School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
Cancer Lett. 2012 Mar;316(1):11-22. doi: 10.1016/j.canlet.2011.10.006. Epub 2011 Oct 10.
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 μM 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.
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预防雄激素与 AR 的结合，从而广泛用于抑制 AR 介导的 PCa 生长；然而，去势雄激素治疗仅在短时间内有效。在这里，我们发现一种天然产物/中药隐丹参酮（CTS），其结构与二氢睾酮（DHT）相似，可有效抑制 DHT 诱导的 AR 转录激活和前列腺癌细胞生长。我们的结果表明，0.5μM CTS 可有效抑制 AR 阳性 PCa 细胞的生长，但对 AR 阴性 PC-3 细胞和非恶性前列腺上皮细胞几乎没有影响。此外，我们的数据表明 CTS 可以调节 AR 转录激活，并抑制 DHT 介导的 AR 靶基因（PSA、TMPRSS2 和 TMEPA1）在雄激素反应性 PCa LNCaP 细胞和去势抵抗 CWR22rv1 细胞中的表达。重要的是，CTS 选择性地抑制 AR，而不抑制其他核受体（包括 ERα、GR 和 PR）的活性。机制研究表明，CTS 作为 AR 抑制剂通过阻断 AR 二聚体和 AR 共激活子复合物的形成来抑制雄激素/AR 介导的细胞生长和 PSA 表达。此外，我们在异种移植动物模型中显示 CTS 有效抑制 CWR22Rv1 细胞生长和 AR 靶基因的表达。CTS 的先前未描述的作用机制可以解释 CTS 如何抑制 PCa 细胞的生长，并帮助我们为治疗 PCa 建立新的治疗概念。
