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Molecular Pharmacology

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Research ArticleArticle

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

Mei-Chih Liang, Sujata Bardhan, Chaomin Li, Emily A. Pace, John A. Porco Jr and Thomas D. Gilmore
Molecular Pharmacology July 2003, 64 (1) 123-131; DOI: https://doi.org/10.1124/mol.64.1.123
Mei-Chih Liang
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Sujata Bardhan
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Chaomin Li
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Emily A. Pace
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John A. Porco Jr
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Thomas D. Gilmore
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Abstract

Rel/nuclear factor-κB (NF-κB) 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-κB. Namely, JD inhibits tumor necrosis factor-α–induced activation of NF-κB in mouse 3T3 and human HeLa cells. JD seems to block the induction of the NF-κB pathway by inhibiting the inhibitor of κB kinase (IKK); that is, treatment of cells with JD blocks phosphorylation of IκBα, inhibits the activity of a constitutively active form of the IKKβcatalytic subunit, and converts IKKβto stable high molecular mass forms. Like JD, a JD-related epoxyquinoid (isotorreyanic acid) inhibits activation of NF-κB at 20 μM, whereas several other epoxyquinoids that are related to JD, including its parent compound jesterone, do not block activation of NF-κB 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-κB activity and demonstrate the usefulness of assessing the bioactivity of synthetic derivatives of natural products.

  • Received October 31, 2002.
  • Accepted April 6, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 64 (1)
Molecular Pharmacology
Vol. 64, Issue 1
1 Jul 2003
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Research ArticleArticle

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

Mei-Chih Liang, Sujata Bardhan, Chaomin Li, Emily A. Pace, John A. Porco and Thomas D. Gilmore
Molecular Pharmacology July 1, 2003, 64 (1) 123-131; DOI: https://doi.org/10.1124/mol.64.1.123

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Research ArticleArticle

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

Mei-Chih Liang, Sujata Bardhan, Chaomin Li, Emily A. Pace, John A. Porco and Thomas D. Gilmore
Molecular Pharmacology July 1, 2003, 64 (1) 123-131; DOI: https://doi.org/10.1124/mol.64.1.123
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