Inhibition of IkappaB kinase activity by acetyl-boswellic acids promotes apoptosis in androgen-independent PC-3 prostate cancer cells in vitro and in vivo.
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.
Syrovets
Tatiana
T
Department of Pharmacology of Natural Products and Clinical Pharmacology and Department of Urology, University of Ulm, Helmholtzstrasse 20, D-89081 Ulm, Germany.
Gschwend
Jürgen E
JE
Büchele
Berthold
B
Laumonnier
Yves
Y
Zugmaier
Waltraud
W
Genze
Felicitas
F
Simmet
Thomas
T
D000728:Androgens / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane; D003505:Cyclodextrins / Q000494:pharmacology; D005347:Fibroblasts; D051550:I-kappa B Kinase; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
C459792:3-O-acetyl-beta-boswellic acid; D000728:Androgens; D003505:Cyclodextrins; D016328:NF-kappa B; D014315:Triterpenes; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse