Betulinic acid exerts anti-hepatitis C virus activity via the suppression of NF-κB- and MAPK-ERK1/2-mediated COX-2 expression

  • Br J Pharmacol. 2015 Sep;172(18):4481-4492. doi: 10.1111/bph.13233.
Chun-Kuang Lin  1 ,  Chin-Kai Tseng  2  3 ,  Kai-Hsun Chen  4 ,  Shih-Hsiung Wu  1  5 ,  Chih-Chuang Liaw  1  4 ,  Jin-Ching Lee  6  7
Affiliations
  • 1. Doctoral Degree Program in Marine Biotechnology, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
  • 2. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 3. Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
  • 4. Department of Marine Biotechnology and Resources, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
  • 5. Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
  • 6. Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 7. Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
PMID: 26102077 DOI: 10.1111/bph.13233
Abstract

Background and purpose: This study was designed to evaluate the effect of betulinic acid (BA), extracted from Avicennia marina, on the replication of hepatitis C virus (HCV) and to investigate the mechanism of this BA-mediated anti-HCV activity.

Experimental approach: HCV replicon and infectious systems were used to evaluate the anti-HCV activity of BA. Exogenous COX-2 or knock-down of COX-2 expression was used to investigate the role of COX-2 in the anti-HCV activity of BA. The effects of BA on the phosphorylation of NF-κB and on kinases in the MAPK signalling pathway were determined. The anti-HCV activity of BA in combination with Other HCV inhibitors was also determined to assess its use as an anti-HCV supplement.

Key results: BA inhibited HCV replication in both Ava5 replicon cells and in a cell culture-derived infectious HCV particle system. Treatment with a combination of BA and IFN-α, the protease inhibitor telaprevir or the NS5B polymerase inhibitor sofosbuvir resulted in the synergistic suppression of HCV RNA replication. Exogenous overexpression of COX-2 gradually attenuated the inhibitory effect of BA on HCV replication, suggesting that BA reduces HCV replication by suppressing the expression of COX-2. In particular, BA down-regulated HCV-induced COX-2 expression by reducing the phosphorylation of NF-κB and ERK1/2 of the MAPK signalling pathway.

Conclusions and implications: BA inhibits HCV replication by suppressing the NF-κB- and ERK1/2-mediated COX-2 pathway and may serve as a promising compound for drug development or as a potential supplement for use in the treatment of HCV-infected patients.

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