A Water-Soluble Parthenolide Analogue Suppresses In Vivo Prostate Cancer Growth by Targeting NFκB and Generating Reactive Oxygen Species

BACKGROUND. To characterize the molecular changes associated with DMAPT-induced prostate cancer cell death and its in vivo activity. METHODS. CWR22Rv1 and PC-3 were subjected to flow cytometry, electrophoretic mobility shift assays, and Western blot studies to measure DMAPT's ability to generate reactive oxygen species (ROS), inhibit NF kappa B DNA binding, and cause changes in anti-apoptotic proteins. N-acetyl cysteine (NAC) and short hairpin RNA (shRNA) were used to determine the contribution of ROS and JNK2 activation, respectively. The BrdU incorporation assay was used to measure proliferation and trypan blue studies assessed cell viability after DMAPT treatment. The in vivo activity of DMAPT as a single agent and in combination with bicalutamide or docetaxel was assessed in a subcutaneous xenograft model with athymic nude female mice. RESULTS. DMAPT generated ROS with subsequent JNK activation and inhibited NF kappa B DNA binding and expression of NF kappa B-regulated anti-apoptotic proteins. DMAPT increased necrotic and apoptotic cell death in a cell-type-dependent manner and both types of cell death were blocked by NAC. Additionally, shRNA JNK2 partially blocked the anti-proliferative activity of DMAPT. DMAPT inhibited CWR22Ryl and PC-3 cellular proliferation by 100% with 10 and 20 mu M respectively and in vivo, DMAPT was more effective at inhibiting growth than biclutamide (CWR22v1) and docetaxel (PC-3). CONCLUSIONS. DMAPT promotes cell death by both generating ROS and inhibition of NF kappa B. Its in vivo activity supports the conduct of clinical trials in patients with castrate-resistant disease. Prostate 70: 1074-1086, 2010. (C) 2010 Wiley-Liss, Inc.