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Cryptotanshinone suppresses androgen receptor-mediated growth in androgen dependent and castration resistant prostate
Defeng Xu1, Tzu-Hua Lin, Shaoshun Li
1School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
Abstract:
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 microM 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.
Insights
Cryptotanshinone (CTS), a natural compound, effectively inhibits prostate cancer (PCa) cell growth by blocking androgen receptor (AR) activity. This discovery offers new therapeutic strategies for PCa treatment.
Area of Science:
- Oncology
- Pharmacology
- Natural Products
Background:
- Androgen receptor (AR) is a key target in prostate cancer (PCa) therapy.
- Current anti-androgen therapies face limitations due to short-term effectiveness.
Purpose of the Study:
- To investigate the efficacy of cryptotanshinone (CTS), a natural product, as a novel therapeutic agent for PCa.
- To elucidate the mechanism by which CTS inhibits AR-mediated PCa growth.
Main Methods:
- In vitro studies using AR-positive and AR-negative PCa cell lines (LNCaP, CWR22rv1, PC-3).
- Assessment of CTS effects on AR transactivation, DHT-mediated gene expression (PSA, TMPRSS2, TMEPA1), and cell proliferation.
- In vivo studies using a xenograft animal model.
- Analysis of AR dimerization and AR-coregulator complex formation.
Main Results:
- CTS (0.5 microM) significantly suppressed AR-positive PCa cell growth, with minimal impact on AR-negative cells and non-malignant prostate cells.
- CTS effectively inhibited DHT-induced AR transactivation and expression of AR target genes in both androgen-responsive and castration-resistant PCa cells.
- CTS selectively inhibited AR without affecting other nuclear receptors (ERα, GR, PR).
- Mechanistic studies revealed CTS blocks AR dimerization and AR-coregulator complex formation.
- CTS demonstrated efficacy in inhibiting tumor growth and AR target gene expression in a xenograft model.
Conclusions:
- Cryptotanshinone (CTS) acts as a potent AR inhibitor, offering a promising therapeutic strategy for prostate cancer.
- CTS selectively targets AR, inhibiting cancer cell proliferation and gene expression through novel mechanisms.
- CTS's efficacy in preclinical models suggests its potential for developing new PCa treatments.
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