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J. Biol. Chem., Vol. 280, Issue 7, 6170-6180, February 18, 2005

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Inhibition of IB Kinase Activity by Acetyl-boswellic Acids Promotes Apoptosis in Androgen-independent PC-3 Prostate Cancer Cells in Vitro and in Vivo^*

Tatiana Syrovets, Jürgen E. Gschwend¶, Berthold Büchele, Yves Laumonnier, Waltraud Zugmaier, Felicitas Genze, and Thomas Simmet||

From the Department of Pharmacology of Natural Products and Clinical Pharmacology and ^¶Department of Urology, University of Ulm, D-89081 Ulm, Germany

Signaling through NF-B has been implicated in the malignant phenotype as well as the chemoresistance of various cancers. Here we show that the natural compounds acetyl--boswellic acid and acetyl-11-keto--boswellic acid (AKBA) inhibit proliferation and elicit cell death in chemoresistant androgen-independent PC-3 prostate cancer cells in vitro and in vivo. Induction of apoptosis was demonstrated in cultured PC-3 cells by several parameters including mitochondrial cytochrome c release and DNA fragmentation. At the molecular level these compounds inhibit constitutively activated NF-B signaling by intercepting the IB kinase (IKK) activity; signaling through the interferon-stimulated response element remained unaffected, suggesting specificity for IKK inhibition. The impaired phosphorylation of p65 and the reduced nuclear translocation of NF-B proteins were associated with down-regulation of the constitutively overexpressed and NF-B-dependent antiapoptotic proteins Bcl-2 and Bcl-x_L. In addition, expression of cyclin D1, a crucial cell cycle regulator, was reduced as well. Down-regulation of IKK by antisense oligodeoxynucleotides confirmed the essential role of IKK inhibition for the proliferation of the PC-3 cells. Both compounds tested were active in vivo, yet AKBA proved to be far superior. Indeed, topical application of water-soluble AKBA--cyclodextrin on PC-3 tumors xenografted onto chick chorioallantoic membranes induced concentration-dependent inhibition of proliferation as well as apoptosis. Similarly, in nude mice carrying PC-3 tumors, systemic application of AKBA--cyclodextrin inhibited tumor growth and triggered apoptosis in the absence of detectable systemic toxicity. Thus, AKBA and related compounds acting on IKK might provide a novel approach for the treatment of chemoresistant human tumors such as androgen-independent human prostate cancers.

Received for publication, August 18, 2004 , and in revised form, November 16, 2004.

^* This work was supported by the Deutsche Krebshilfe. 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.

These authors contributed equally to this work.

^|| To whom correspondence should be addressed: Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Helmholtzstrasse 20, D-89081 Ulm, Germany. Tel.: 49-731-500-24280; Fax: 49-731-500-24299; E-mail: thomas.simmet{at}medizin.uni-ulm.de.

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