Document Detail


Cryptotanshinone suppresses androgen receptor-mediated growth in androgen dependent and castration resistant prostate cancer cells.
MedLine Citation:
PMID:  22154085     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Androgen receptor (AR) is the major therapeutic target for the treatment of prostate cancer (PCa). Anti-androgens to reduce or prevent androgens binding to AR are widely used to suppress AR-mediated PCa growth; however, the androgen depletion therapy is only effective for a short period of time. Here we found a natural product/Chinese herbal medicine cryptotanshinone (CTS), with a structure similar to dihydrotestosterone (DHT), can effectively inhibit the DHT-induced AR transactivation and prostate cancer cell growth. Our results indicated that 0.5 μM CTS effectively suppresses the growth of AR-positive PCa cells, but has little effect on AR negative PC-3 cells and non-malignant prostate epithelial cells. Furthermore, our data indicated that CTS could modulate AR transactivation and suppress the DHT-mediated AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive PCa LNCaP cells and castration resistant CWR22rv1 cells. Importantly, CTS selectively inhibits AR without repressing the activities of other nuclear receptors, including ERα, GR, and PR. The mechanistic studies indicate that CTS functions as an AR inhibitor to suppress androgen/AR-mediated cell growth and PSA expression by blocking AR dimerization and the AR-coregulator complex formation. Furthermore, we showed that CTS effectively inhibits CWR22Rv1 cell growth and expressions of AR target genes in the xenograft animal model. The previously un-described mechanisms of CTS may explain how CTS inhibits the growth of PCa cells and help us to establish new therapeutic concepts for the treatment of PCa.
Authors:
Defeng Xu; Tzu-Hua Lin; Shaoshun Li; Jun Da; Xing-Qiao Wen; Jiang Ding; Chawnshang Chang; Shuyuan Yeh
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-10-10
Journal Detail:
Title:  Cancer letters     Volume:  316     ISSN:  1872-7980     ISO Abbreviation:  Cancer Lett.     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-01-09     Completed Date:  2012-05-16     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  7600053     Medline TA:  Cancer Lett     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  11-22     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Affiliation:
School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
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MeSH Terms
Descriptor/Qualifier:
Androgen Receptor Antagonists / pharmacology*
Androgens / metabolism*
Animals
Cell Growth Processes / drug effects
Cell Line, Tumor
Dihydrotestosterone / pharmacology
Dimerization
Drugs, Chinese Herbal / pharmacology
Gene Expression / drug effects
HEK293 Cells
Humans
Male
Mice
Mice, Nude
Orchiectomy
Phenanthrenes / pharmacology*
Prostatic Neoplasms / drug therapy*,  genetics,  metabolism
Receptors, Androgen / genetics,  metabolism*
Salvia miltiorrhiza / chemistry
Transcriptional Activation / drug effects
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
CA156700/CA/NCI NIH HHS; R01 CA156700-02/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Androgen Receptor Antagonists; 0/Androgens; 0/Drugs, Chinese Herbal; 0/Phenanthrenes; 0/Receptors, Androgen; 35825-57-1/cryptotanshinone; 521-18-6/Dihydrotestosterone
Comments/Corrections

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