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Cinnamic Acid Derivatives Enhance the Efficacy of Transarterial Embolization in a Rat Model of Hepatocellular Carcinoma

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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.

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Acknowledgements

The authors wish to thank Mark Conway, PhD for his assistance in the statistical analysis of this study.

Funding

The research presented in this manuscript was supported by the Thelma R. Swortzel Collaborative Research Grant from the University of Virginia, the Paul Mellon Institute of the University of Virginia, and a grant from the NCI, NIH.

Author information

Authors and Affiliations

  1. Department of Radiology and Medical Imaging, University of Virginia Health Systems, 1215 Lee Street, Box 800170, Charlottesville, VA, 22908, USA

    Luke R. Wilkins

  2. Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, 22908, USA

    David L. Brautigan & Ewa Kubicka

  3. Department of Radiology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH, 44106, USA

    Hanping Wu & John R. Haaga

  4. Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA

    Hooman Yarmohammadi

  5. Department of Pharmacology, University of Virginia, Charlottesville, VA, 22908, USA

    Vlad Serbulea & Norbert Leitinger

  6. Department of Pathology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH, 44106, USA

    Wendy Liu

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  1. Luke R. Wilkins
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Correspondence to Luke R. Wilkins.

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On behalf of all authors, the corresponding author states that there are no conflicts of interest.

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All applicable institutional and/or national guidelines for the care and use of animals were followed.

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Wilkins, L.R., Brautigan, D.L., Wu, H. et al. Cinnamic Acid Derivatives Enhance the Efficacy of Transarterial Embolization in a Rat Model of Hepatocellular Carcinoma. Cardiovasc Intervent Radiol 40, 430–437 (2017). https://doi.org/10.1007/s00270-016-1515-y

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  • DOI: https://doi.org/10.1007/s00270-016-1515-y

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