Visit our Expo - Redox and Inflammation signaling 2012

Session XVI : Chemopreventive agents Poster XVI, 4
Inhibition of TNF-alpha induced NF-kappa B activation by kava (Piper methysticum)
derivatives
Folmer Florence1, Marc Diederich2, Marcel Jaspars1, Romain Blasius2, Jioji
Tabudravu1
1Marine Natural Products Laboratory, Department of Chemistry, University of
Aberdeen, Aberdeen AB24 3UE, Scotland. E-mail: f.folmer@abdn.ac.uk
2Laboratoire de biologie moleculaire et cellulaire du cancer (LBMCC), Hopital du
Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg. Email :
marc.diederich@lbmcc.lu
The inducible transcription factor NF-kappa B plays a central role in the regulation of
immune, inflammatory, and carcinogenic responses. While normal activation of NF-kappa B
is required for cell survival and immunity, its deregulated expression is characteristic for
inflammatory and infectious diseases and for cancer. NF-kappa B has hence become a major
target in anti-inflammatory and anti-cancer drug discovery. In the present study, we
investigated molecular mechanisms induced by lactones and chalcones isolated from Fijian
kava (Piper methysticum) used in traditional medicine against urinary tract infections and
asthma. In order to understand underlying regulatory mechanisms, inhibition of both NFkappa
B-driven reporter gene expression and TNF-alpha induced NF-kappa B binding to a
consensus response element were assayed. Total inhibition was achieved at the concentrations
of 320 microM (flavokavain A), 175 microM (flavokavain B), and 870 microM (kavain and
dihydrokavain). Moreover, treatment with either kavain, flavokavain A, or flavokavain B led
to the inhibition of both the degradation of the inhibitor of kappa B (IkappaB) and the
subsequent translocation of the p50 and p65 subunits of NF-kappa B from the cytoplasm to
the nucleus, as shown by western blot analysis. Additionally, kinase specific screening and
co-transfections with IKK (kinase of IkappaB) and IKK dominant negative expression genes
showed that flavokavain A, but not kavain, nor flavokavain B, inhibits IKK. Flavokavain A
was also shown to inhibit PRAK (p38 regulated/activated kinase), MAPKAP-K3 (MAPKactivated
protein kinase 3), DYRK1A (dual-specificity tyrosine-phosphorylated and regulated
kinase 1A), and Aurora B. Altogether, these results give a first insight into anti-inflammatory
mechanisms triggered by traditionally used chemopreventive kava derivatives.
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