Inhibition of IkappaB kinase activity by acetyl-boswellic acids promotes apoptosis in androgen-independent PC-3 prostate cancer cells in vitro and in vivo.

Abstract

Signaling through NF-kappaB has been implicated in the malignant phenotype as well as the chemoresistance of various cancers. Here we show that the natural compounds acetyl-beta-boswellic acid and acetyl-11-keto-beta-boswellic acid (AKbetaBA) 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-kappaB signaling by intercepting the IkappaB 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-kappaB proteins were associated with down-regulation of the constitutively overexpressed and NF-kappaB-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 AKbetaBA proved to be far superior. Indeed, topical application of water-soluble AKbetaBA-gamma-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 AKbetaBA-gamma-cyclodextrin inhibited tumor growth and triggered apoptosis in the absence of detectable systemic toxicity. Thus, AKbetaBA 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.

• Authors: Tatiana Syrovets, Jürgen E Gschwend, Berthold Büchele, Yves Laumonnier, Waltraud Zugmaier, Felicitas Genze, Thomas Simmet
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 280 Issue 7 Pg. 6170-80 (Feb 18 2005) ISSN: 0021-9258 [Print] United States
• PMID: 15576374 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-O-acetyl-beta-boswellic acid
• Androgens
• Cyclodextrins
• NF-kappa B
• Triterpenes
• Protein Serine-Threonine Kinases
• Chuk protein, mouse
• I-kappa B Kinase
• Ikbkb protein, mouse
• Ikbke protein, mouse

Topics

• Androgens (metabolism)
• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Chick Embryo
• Chorioallantoic Membrane
• Cyclodextrins (pharmacology)
• Fibroblasts
• I-kappa B Kinase
• Male
• Mice
• Mice, Nude
• NF-kappa B (metabolism)
• Neoplasm Invasiveness
• Prostatic Neoplasms (enzymology, metabolism, pathology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Triterpenes (pharmacology)
• Xenograft Model Antitumor Assays