar
authors.initials: E
authors.lastname: Dayanandam
authors.forename: Albert S
authors.initials: AS
authors.lastname: Denittis
authors.forename: George C
authors.initials: GC
authors.lastname: Prendergast
authors.forename: Iraimoudi S
authors.initials: IS
authors.lastname: Ayene
mesh_terms: D002588:Cesium Radioisotopes; D003110:Colonic Neoplasms; D004265:DNA Helicases / Q000378:metabolism; D004220:Disulfides / Q000494:pharmacology*; D000431:Ethanol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005720:Gamma Rays; D005947:Glucose / Q000172:deficiency*; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D000072200:Ku Autoantigen; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010427:Pentose Phosphate Pathway / Q000187:drug effects* / Q000502:physiology; D013438:Sulfhydryl Compounds / Q000378:metabolism
chemical_list: D002588:Cesium Radioisotopes; D004220:Disulfides; D013438:Sulfhydryl Compounds; D000431:Ethanol; C031319:2-hydroxyethyl disulfide; D009249:NADP; D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen; D005978:Glutathione; D005947:Glucose; D019803:Glutathione Disulfide