Chemopreventive effects of a curcumin-like diarylpentanoid [2,6-bis(2,5-dimethoxybenzylidene)cyclohexanone] in cellular targets of rheumatoid arthritis in vitro

Int J Rheum Dis. 2015 Jul;18(6):616-27. doi: 10.1111/1756-185X.12341. Epub 2014 May 16.


Aim: Synovial fibroblast has emerged as a potential cellular target in progressive joint destruction in rheumatoid arthritis development. In this study, BDMC33 (2,6-bis[2,5-dimethoxybenzylidene]cyclohexanone), a curcumin analogue with enhanced anti-inflammatory activity has been synthesized and the potency of BDMC33 on molecular and cellular basis of synovial fibroblasts (SF) were evaluated in vitro.

Methods: Synovial fibroblast cells (HIG-82) were cultured in vitro and induced by phorbol-12-myristate acetate (PMA) to stimulate the expression of matrix metalloproteinase (MMPs) and pro-inflammatory cytokines. The protective effects of BDMC33 were evaluated toward MMP activities, pro-inflammatory cytokine expression and nuclear factor kappa-B (NF-κB) activation by using various bioassay methods, including zymography, Western blotting, reverse transcription polymerase chain reaction, immunofluorescense microscopy and electrophoretic mobility shift assay.

Results: The results showed that BDMC33 significantly inhibited the pro-gelatinase B (pro-MMP-9) and collagenase activities via suppression of MMP-1 in activated SF. In addition, BDMC33 strongly suppressed MMP-3 gene expression as well as inhibited COX-2 and IL-6 pro-inflammatory gene expression. We also demonstrated that BDMC33 abolished the p65 NF-κB nuclear translocation and NF-κB DNA binding activity in PMA-stimulated SF.

Conclusions: BDMC33 represents an effective chemopreventive agent and could be used as a promising lead compound for further development of rheumatoid arthritis therapeutic intervention.

Keywords: BDMC33; HIG-82; NF-κB; curcumin; matrix metalloproteinase; synovial fibroblast.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antirheumatic Agents / pharmacology*
  • Benzylidene Compounds / pharmacology*
  • Cell Line
  • Cyclohexanones / pharmacology*
  • Cytokines / metabolism
  • Dose-Response Relationship, Drug
  • Fibroblasts / drug effects*
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Inflammation Mediators / metabolism
  • Matrix Metalloproteinases / metabolism
  • Rabbits
  • Signal Transduction / drug effects
  • Synovial Membrane / drug effects*
  • Synovial Membrane / immunology
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology
  • Tetradecanoylphorbol Acetate / pharmacology


  • 2,6-bis(2,5-dimethoxybenzylidene)cyclohexanone
  • Antirheumatic Agents
  • Benzylidene Compounds
  • Cyclohexanones
  • Cytokines
  • Inflammation Mediators
  • Matrix Metalloproteinases
  • Tetradecanoylphorbol Acetate