Differential androgen deprivation therapies with anti-androgens casodex/bicalutamide or MDV3100/Enzalutamide versus anti-androgen receptor ASC-J9® lead to promotion versus suppression of prostate cancer metastasis

Tzu Hua Lin, Soo Ok Lee, Yuanjie Niu, Defeng Xu, Liang Liang, Lei Li, Shauh Der Yeh, Naohiro Fujimoto, Shuyuan Yeh, Chawnshang Chang

Research output: Contribution to journalArticle

66 Citations (Scopus)

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 μM 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-β1/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.

Original languageEnglish
Pages (from-to)19359-19369
Number of pages11
JournalJournal of Biological Chemistry
Volume288
Issue number27
DOIs
Publication statusPublished - Jul 5 2013
Externally publishedYes

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Androgen Receptors
Androgens
Prostatic Neoplasms
Neoplasm Metastasis
Cell growth
Prostate-Specific Antigen
Therapeutics
Tumors
Dissection
Growth
bicalutamide
MDV 3100
Heterografts
Castration
Cells
Neoplasms
Down-Regulation
Cell Line
Incidence

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Differential androgen deprivation therapies with anti-androgens casodex/bicalutamide or MDV3100/Enzalutamide versus anti-androgen receptor ASC-J9® lead to promotion versus suppression of prostate cancer metastasis. / Lin, Tzu Hua; Lee, Soo Ok; Niu, Yuanjie; Xu, Defeng; Liang, Liang; Li, Lei; Yeh, Shauh Der; Fujimoto, Naohiro; Yeh, Shuyuan; Chang, Chawnshang.

In: Journal of Biological Chemistry, Vol. 288, No. 27, 05.07.2013, p. 19359-19369.

Research output: Contribution to journalArticle

Lin, Tzu Hua ; Lee, Soo Ok ; Niu, Yuanjie ; Xu, Defeng ; Liang, Liang ; Li, Lei ; Yeh, Shauh Der ; Fujimoto, Naohiro ; Yeh, Shuyuan ; Chang, Chawnshang. / Differential androgen deprivation therapies with anti-androgens casodex/bicalutamide or MDV3100/Enzalutamide versus anti-androgen receptor ASC-J9® lead to promotion versus suppression of prostate cancer metastasis. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 27. pp. 19359-19369.
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AU - Lee, Soo Ok

AU - Niu, Yuanjie

AU - Xu, Defeng

AU - Liang, Liang

AU - Li, Lei

AU - Yeh, Shauh Der

AU - Fujimoto, Naohiro

AU - Yeh, Shuyuan

AU - Chang, Chawnshang

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AB - 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 μM 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-β1/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.

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