Curcumin Clinical studies
Inhibition of the NF-κB Signaling Pathway by a Novel Heterocyclic Curcumin Analogue
Anna-Maria Katsori 1, Ajay Palagani 2, Nadia Bougarne 3, Dimitra Hadjipavlou-Litina 1, Guy Haegeman 3 and Wim Vanden Berghe 2,3,*
1Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
Laboratory of Protein Chemistry, Proteomics and Epigenetic Signaling (PPES), Department of Biomedical Sciences, University of Antwerp, Wilrijk 2610, Belgium
Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST), Department of Physiology, University of Ghent, Ghent 9000, Belgium
In this study a series of curcumin analogues were evaluated for their ability to inhibit the activation of NF-κΒ, a transcription factor at the crossroads of cancer-inflammation. Our novel curcumin analogue BAT3 was identified to be the most potent NF-κB inhibitor and EMSA assays clearly showed inhibition of NF-κB/DNA-binding in the presence of BAT3, in agreement with reporter gene results. Immunofluorescence experiments demonstrated that BAT3 did not seem to prevent nuclear p65 translocation, so our novel analogue may interfere with NF-κB/DNA-binding or transactivation, independently of IKK2 regulation and NF-κB-translocation. Gene expression studies on endogenous NF-κB target genes revealed that BAT3 significantly inhibited TNF-dependent transcription of IL6, MCP1 and A20 genes, whereas an NF-κB independent target gene heme oxygenase-1 remained unaffected. In conclusion, we demonstrate that BAT3 seems to inhibit different cancer-related inflammatory targets in the NF-κB signaling pathway through a different mechanism in comparison to similar analogues which were reported previously.
Previous reports have shown that curcumin analogues inhibit NF-κΒ transcriptional activity by blocking general activation and nuclear translocation of NF-κB. Interestingly, our results reveal that the novel analogue BAT3 selectively inhibits ΝF-κΒ-dependent gene expression, most presumably through gene specific effects of NF-κB binding to chromatin-DNA. Altogether we demonstrate that the BAT3 curcumin analogue holds promise to selectively suppress the NF-κB signaling pathway, thereby restricting tumour activity. This study strongly suggests curcumin possessing anti-cancer properties.