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J. Biol. Chem., Vol. 281, Issue 25, 17023-17033, June 23, 2006

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Plumbagin (5-Hydroxy-2-methyl-1,4-naphthoquinone) Suppresses NF-B Activation and NF-B-regulated Gene Products Through Modulation of p65 and IB Kinase Activation, Leading to Potentiation of Apoptosis Induced by Cytokine and Chemotherapeutic Agents^*

From the Cytokine Research Laboratory, Department of Experimental Therapeutics, Unit 143, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Plumbagin, derived from the medicinal plant Plumbago zeylanica, modulates cellular proliferation, carcinogenesis, and radioresistance, all known to be regulated by the activation of the transcription factor NF-B, suggesting plumbagin might affect the NF-B activation pathway. We found that plumbagin inhibited NF-B activation induced by TNF, and other carcinogens and inflammatory stimuli (e.g. phorbol 12-myristate 13-acetate, H₂O₂, cigarette smoke condensate, interleukin-1, lipopolysaccharide, and okadaic acid). Plumbagin also suppressed the constitutive NF-B activation in certain tumor cells. The suppression of NF-B activation correlated with sequential inhibition of the tumor necrosis factor (TNF)-induced activation of IB kinase, IB phosphorylation, IB degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-B-dependent reporter gene expression activated by TNF, TNFR1, TRAF2, NIK, IKK-, and the p65 subunit of NF-B. Plumbagin also suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by dithiothreitol both in vitro and in vivo. However, plumbagin did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine 38 mutated to serine. Plumbagin down-regulated the expression of NF-B-regulated anti-apoptotic (IAP1, IAP2, Bcl-2, Bcl-xL, cFLIP, Bfl-1/A1, and survivin), proliferative (cyclin D1 and COX-2), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by TNF and paclitaxel and inhibited cell invasion. Overall, our results indicate that plumbagin is a potent inhibitor of the NF-B activation pathway that leads to suppression of NF-B-regulated gene products. This may explain its cell growth modulatory, anticarcinogenic, and radiosensitizing effects previously described.

Received for publication, February 21, 2006 , and in revised form, April 18, 2006.

^* This work was supported by the Clayton Foundation for Research (to B. B. A.), Department of Defense United States Army Breast Cancer Research Program Grant BC010610 (to B. B. A.), National Institutes of Health on lung chemoprevention Grant PO1 CA91844 (to B. B. A.), and National Institutes of Health P50 Head and Neck SPORE Grant P50CA97007 (to B. B. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-794-1817; Fax: 713-794-1613; E-mail: aggarwal{at}mdanderson.org.

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