The selective inhibitory effect of a synthetic tanshinone derivative on prostate cancer cells†
Defeng Xu
Department of Urology, Pathology, Radiation Oncology, George H. Whipple Laboratory for Cancer Research, and The Cancer Center, University of Rochester Medical Center, Rochester, New York
School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P. R. China
Search for more papers by this authorTzu-Hua Lin
Department of Urology, Pathology, Radiation Oncology, George H. Whipple Laboratory for Cancer Research, and The Cancer Center, University of Rochester Medical Center, Rochester, New York
Search for more papers by this authorCaixia Zhang
Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
Search for more papers by this authorYu-Chieh Tsai
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
Search for more papers by this authorShaoshun Li
School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P. R. China
Search for more papers by this authorJing Zhang
School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P. R. China
Search for more papers by this authorMin Yin
School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P. R. China
Search for more papers by this authorCorresponding Author
Shuyuan Yeh
Department of Urology, Pathology, Radiation Oncology, George H. Whipple Laboratory for Cancer Research, and The Cancer Center, University of Rochester Medical Center, Rochester, New York
Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, 601 Elmwood Ave, Box 626, NY 14642.Search for more papers by this authorCorresponding Author
Chawnshang Chang
Department of Urology, Pathology, Radiation Oncology, George H. Whipple Laboratory for Cancer Research, and The Cancer Center, University of Rochester Medical Center, Rochester, New York
School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P. R. China
Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, 601 Elmwood Ave, Box 626, NY 14642.Search for more papers by this authorDefeng Xu
Department of Urology, Pathology, Radiation Oncology, George H. Whipple Laboratory for Cancer Research, and The Cancer Center, University of Rochester Medical Center, Rochester, New York
School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P. R. China
Search for more papers by this authorTzu-Hua Lin
Department of Urology, Pathology, Radiation Oncology, George H. Whipple Laboratory for Cancer Research, and The Cancer Center, University of Rochester Medical Center, Rochester, New York
Search for more papers by this authorCaixia Zhang
Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
Search for more papers by this authorYu-Chieh Tsai
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
Search for more papers by this authorShaoshun Li
School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P. R. China
Search for more papers by this authorJing Zhang
School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P. R. China
Search for more papers by this authorMin Yin
School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P. R. China
Search for more papers by this authorCorresponding Author
Shuyuan Yeh
Department of Urology, Pathology, Radiation Oncology, George H. Whipple Laboratory for Cancer Research, and The Cancer Center, University of Rochester Medical Center, Rochester, New York
Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, 601 Elmwood Ave, Box 626, NY 14642.Search for more papers by this authorCorresponding Author
Chawnshang Chang
Department of Urology, Pathology, Radiation Oncology, George H. Whipple Laboratory for Cancer Research, and The Cancer Center, University of Rochester Medical Center, Rochester, New York
School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P. R. China
Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, 601 Elmwood Ave, Box 626, NY 14642.Search for more papers by this authorDefeng Xu and Tzu-Hua Lin contributed equally to this work.
Abstract
BACKGROUND
Androgen receptor (AR) is the main 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 (ADT) is only effective for a short period of time. Here we tested PTS33, a new sodium derivative of cryptotanshinone, which can effectively inhibit the DHT-induced AR transactivation and PCa cell growth, and then explored the effects of PTS33 on inhibiting the expressions of AR target genes and proteins.
METHODS
PCa cells, LNCaP, CWR22Rv1, C4-2, PC-3, and DU145, were treated with PTS33 and luciferase assay was used to evaluate the ability of each to regulate AR transactivation. RT-PCR was used to evaluate the mRNA levels of AR target genes such as PSA, TMPRSS2, and TMEPA1. Western blot was used to determine AR, PSA, estrogen receptor alpha (ERα), glucocorticoid receptor (GR), and progesterone receptor (PR) protein expression. Cell growth and IC50 were determined by MTT assay after 48 hr treatment.
RESULTS
Our data showed that PTS33 selectively inhibits AR activities, but PTS33 does not repress the activities of other nuclear receptors, including ERα, GR, and PR. At a low concentration, 2 µM of PTS33 effectively suppresses the growth of AR-positive PCa cells, and has little effect on AR-negative PCa cells. Furthermore, our data indicated that PTS33 could modulate AR transactivation and suppress the AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive PCa LNCaP cells and castration-resistant C4-2 cells. In addition, PTS33 can also inhibit estrogen/Δ5-androstenediol induced AR activities. The mechanistic studies indicate that PTS33 can inhibit AR function by suppression of AR protein expression, the AR N–C interaction, and AR–coregulator interaction.
CONCLUSIONS
PTS33 has shown a good efficacy to inhibit AR transactivation, block AR regulated gene expression, and reduce cell growth in AR positive PCa cells. The structure of PTS33 could be used as a base for development of novel AR signaling inhibitors to treat PCa. Prostate 72:803–816, 2012. © 2011 Wiley Periodicals, Inc.
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