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

Departments of Biology (M.-C.L., E.A.P., T.D.G.) and Chemistry (S.B., C.L., J.A.P.) and Center for Chemical Methodology and Library Development (S.B., C.L., J.A.P, T.D.G.), Boston University, Boston, Massachusetts

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 IKKcatalytic subunit, and converts IKKto stable high molecular mass forms. Like JD, a JD-related epoxyquinoid (isotorreyanic acid) inhibits activation of NF-B at 20 µM, 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.

Address correspondence to: Dr. Thomas D. Gilmore, Boston University, Biology Department, 5 Cummington Street, Boston, MA 02215. E-mail: gilmore{at}bu.edu

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