Department of Research and Development, Nipro Patch Co., Ltd., Kasukabe, Saitama, Japan.
Oncol Rep. 2010 Jan;23(1):165-70.
Androgen and androgen receptor (AR)-mediated signaling are crucial for the development of prostate cancer. The present study indicates that the topoisomerase II inhibitor etoposide strikingly inhibits androgen/AR-mediated cell growth and androgen-stimulated DNA synthesis in prostate cancer cells. Etoposide significantly repressed the AR mRNA and protein expression in a dose-dependent manner. Etoposide-mediated down-regulation of AR was associated with blocking androgen-induced AR translocation from cytoplasm into nucleus of cells. Additionally, etoposide disrupted the association of AR and heat shock protein 90 and impeded binding of the synthetic androgen [3H]R1881 to AR in LNCaP cells. Etoposide simultaneously reduced the intracellular and secreted PSA levels, a marker for the progression of prostate cancer. These findings collectively reveal that etoposide not only serves as a traditional genotoxic agent but directly targets AR as an AR disrupting therapeutic strategy in prostate cancer.
雄激素和雄激素受体（AR）介导的信号转导对前列腺癌的发展至关重要。本研究表明，拓扑异构酶 II 抑制剂依托泊苷可显著抑制前列腺癌细胞中雄激素/AR 介导的细胞生长和雄激素刺激的 DNA 合成。依托泊苷以剂量依赖性方式显著抑制 AR mRNA 和蛋白表达。依托泊苷介导的 AR 下调与阻断雄激素诱导的 AR 从细胞质向细胞核易位有关。此外，依托泊苷破坏了 AR 和热休克蛋白 90 的结合，并阻碍了合成雄激素[3H]R1881与 LNCaP 细胞中 AR 的结合。依托泊苷同时降低了细胞内和分泌的 PSA 水平，PSA 是前列腺癌进展的标志物。这些发现共同揭示，依托泊苷不仅作为一种传统的遗传毒性药物，而且还直接靶向 AR，作为一种 AR 破坏的治疗策略用于前列腺癌。
