title: Glucose uptake inhibitor sensitizes cancer cells to daunorubicin and overcomes drug resistance in hypoxia.
abstract: OBJECTIVE
  A high-rate glycolysis is a fundamental property of solid tumors and is associated with an over-expression of glucose transporters and glycolytic enzymes. We hypothesize that over-expression of glucose transporters in tumors prevents apoptosis, promotes cancer cell survival, and confers drug resistance. Inhibition of glucose transporter will preferentially sensitize the anticancer effects of chemotherapeutic drugs to overcome drug resistance in hypoxia.
  
  
  METHODS
  Glucose transporter expressions were detected in cancer tissues and NCI 60 cancer cells with immunostaining and DNA microarray. Glucose uptake was measured with 3H-2-deoxy-glucose. Cytotoxicity of daunorubicin (DNR) in combination of glucose inhibitor was detected by MTS assay under hypoxic condition. Early stage apoptosis was monitored with Annexin V-FITC staining.
  
  
  RESULTS
  Immunostaining showed that GLUT1 was significantly increased in hypoxic regions of the human colon and breast tumors. The expression profiles of all glucose transporters in NCI 60 cancer cells exhibited distinct expression patterns. Phloretin exhibited more than 60% glucose uptake inhibition. Hypoxia conferred two to fivefold higher drug resistance in SW620 and K562 to DNR. Inhibition of glucose uptake by phloretin sensitized cancer cells to DNR for its anticancer activity and apoptosis to overcome drug resistance only under hypoxia.
  
  
  CONCLUSIONS
  Cancer cells heavily rely on glucose transporters for glucose uptake to facilitate a high-rate glycolysis under hypoxia for their survival and drug resistance. Combination of glucose transporter inhibitors and chemotherapeutic drugs may provide a preferential novel therapeutic strategy to overcome drug resistance in hypoxia.
authors.affiliation: Division of Pharmaceutics, School of Pharmacy, The Ohio State University, 500 W. 12th Ave, Columbus, OH 43210, USA.
authors.forename: Xianhua
authors.initials: X
authors.lastname: Cao
authors.forename: Lanyan
authors.initials: L
authors.lastname: Fang
authors.forename: Seth
authors.initials: S
authors.lastname: Gibbs
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Zunyan
authors.initials: Z
authors.lastname: Dai
authors.forename: Ping
authors.initials: P
authors.lastname: Wen
authors.forename: Xincheng
authors.initials: X
authors.lastname: Zheng
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sadee
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003630:Daunorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005947:Glucose / Q000378:metabolism; D051246:Glucose Transport Proteins, Facilitative / Q000037:antagonists & inhibitors*; D051272:Glucose Transporter Type 1 / Q000032:analysis; D051274:Glucose Transporter Type 3 / Q000032:analysis; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010693:Phloretin / Q000494:pharmacology*
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; C495677:SLC2A1 protein, human; C495687:SLC2A3 protein, human; D005947:Glucose; D010693:Phloretin; D003630:Daunorubicin