Differential Androgen Deprivation Therapies with Anti-androgens ...

1. Tzu-Hua Lin^?,
2. Soo Ok Lee^?,
3. Yuanjie Niu^?,^?,
4. Defeng Xu^?,
5. Liang Liang^?,
6. Lei Li^?,
7. Shauh-Der Yeh^?,
8. Naohiro Fujimoto^?,
9. Shuyuan Yeh^? and
10. Chawnshang Chang^?,^?1

1. From the ^?George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, and the Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York 14642,
2. the ^?Chawnshang Chang Sex Hormone Research Center, Tianjin Institute of Urology, Tianjin Medical University, Tianjin 300211, China, and
3. the ^?Sex Hormone Research Center, China Medical University and Hospital, Taichung 404, Taiwan

1. ?1 To whom correspondence should be addressed. E-mail: chang{at}urmc.rochester.edu.

Background: Androgen deprivation therapy (ADT) suppresses prostate cancer (PCa) growth, yet its effects on PCa metastasis remain unclear.

Results: ADT with MDV3100/enzalutamide or Casodex/bicalutamide versus ASC-J9? led to enhanced versus suppressed PCa metastasis.

Conclusion: Casodex/MDV3100 induces PCa metastasis via modulation of TGF-?1/Smad3/MMP9 signaling.

Significance: Targeting androgen receptor with ASC-J9? is better than targeting androgens with Casodex/MDV3100 to better battle PCa metastasis.

Abstract

Despite the fact that androgen deprivation therapy (ADT) can effectively reduce prostate cancer (PCa) size, its effect on PCa metastasis remains unclear. We examined the existing data on PCa patients treated with ADT plus anti-androgens to analyze ADT effects on primary tumor size, prostate-specific antigen (PSA) values, and metastatic incidence. We found that the current ADT with anti-androgens might lead to primary tumor reduction, with PSA decreased yet metastases increased in some PCa patients. Using in vitro and in vivo metastasis models with four human PCa cell lines, we evaluated the effects of the currently used anti-androgens, Casodex/bicalutamide and MDV3100/enzalutamide, and the newly developed anti-AR compounds, ASC-J9? and cryptotanshinone, on PCa cell growth and invasion. In vitro results showed that 10 ?m Casodex or MDV3100 treatments suppressed PCa cell growth and reduced PSA level yet significantly enhanced PCa cell invasion. In vivo mice studies using an orthotopic xenograft mouse model also confirmed these results. In contrast, ASC-J9? led to suppressed PCa cell growth and cell invasion in in vitro and in vivo models. Mechanism dissection indicated these Casodex/MDV3100 treatments enhanced the TGF-?1/Smad3/MMP9 pathway, but ASC-J9? and cryptotanshinone showed promising anti-invasion effects via down-regulation of MMP9 expression. These findings suggest the potential risks of using anti-androgens and provide a potential new therapy using ASC-J9? to battle PCa metastasis at the castration-resistant stage.

Footnotes

• ?* This work was supported, in whole or in part, by National Institutes of Health Grant CA156700. This work was also supported by the George Whipple Professorship Endowment and Taiwan Department of Health Clinical Trial and Research Center of Excellence Grant DOH99-TD-B-111-004. ASC-J9? was patented by the University of Rochester, University of North Carolina, and AndroScience and then licensed to AndroScience. Both the University of Rochester and C. Chang own royalties and equity in AndroScience.

• ? This article contains supplemental Materials and Methods.

• Received April 12, 2013.
• Revision received May 14, 2013.

• ? 2013 by The American Society for Biochemistry and Molecular Biology, Inc.

Source: http://www.jbc.org/content/288/27/19359.abstract

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