Research and Development Department, Nipro Patch Co., Ltd., 8-1, Minamisakae-cho, Kasukabe, Saitama 344-0057, Japan.
Biochem Biophys Res Commun. 2010 Apr 2;394(2):297-302. doi: 10.1016/j.bbrc.2010.02.164. Epub 2010 Mar 2.
The androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers. The present study demonstrates that the topoisomerase I inhibitor camptothecin selectively inhibits androgen-responsive growth of prostate cancer cells. Camptothecin strikingly inhibited mutated and wild-type AR protein expression in LNCaP and PC-3/AR cells. This inhibition coincided with decreased androgen-mediated AR phosphorylation at Ser(81) and reduced androgen-mediated AR transcriptional activity in a dose-dependent manner. Additionally, camptothecin disrupted the association between AR and heat shock protein 90 and impeded binding of the synthetic androgen [3H]R1881 to AR in LNCaP cells. Camptothecin also blocked androgen-induced AR nuclear translocation, leading to downregulation of the AR target gene PSA. In addition to decreasing the intracellular and secreted prostate-specific antigen (PSA) levels, camptothecin markedly inhibited androgen-stimulated PSA promoter activity. Collectively, our data reveal that camptothecin not only serves as a traditional genotoxic agent but, by virtue of its ability to target and disrupt AR, may also be a novel candidate for the treatment of prostate cancer.
雄激素受体（AR）是治疗转移性前列腺癌的主要治疗靶点。本研究表明，拓扑异构酶 I 抑制剂喜树碱选择性抑制雄激素反应性前列腺癌细胞的生长。喜树碱可显著抑制 LNCaP 和 PC-3/AR 细胞中突变型和野生型 AR 蛋白的表达。这种抑制作用与雄激素介导的 AR 在丝氨酸 81 位磷酸化的减少以及雄激素介导的 AR 转录活性的降低呈剂量依赖性一致。此外，喜树碱破坏了 AR 与热休克蛋白 90 之间的结合，并阻碍了[3H]R1881 与 LNCaP 细胞中 AR 的结合。喜树碱还阻止了雄激素诱导的 AR 核转位，导致 AR 靶基因 PSA 的下调。除了降低细胞内和分泌的前列腺特异性抗原（PSA）水平外，喜树碱还显著抑制了雄激素刺激的 PSA 启动子活性。总的来说，我们的数据表明，喜树碱不仅作为传统的遗传毒性剂，而且由于其靶向和破坏 AR 的能力，也可能成为治疗前列腺癌的一种新的候选药物。
