The Anti-inflammatory Sesquiterpene Lactone Helenalin Inhibits the Transcription Factor NF-κB by Directly Targeting p65

Abstract

The sesquiterpene lactone helenalin is a potent antiinflammatory drug whose molecular mechanism of action remains unclear despite numerous investigations. We have previously shown that helenalin and other sesquiterpene lactones selectively inhibit activation of the transcription factor NF-B, a central mediator of the human immune response. These drugs must target a central step in NF-B pathway, since they inhibit NF-B induction by four different stimuli. It has previously been reported that sesquiterpene lactones exert their effect by inhibiting degradation of IB, the inhibitory subunit of NF-B. These data contradicted our report that IB is not detectable in helenalin-treated, ocadaic acid-stimulated cells. Here we use confocal laser scanning microscopy to demonstrate the presence of IBreleased, nuclear NF-B in helenalin-treated, tumor necrosis factor-␣ stimulated cells. These data show that neither IB degradation nor NF-B nuclear translocation are inhibited by helenalin. Rather, we provide evidence that helenalin selectively alkylates the p65 subunit of NF-B. This sesquiterpene lactone is the first anti-inflammatory agent shown to exert its effect by directly modifying NF-B.

Delayed radioprotection by nuclear transcription factor κB -mediated induction of manganese superoxide dismutase in human microvascular endothelial cells after exposure to the free radical scavenger WR1065

“…Helenalin is an anti-inflammatory sesquiterpene lactone that can effectively inhibit NFκB through the selective alkylation of the p65 subunit [32]. We determined the effect of this agent on WR1065-induced NFκB activation and the subsequent elevation of MnSOD.…”

Inhibition of Myb-dependent gene expression by the sesquiterpene lactone mexicanin-I

“…[35][36][37] On the molecular level, the effects of STLs on cell signaling pathways such as nuclear transcription factorkappaB (NF-kB) and mitogen-activated protein kinases have been intensely studied. [38][39][40] Previous work has implicated c-Myb as a potential therapeutic target in several types of human tumors, including colon cancer, breast cancer and leukemia. 3 Studies employing antisense oligodeoxynucleotides or dominantnegative forms of Myb have shown that Myb activity is essential for the continued proliferation of AML and chronic myeloid leukemia (CML) cells.…”

Terpenoids from a multiple shoot culture of Telekia speciosa

“…Except for widely investigated alantolactone and isoalantolactone, other sesquiterpene lactones -telekin and 2,3-dihydroaromaticin have also shown marked antiproliferative activity against human cancer cell lines in vitro [7,8]. Moreover, 2,3-dihydroaromaticin is a potent inhibitor of lipopolisaccharide induced nitric oxide synthesis and a moderate inhibitor of the transcription factor NF-κB activation [9,10].…”

“…Except for widely investigated alantolactone and isoalantolactone, other sesquiterpene lactones -telekin and 2,3-dihydroaromaticin have also shown marked antiproliferative activity against human cancer cell lines in vitro [7,8]. Moreover, 2,3-dihydroaromaticin is a potent inhibitor of lipopolisaccharide induced nitric oxide synthesis and a moderate inhibitor of the transcription factor NF-κB activation [9,10].Telekin affected activity of some antioxidant and drug-metabolizing enzymes in rat liver and kidney [11,12]. In a recently published report on antiproliferative and direct cytotoxic activity of extracts from T. speciosa an interference of these preparations with cell proliferation in vitro has been proven [13].…”