Styryl-lactone goniothalamin inhibits TNF-α-induced NF-κB activation

Abstract

(R)-(+)-Goniothalamin (GTN), a styryl-lactone isolated from the medicinal plant Goniothalamus macrophyllus, exhibits pharmacological activities including cytotoxic and anti-inflammatory effects. In this study, GTN modulated TNF-α induced NF-κB activation. GTN concentrations up to 20 μM showed low cytotoxic effects in K562 chronic myelogenous leukemia and in Jurkat T cells. Importantly, at these concentrations, no cytotoxicity was observed in healthy peripheral blood mononuclear cells. Our results confirmed that GTN inhibited tumor necrosis factor-α (TNF-α)-induced NF-κB activation in Jurkat and K562 leukemia cells at concentrations as low as 5 μM as shown by reporter gene assays and western blots. Moreover, GTN down-regulated translocation of the p50/p65 heterodimer to the nucleus, prevented binding of NF-κB to its DNA response element and reduced TNF-α-activated interleukin-8 (IL-8) expression. In conclusion, GTN inhibits TNF-α-induced NF-κB activation at non-apoptogenic concentrations in different leukemia cell models without presenting toxicity towards healthy blood cells underlining the anti-leukemic potential of this natural compound.

Keywords: Anti-cancer drug discovery; BSA; Cancer; EMSA; GTN; IKKβ; IL-8; Inflammation; NF-κB; NF-κB inducing kinase; NIK; PBMC; Plant natural product; TAB1; TAK1; TAK1-binding protein 1; TNF-α; TNF-α-receptor-1; TNFR-1; TNFR-1 associated death domain; TNFR-associated factor-2; TRADD; TRAF2; bovine serum albumin; electrophoretic mobility shift assay; goniothalamin; inhibitor of κB kinase beta; interleukine-8; nuclear factor κB; peripheral blood mononuclear cells; tumor growth factor activated kinase 1; tumor necrosis factor alpha.