Luke R Wilkins1, David L Brautigan2, Hanping Wu3, Hooman Yarmohammadi4, Ewa Kubicka2, Vlad Serbulea5, Norbert Leitinger5, Wendy Liu6, John R Haaga3. 1. Department of Radiology and Medical Imaging, University of Virginia Health Systems, 1215 Lee Street, Box 800170, Charlottesville, VA, 22908, USA. lrw6n@virginia.edu. 2. Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, 22908, USA. 3. Department of Radiology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH, 44106, USA. 4. Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA. 5. Department of Pharmacology, University of Virginia, Charlottesville, VA, 22908, USA. 6. Department of Pathology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH, 44106, USA.
Abstract
INTRODUCTION: 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. CONCLUSION: Addition of CA or FA enhances the effectiveness of TAE therapy for HCC in part by blocking lactate efflux.
INTRODUCTION: 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-S1hepatoma 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. CONCLUSION: Addition of CA or FA enhances the effectiveness of TAE therapy for HCC in part by blocking lactate efflux.
Authors: Tiago C Leite; Raquel G Coelho; Daniel Da Silva; Wagner S Coelho; Monica M Marinho-Carvalho; Mauro Sola-Penna Journal: FEBS Lett Date: 2010-11-11 Impact factor: 4.124
Authors: Jessica N Patterson; Katelyn Cousteils; Jennifer W Lou; Jocelyn E Manning Fox; Patrick E MacDonald; Jamie W Joseph Journal: J Biol Chem Date: 2014-03-27 Impact factor: 5.157