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A water‐soluble parthenolide analogue suppresses in vivo prostate cancer growth by targeting NFκB and generating reactive oxygen species
Author(s) -
Shanmugam Rajasubramaniam,
Kusumanchi Praveen,
Cheng Liang,
Crooks Peter,
Neelakantan Sundar,
Matthews William,
Nakshatri Harikrishna,
Sweeney Christopher J.
Publication year - 2010
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21141
Subject(s) - parthenolide , in vivo , prostate cancer , reactive oxygen species , cancer research , medicine , nf κb , cancer , prostate , oxygen , chemistry , biology , apoptosis , biochemistry , inflammation , microbiology and biotechnology , organic chemistry
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 NFκB 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 NFκB DNA binding and expression of NFκB‐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 CWR22Rv1 and PC‐3 cellular proliferation by 100% with 10 and 20 µM 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 NFκB. Its in vivo activity supports the conduct of clinical trials in patients with castrate‐resistant disease. Prostate 70: 1074–1086, 2010. © 2010 Wiley‐Liss, Inc.