title: Targeting cisplatin-resistant human tumor cells with metabolic inhibitors.
abstract: OBJECTIVE
  Although cisplatin is the drug of choice in treating lung cancer patients, relapse and resistance is a common drawback to its clinical effectiveness. Based on cisplatin's reported ability to interfere with numerous cellular components, including mitochondria, we probed alterations in metabolism in cisplatin-resistant tumor cell lines to reveal targets for overcoming this important form of resistance.
  
  
  METHODS
  Cisplatin-resistant lung and ovarian cancer cell lines were used to evaluate the efficacy of metabolic inhibitors for selectively targeting cisplatin-resistant cells under varying oxygen conditions.
  
  
  RESULTS
  Three cisplatin-resistant cancer cell lines expressed lower HKII protein when compared to the respective cisplatin-sensitive cancer cell lines from which they were derived. Under anaerobic and hypoxic conditions, treatment with the glycolytic inhibitors 2-deoxyglucose (2-DG) and 2-fluorodeoxyglucose (2-FDG) correlated with increased cytotoxicity and more pronounced decreases in lactate production in cisplatin-resistant cells, indicating a greater blockage of glycolysis. Knockdown of HKI or HKII with siRNA in the parental lung cancer cell lines led to increased 2-FDG-induced cell death under anaerobic conditions. Under normal oxygen conditions, blockage of either fatty acid oxidation or deprivation of glutamine resulted in cell death in cisplatin-resistant lung cancer cell lines.
  
  
  CONCLUSIONS
  Altered hexokinase levels in cisplatin-resistant cancer cell lines leads to increased sensitivity to glycolytic inhibition under anaerobic conditions, whereas under normoxic conditions, blockage of either fatty acid oxidation or deprivation of glutamine leads to cell death. These findings may be clinically applicable when considering cisplatin resistance.
authors.affiliation: Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, P.O. Box 016960 (R124), Miami, FL, 33101, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Sullivan
authors.forename: Metin
authors.initials: M
authors.lastname: Kurtoglu
authors.forename: Randall
authors.initials: R
authors.lastname: Brenneman
authors.forename: Huaping
authors.initials: H
authors.lastname: Liu
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Lampidis
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D003847:Deoxyglucose / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D019344:Lactic Acid; D003847:Deoxyglucose; D006593:Hexokinase; D002945:Cisplatin