丹参酮衍生物对前列腺癌细胞的选择性抑制作用。
The selective inhibitory effect of a synthetic tanshinone derivative on prostate cancer cells.
机构信息
Department of Urology, Pathology, Radiation Oncology, George H. Whipple Laboratory for Cancer Research, University of Rochester Medical Center, Rochester, New York, USA.
出版信息
Prostate. 2012 May 15;72(7):803-16. doi: 10.1002/pros.21474. Epub 2011 Sep 19.
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.
背景
雄激素受体（AR）是治疗前列腺癌（PCa）的主要治疗靶点。抗雄激素药物可减少或防止雄激素与 AR 结合，广泛用于抑制 AR 介导的 PCa 生长；然而，去势治疗（ADT）仅在短时间内有效。在这里，我们测试了 PTS33，一种丹参酮的新型钠衍生物，它可以有效抑制 DHT 诱导的 AR 转录激活和 PCa 细胞生长，然后探讨了 PTS33 对抑制 AR 靶基因和蛋白表达的影响。
方法
用 PTS33 处理 PCa 细胞 LNCaP、CWR22Rv1、C4-2、PC-3 和 DU145，用荧光素酶报告基因检测评估其调节 AR 转录激活的能力。用 RT-PCR 评估 AR 靶基因 PSA、TMPRSS2 和 TMEPA1 的 mRNA 水平。用 Western blot 测定 AR、PSA、雌激素受体α（ERα）、糖皮质激素受体（GR）和孕激素受体（PR）蛋白表达。用 MTT 法测定 48 小时后细胞生长和 IC50。
结果
我们的数据表明，PTS33 选择性抑制 AR 活性，但 PTS33 不抑制其他核受体，包括 ERα、GR 和 PR 的活性。在低浓度下，2μM 的 PTS33 可有效抑制 AR 阳性 PCa 细胞的生长，对 AR 阴性 PCa 细胞影响较小。此外，我们的数据表明，PTS33 可调节 AR 转录激活，并抑制雄激素反应性 PCa LNCaP 细胞和去势抵抗性 C4-2 细胞中 AR 靶基因（PSA、TMPRSS2 和 TMEPA1）的表达。此外，PTS33 还可以抑制雌激素/Δ5-雄烯二酮诱导的 AR 活性。机制研究表明，PTS33 通过抑制 AR 蛋白表达、AR N-C 相互作用和 AR 共激活因子相互作用抑制 AR 功能。
结论
PTS33 已显示出良好的疗效，可抑制 AR 转录激活，阻断 AR 调节基因表达，降低 AR 阳性 PCa 细胞的细胞生长。PTS33 的结构可作为开发新型 AR 信号抑制剂治疗 PCa 的基础。
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