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Research Articles: Therapeutics, Targets, and Development

Identification of a novel blocker of IB kinase activation that enhances apoptosis and inhibits proliferation and invasion by suppressing nuclear factor-B

¹ Cytokine Research Section, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas and ² Niigata University of Pharmacy and Applied Life Science, Higashijima, Niigata-shi, Japan

Requests for reprints: Bharat B. Aggarwal, Cytokine Research Section, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Unit 143, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3503; Fax: 713-794-1613. E-mail: aggarwal{at}mdanderson.org

Abstract

3,4-Dihydroxybenzalacetone (DBL) is a polyphenol derived from the medicinal plant Chaga [Inonotus obliquus (persoon) Pilat]. Although Chaga is used in Russia folk medicine to treat tumors, very little is known about its mechanism of action. Because most genes involved in inflammation, antiapoptosis, and cell proliferation are regulated by the transcription factor nuclear factor-B (NF-B), we postulated that DBL activity is mediated via modulation of the NF-B activation pathway. We investigated the effects of DBL on NF-B activation by electrophoretic mobility shift assay and on NF-B-regulated gene expression by Western blot analysis. We found that DBL suppressed NF-B activation by a wide variety of inflammatory agents, including tumor necrosis factor (TNF), interleukin-1β, epidermal growth factor, okadaic acid, phorbol 12-myristate 13-acetate, and lipopolysaccharide. The suppression was not cell type specific and inhibited both inducible and constitutive NF-B activation. DBL did not interfere with the binding of NF-B to DNA but rather inhibited IB kinase activity, IB phosphorylation and degradation, p65 phosphorylation, and translocation. DBL also suppressed the expression of TNF-induced and NF-B-regulated proliferative, antiapoptotic, and metastatic gene products. These effects correlated with enhancement of TNF-induced apoptosis and suppression of TNF-induced invasion. Together, our results indicate that DBL inhibits NF-B activation and NF-B-regulated gene expression, which may explain the ability of DBL to enhance apoptosis and inhibit invasion. [Mol Cancer Ther 2008;7(1):191–201]

Grant support: Clayton Foundation for Research (B. B. Aggarwal), NIH Lung Chemoprevention grant PO1 CA91844 (B.B. Aggarwal), and grant 5P30CA016672-32 for flow cytometric analysis.

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.

Note: B.B. Aggarwal is a Ransom Horne, Jr., Professor of Cancer Research.

Received 6/14/07; revised 11/ 1/07; accepted 11/30/07.