Open AccessAilanthone targets p23 to overcome MDV3100 resistance in castration-resistant prostate cancer
Author(s) -
Yundong He,
Shihong Peng,
Jinhua Wang,
Chen Huang,
Xiaonan Cong,
Ang Chen,
Meichun Hu,
Min Qin,
Haigang Wu,
Shuman Gao,
Liguo Wang,
Xin Wang,
Zhengfang Yi,
Mingyao Liu
Publication year - 2016
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/ncomms13122
Subject(s) - androgen receptor , prostate cancer , cancer research , hsp90 , chemistry , pharmacology , medicine , biology , gene , cancer , biochemistry , heat shock protein
Androgen receptor (AR) antagonist MDV3100 is the first therapeutic approach in treating castration-resistant prostate cancer (CRPC), but tumours frequently become drug resistant via multiple mechanisms including AR amplification and mutation. Here we identify the small molecule Ailanthone (AIL) as a potent inhibitor of both full-length AR (AR-FL) and constitutively active truncated AR splice variants (AR-Vs). AIL binds to the co-chaperone protein p23 and prevents AR's interaction with HSP90, thus resulting in the disruption of the AR-chaperone complex followed by ubiquitin/proteasome-mediated degradation of AR as well as other p23 clients including AKT and Cdk4, and downregulates AR and its target genes in PCa cell lines and orthotopic animal tumours. In addition, AIL blocks tumour growth and metastasis of CRPC. Finally, AIL possesses favourable drug-like properties such as good bioavailability, high solubility, lack of CYP inhibition and low hepatotoxicity. In general, AIL is a potential candidate for the treatment of CRPC.