title: Cinnamic Acid Derivatives Enhance the Efficacy of Transarterial Embolization in a Rat Model of Hepatocellular Carcinoma.
abstract: BACKGROUND
  We hypothesize that the combination of transarterial embolization (TAE) plus inhibition of lactate export will limit anaerobic metabolism and reduce tumor survival compared to TAE alone. The purpose of this study was to test this hypothesis in a rat model of hepatocellular carcinoma (HCC).
  
  
  METHODS
  Rat N1-S1 hepatoma cells were assayed in vitro using the Seahorse XF analyzer to measure extracellular acidification (lactate excretion) comparing effects of the addition of caffeic acid (CA) or ferulic acid (FA) or UK-5099 with control. Monocarboxylate transporter Slc16a3 was knocked down by RNAi. N1S1 tumors were orthotopically implanted in rats and 4 groups evaluated: (1) Control, (2) TAE-only, (3) TAE plus CA, and (4) TAE plus FA. Tumor size was determined by ultrasound and analyzed by repeated measures statistics. Tumors harvested at 4 weeks were examined by microscopy.
  
  
  RESULTS
  Seahorse assays showed that CA and FA caused a significant reduction by >90% in lactate efflux by N1S1 tumor cells (p < 0.01). Knockdown of Slc16a3 prevented inhibition by CA. In vivo tumors grew 30-fold in volume over 4 weeks in untreated controls. By comparison, TAE resulted in near cessation of growth (10% in 4-week time period). However, both TAE + CA and TAE + FA caused a significant reduction of tumor volumes (87 and 72%, respectively) compared to control and TAE (p < 0.05). Pathologic evaluation revealed residual tumor in the TAE group but no residual viable tumor cells in the TAE + CA and TAE + FA groups.
  
  
  CONCLUSIONS
  Addition of CA or FA enhances the effectiveness of TAE therapy for HCC in part by blocking lactate efflux.
authors.affiliation: Department of Radiology and Medical Imaging, University of Virginia Health Systems, 1215 Lee Street, Box 800170, Charlottesville, VA, 22908, USA. lrw6n@virginia.edu.
authors.forename: Luke R
authors.initials: LR
authors.lastname: Wilkins
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, 22908, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Brautigan
authors.affiliation: Department of Radiology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH, 44106, USA.
authors.forename: Hanping
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.
authors.forename: Hooman
authors.initials: H
authors.lastname: Yarmohammadi
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, 22908, USA.
authors.forename: Ewa
authors.initials: E
authors.lastname: Kubicka
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA, 22908, USA.
authors.forename: Vlad
authors.initials: V
authors.lastname: Serbulea
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, VA, 22908, USA.
authors.forename: Norbert
authors.initials: N
authors.lastname: Leitinger
authors.affiliation: Department of Pathology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH, 44106, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Radiology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH, 44106, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Haaga
mesh_terms: D000179:Acrylates / Q000494:pharmacology*; D000818:Animals; D002109:Caffeic Acids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003373:Coumaric Acids / Q000494:pharmacology*; D004195:Disease Models, Animal; D004621:Embolization, Therapeutic / Q000379:methods*; D005260:Female; D019344:Lactic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D008113:Liver Neoplasms / Q000628:therapy; D008114:Liver Neoplasms, Experimental / Q000628:therapy*; D008297:Male; D009368:Neoplasm Transplantation; D051381:Rats; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000179:Acrylates; D002109:Caffeic Acids; D003373:Coumaric Acids; D019344:Lactic Acid; C043654:2-cyano-3-(1-phenylindol-3-yl)acrylate; C004999:ferulic acid; C040048:caffeic acid
keywords: Embolization; Interventional oncology; Lactate; Translational; Tumor metabolism