1. ¹Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
2. ²NN Blokhin Russian Cancer Research Center, Moscow, Russia
3. ³Millennium Pharmaceuticals Inc., Cambridge, MA, USA

Correspondence: Dr I Budunova, Department of Dermatology, Northwestern University, Ward Building 9-332, 303 East Chicago Avenue, Chicago, IL 60611, USA. E-mail: i-budunova@northwestern.edu

⁴These two authors contributed equally to this work.

⁵Current address: Merck Research Laboratories Boston, Boston, MA, USA.

Received 4 May 2005; Revised 27 July 2005; Accepted 27 July 2005; Published online 19 September 2005.

Abstract

A key antiapoptotic transcription factor, nuclear factor kappa-B (NF-B), is known to be critically important for tumor cell growth, angiogenesis and development of metastatic lesions. We and others showed previously that NF-B transcription factor was constitutively activated in androgen-independent prostate carcinoma (PC) cell lines due to the upregulated activity of inhibitor of NF-B kinases (IKK). In this work, using luciferase assay, electrophoretic mobility shift assay and Northern blot analysis of expression of endogenous B-responsive genes, we demonstrate that a novel highly specific small-molecule IKK inhibitor, PS1145, efficiently inhibited both basal and induced NF-B activity in PC cells. We found that PS1145 induced caspase 3/7-dependent apoptosis in PC cells and significantly sensitized PC cells to apoptosis induced by tumor necrosis factor alpha. We also showed that PS1145 inhibited PC cell proliferation. Effects of PS1145 on proliferation and apoptosis correlated with inhibition of interleukin (IL)-6, cyclin D1, D2, inhibitor of apoptosis (IAP)-1 and IAP-2 gene expression and decreased IL-6 protein level. In addition, we found that incubation with PS1145 inhibited the invasion activity of highly invasive PC3-S cells in invasion chamber assay in a dose-dependent manner. Overall, this study provides the framework for development of a novel therapeutic approach targeting NF-B transcription factor to treat advanced PC.