Alantolactone derivatives inhibit the tumor necrosis factor α-induced nuclear factor κB pathway by a different mechanism from alantolactone

Sesquiterpene Lactones Containing an α-Methylene-γ-Lactone Moiety Selectively Down-Regulate the Expression of Tumor Necrosis Factor Receptor 1 by Promoting Its Ectodomain Shedding in Human Lung Adenocarcinoma A549 Cells

“…As one of the cellular molecular targets, alantolactone has been reported to inhibit IκB kinase activity by interacting with the ATP-binding site [29]. Consistent with this finding, we recently showed that alantolactone inhibited the TNFα-induced phosphorylation and degradation of the IκBα protein, whereas alantolactone derivatives without an α-methylene-γ-lactone moiety suppressed the binding of NF-κB subunits to DNA downstream of IκB kinase activation [30]. These findings suggest the potential of alantolactone to target multiple steps in the NF-κB signaling pathway.…”

“…( 2) Alantolactone inhibits IκB kinase β by interacting with the ATP-binding site [29]. (3) Three alantolactone derivatives inhibit RelA binding to DNA, but not its nuclear translocation [30]. (4) Eudesmane derivatives 3, 4, and 7 promote the ectodomain shedding of TNF-R1 and thereby down-regulate the expression of cell-surface TNF-R1 (this study).…”

“…Previous studies reported that alantolactone inhibited the NF-κB signaling pathway, when it was constitutively activated and induced by different stimuli [25][26][27][37][38][39][40][41][42][43][44][45][46][47]. In the TNF-α-dependent NF-κB signaling pathway, we and others demonstrated that alantolactone inhibited IκBα phosphorylation [28,30]. Alantolactone was also shown to inhibit IκB kinase β by interacting with the ATP-binding site [29].…”

“…We recently reported that alantolactone inhibited the TNF-α-induced phosphorylation of IκBα and its proteasomal degradation in A549 cells [30]. In A549 cells, TNF-R1, but not TNF-R2, was mainly expressed at the mRNA and protein levels, in contrast to human histiocytic lymphoma U937 cells, which were used as the positive control [31].…”

“…We recently reported that the inhibitory activity of alantolactone was attenuated by glutathione, NAC, and L-cysteine, which are thiol-containing compounds [30], indicating that the α-methylene-γ-lactone moiety of alantolactone is essential for its inhibitory activity. Nevertheless, alantolactone derivatives lacking an α-methylene-γ-lactone moiety, but containing an epoxide moiety, inhibited the TNF-α-induced NF-κB signaling pathway by a different mechanism from that of alantolactone; alantolactone derivatives did not affect TNF-α-induced IκBα phosphorylation and degradation or nuclear RelA translocation, but inhibited RelA binding to the promoter region of its target gene [30]. Therefore, the structural modification of alantolactone revealed potential hidden targets downstream of IκB kinase β activation.…”