2287

Proteasome inhibitor bortezomib (PS-341) has been shown to confer antitumor activity in a number of malignancies including prostate cancer. Its primary mechanism of action is postulated to be mitigated through the inhibition of the nuclear translocation/activation of the nuclear factor kB (NF-kB). However, additional mechanisms may account for the drug’s potent cytotoxic activity. In this report we set out to investigate possible additional mechanisms that could account for bortezomib’s activity in prostate cancer. Bortezomib was very effective in inhibiting the growth of both PC-3 and LNCaP human prostate cancer cell lines with IC50s (approximately 15 to 25 nM) that are clinically relevant. When these cells were exposed to bortezomib, cells rapidly underwent G2/M arrest at 24 h followed by a dramatic increase of apoptotic cell death at 48 h, indicating that bortezomib inhibited cell growth through induction of growth arrest and apoptosis. In conjunction with growth arrest and apoptosis, we found that bortezomib inhibited the levels of phosphorylated Akt in these cell lines, suggesting that suppression of Akt signaling pathway may play a role in mediating bortezomib-induced growth arrest and apoptosis. In addition, we found that bortezomib reduced the levels of the androgen receptor (AR) and its downstream target PSA in a dose dependent fashion in the AR-expressing LNCaP cell line. Down regulation of the AR may be central to the drug’s activity in advanced prostate cancer since functional AR is reported in the vast majority of clinical specimens from patients with androgen independent prostate cancer. Therefore, we are currently investigating how bortezomib down-regulates AR expression. Furthermore, we are interested in probing the potential synergy of bortezomib with non-cytotoxic steroids as it relates to the inhibition of redundant signaling pathways that allow survival and proliferation in androgen independent prostate cancer.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]