title: Inhibition of Lipid Oxidation Increases Glucose Metabolism and Enhances 2-Deoxy-2-[(18)F]Fluoro-D-Glucose Uptake in Prostate Cancer Mouse Xenografts.
abstract: OBJECTIVE
  Prostate cancer (PCa) is the second most common cause of cancer-related death among men in the United States. Due to the lipid-driven metabolic phenotype of PCa, imaging with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) is suboptimal, since tumors tend to have low avidity for glucose.
  
  
  METHODS
  We have used the fat oxidation inhibitor etomoxir (2-[6-(4-chlorophenoxy)-hexyl]oxirane-2-carboxylate) that targets carnitine-palmitoyl-transferase-1 (CPT-1) to increase glucose uptake in PCa cell lines. Small hairpin RNA specific for CPT1A was used to confirm the glycolytic switch induced by etomoxir in vitro. Systemic etomoxir treatment was used to enhance [(18)F]FDG-positron emission tomography ([(18)F]FDG-PET) imaging in PCa xenograft mouse models in 24 h.
  
  
  RESULTS
  PCa cells significantly oxidize more of circulating fatty acids than benign cells via CPT-1 enzyme, and blocking this lipid oxidation resulted in activation of the Warburg effect and enhanced [(18)F]FDG signal in PCa mouse models.
  
  
  CONCLUSIONS
  Inhibition of lipid oxidation plays a major role in elevating glucose metabolism of PCa cells, with potential for imaging enhancement that could also be extended to other cancers.
authors.affiliation: Division of Medical Oncology, Genitourinary Cancer Program, University of Colorado School of Medicine, MS 8117 12801 E. 17th Ave, Room L18-8101D, Aurora, CO, 80045, USA, isabel.schlaepfer@ucdenver.edu.
authors.forename: Isabel R
authors.initials: IR
authors.lastname: Schlaepfer
authors.forename: L Michael
authors.initials: LM
authors.lastname: Glodé
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Hitz
authors.forename: Colton T
authors.initials: CT
authors.lastname: Pac
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Boyle
authors.forename: Paul
authors.initials: P
authors.lastname: Maroni
authors.forename: Gagan
authors.initials: G
authors.lastname: Deep
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lucia
authors.forename: Scott D
authors.initials: SD
authors.lastname: Cramer
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Serkova
authors.forename: Robert H
authors.initials: RH
authors.lastname: Eckel
mesh_terms: D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004852:Epoxy Compounds / Q000494:pharmacology; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D005947:Glucose / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010084:Oxidation-Reduction / Q000187:drug effects; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging*
chemical_list: D004852:Epoxy Compounds; D007004:Hypoglycemic Agents; D019788:Fluorodeoxyglucose F18; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose; C054207:etomoxir