Identification of plumericin as a potent new inhibitor of the NF-κB pathway with anti-inflammatory activity in vitro and in vivo.

Abstract

BACKGROUND AND PURPOSE:

The transcription factor NF-κB orchestrates many pro-inflammatory signals and its inhibition is considered a promising strategy to combat inflammation. Here we report the characterization of the natural product plumericin as a highly potent inhibitor of the NF-κB pathway with a novel chemical scaffold, which was isolated via a bioactivity-guided approach, from extracts of Himatanthus sucuuba, an Amazonian plant traditionally used to treat inflammation-related disorders.

EXPERIMENTAL APPROACH:

A NF-κB luciferase reporter gene assay was used to identify NF-κB pathway inhibitors from H. sucuuba extracts. Monitoring of TNF-α-induced expression of the adhesion molecules VCAM-1, ICAM-1 and E-selectin by flow cytometry was used to confirm NF-κB inhibition in endothelial cells, and thioglycollate-induced peritonitis in mice to confirm effects in vivo. Western blotting and transfection experiments were used to investigate the mechanism of action of plumericin.

KEY RESULTS:

Plumericin inhibited NF-κB-mediated transactivation of a luciferase reporter gene (IC50 1 μM), abolished TNF-α-induced expression of the adhesion molecules VCAM-1, ICAM-1 and E-selectin in endothelial cells and suppressed thioglycollate-induced peritonitis in mice. Plumericin exerted its NF-κB pathway inhibitory effect by blocking IκB phosphorylation and degradation. Plumericin also inhibited NF-κB activation induced by transfection with the constitutively active catalytic subunit of the IκB kinase (IKK-β), suggesting IKK involvement in the inhibitory action of this natural product.

CONCLUSION AND IMPLICATIONS:

Plumericin is a potent inhibitor of NF-κB pathways with a new chemical scaffold. It could be further explored as a novel anti-inflammatory lead compound.

• Authors: N Fakhrudin, B Waltenberger, M Cabaravdic, A G Atanasov, C Malainer, D Schachner, E H Heiss, R Liu, S M Noha, A M Grzywacz, J Mihaly-Bison, E M Awad, D Schuster, J M Breuss, J M Rollinger, V Bochkov, H Stuppner, V M Dirsch
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 171 Issue 7 Pg. 1676-86 (Apr 2014) ISSN: 1476-5381 [Electronic] England
• PMID: 24329519 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 The Authors. British Journal of Pharmacology published by John Wiley &. Sons Ltd on behalf of The British Pharmacological Society.

Chemical References

• Anti-Inflammatory Agents
• Cell Adhesion Molecules
• I-kappa B Proteins
• Indenes
• Inflammation Mediators
• Iridoids
• NF-kappa B
• Plant Extracts
• Thioglycolates
• I-kappa B Kinase
• plumericin

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Apocynaceae
• Cell Adhesion Molecules (metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• HEK293 Cells
• Human Umbilical Vein Endothelial Cells (drug effects, immunology, metabolism)
• Humans
• I-kappa B Kinase (metabolism)
• I-kappa B Proteins (metabolism)
• Indenes (pharmacology)
• Inflammation (chemically induced, genetics, immunology, metabolism, prevention & control)
• Inflammation Mediators (antagonists & inhibitors, metabolism)
• Iridoids (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• NF-kappa B (antagonists & inhibitors, genetics, metabolism)
• Phosphorylation
• Plant Extracts (pharmacology)
• Signal Transduction (drug effects)
• Thioglycolates
• Transfection