Jesterone Dimer, a Synthetic Derivative of the Fungal Metabolite Jesterone, Blocks Activation of Transcription Factor Nuclear Factor κB by Inhibiting the Inhibitor of κB Kinase

Abstract

Rel/nuclear factor-B (NF-B) transcription factors control a variety of cellular processes, such as cell growth and apoptosis, and are continually activated in many human diseases, including chronic inflammatory diseases and cancer. Jesterone dimer (JD) is a synthetic derivative of the natural fungal metabolite jesterone, and JD has previously been shown to be cytotoxic in select tumor cell lines. In this report, we demonstrate that JD is a potent inhibitor of the activation of transcription factor NF-B. Namely, JD inhibits tumor necrosis factor-␣-induced activation of NF-B in mouse 3T3 and human HeLa cells. JD seems to block the induction of the NF-B pathway by inhibiting the inhibitor of B kinase (IKK); that is, treatment of cells with JD blocks phosphorylation of IB␣, inhibits the activity of a constitutively active form of the IKK␤ catalytic subunit, and converts IKK␤ to stable high molecular mass forms. Like JD, a JD-related epoxyquinoid (isotorreyanic acid) inhibits activation of NF-B at 20 M, whereas several other epoxyquinoids that are related to JD, including its parent compound jesterone, do not block activation of NF-B at this concentration. Finally, JD inhibits both proliferation and DNA binding by REL-containing complexes in the human lymphoma SUDHL-4 cell line, and JD activates caspase-3 activity in these cells. In summary, these results suggest that JD induces apoptosis in tumor cells through a mechanism that involves the inhibition of Rel/NF-B activity and demonstrate the usefulness of assessing the bioactivity of synthetic derivatives of natural products.

Mutation of an IKK phosphorylation site within the transactivation domain of REL in two patients with B-cell lymphoma enhances REL's in vitro transforming activity

“…Kinase assays IKK kinase assays were performed as described previously (Liang et al, 2003). After heating at 901C in sodium dodecyl sulfate (SDS) sample buffer, samples were electrophoresed on 7.5% SDS-polyacrylamide (SDS-PAGE) gels.…”

NF-κB signaling, liver disease and hepatoprotective agents

“…As mentioned above, a variety of 'old' drugs, such as aspirin and sulfasalazin, were found to inhibit IKK catalytic activity. However, new IKK inhibitors that alter assembly of the IKK complex and impede the downstream activation of NF-kB have also been described (Liang et al, 2003;Bernier et al, 2006). In addition, a cell permeable peptide corresponding to the NEMObinding domain of IKKb is able to block the association of IKKg/NEMO with IKKb and thereby inhibit NF-kB activation (May et al, 2000).…”

Chemical biology of inflammatory cytokine signaling

“…Chemical biology of inflammatory cytokine signaling T Kataoka epoxyquinol B, 88 epoxyquinone A monomer, 87 jesterone dimer, 89,90 manumycin A 60 and panepoxydone, 91 have been reported to inhibit NF-kB activation. Epoxyquinoids contain the epoxide structure that is known to react with nucleophiles, such as cysteine thiol groups.…”