Flavan-3 ols and procyanidins in the regulation of NF-êB: possible therapeutic actions in inflammation and cancer.

GERARDO G. MACKENZIE; ANA M. ADAMO; PATRICIA I. OTEIZA

Damai Beach, Sarawak, Malaysia,

Workshop; 6th COSTAM/SFRR(ASEAN) International Workshop 2006 Micronutrients, Oxidative Stress and Environment; 2006

COSTAM/SFRR(ASEAN)

Flavan-3 ols and procyanidins in the regulation of NF-êB: possible therapeutic actions in inflammation and cancer. Gerardo G. Mackenzie, Ana M. Adamo and Patricia I. Oteiza  Departments of Nutrition and Environmental Toxicology, University of California, Davis and Dept. Biological Chemistry, IQUIFIB (UBA-CONICET), School of Pharmacy and Biochemistry, UBA., Buenos Aires, Argentina   Rel/NF-êB transcription factor regulates the transcription of several genes that are implicated in inflammation, cell survival, proliferation, tumor promotion and angiogenesis.  NF-êB has been proposed to be the link between inflammation and tumor promotion in part through the upregulation of TNF-a.  The activation of NF-êB has been described in solid tumors (breast, gastric, colonic cancers) as well as in leukemia and lymphoma, including Hodgkin’s disease (HD). As the deregulation of NF-êB occurs in different types of cancer, this has intensified the research interest in this pathway, to search for molecules that could inhibit NF-êB, as a therapeutically strategy against cancer.   Different plant polyphenos have been shown to inhibit NF-êB activation and the expression of NF-êB-regulated genes.    We found  that (+)-catechin, (-)-epicatechin (EC) and the dymeric procyanidin B2 inhibited PMA-induced NF-êB activation in Jurkat T cells.  Based on this evidence, we subsequently investigated the capacity of EC and B2 to inhibit NF-êB in H-RS cells characterizing the functional consequences. High concentrations of EC were necessary to inhibit NF-êB in H-RS cells and EC had a modest effects on cell viability.   B2  (5- 50 µM) inhibited NF-êB binding activity and NF-êB-dependent gene expression.  B2 prevented NF-êB-dependent cytokine (TNFá, IL-6 and RANTES) production and down regulated the NF-êB-dependent expression of proteins involved in cell survival.  After 72 h, B2 caused a dose-dependent decrease in cell viability in H-RS cells, while had minor effects on cells without a constitutive activation of NF-êB (Jurkat, Daudi).  The observed B2-mediated decrease in cell viability is not associated with alterations of the cell cycle but to the induction of cell apoptosis.  The findings that in H-RS cells, EC and B2: i) do not inhibit NF-êB through its antioxidant activity; ii) do not affect NF-kB activation at the level of p65 phosphorylation, iii) do not affect NF-kB  translocation and; iii) at the nucleus, inhibit NF-kB-DNA binding not affecting p65 and p50 nuclear content; further support our previously proposed mechanism of a direct interaction of EC and B2 with NF-kB proteins and subsequent inhibition of NF-kB binding to DNA. Although EC showed modest effects, B2 could have potential antitumorogenic actions in Hodgkin’s lymphoma. Furthermore, it is very important to point out that even when the combined treatment with EC and an inhibitor of NF-êB nuclear translocation led to an almost complete inhibition of NF-kB-DNA binding activity, this translated in a partial effect on cell viability.  Thus, the inhibition of additional signaling pathways should be also considered when designing combined therapeutic approaches for Hodgkin’s lymphoma and other types of cancer.. In summary, through the inhibition of NF-êB, B2 could be of potential therapeutic value in Hodgkin’s lymphoma.  By inhibiting NF-êB, EC and B2 could also have relevant roles in the inhibition of inflammatory processes.