Prostate cancer (PCa) progression is characterized by increased expression and transcriptional activity of the androgen receptor (AR). In the advanced stages of prostate cancer, AR significantly upregulates the expression of genes involved in DNA repair. Upregulation of expression for base excision repair (BER) related genes is associated with poor patient survival. Thus, inhibition of the BER pathway may prove to be an effective therapy for prostate cancer. Using a high throughput BER capacity screening assay, we sought to identify BER inhibitors that can synergize with castration therapy. An FDA-approved drug library was screened to identify inhibitors of BER using a fluorescence-based assay suitable for HTS. A gel-based secondary assay confirmed the reduction of BER capacity by compounds identified in the primary screen. Five compounds were then selected for further testing in the independently derived, androgen-dependent prostate cancer cell lines, LNCaP and LAPC4, and in the nonmalignant prostate derived cell lines PNT1A and RWPE1. Further analysis led to the identification of a lead compound, natamycin, as an effective inhibitor of key BER enzymes DNA polymerase β (pol β) and DNA Ligase I (LIG I). Natamycin significantly inhibited proliferation of PCa cells in an androgen depleted environment at 1 μM concentration, however, growth inhibition did not occur with nonmalignant prostate cell lines, suggesting that BER inhibition may improve efficacy of the castration therapies.

中文翻译：

---

游霉素抑制碱基切除修复可抑制前列腺癌细胞增殖。

前列腺癌 (PCa) 进展的特点是雄激素受体 (AR) 的表达和转录活性增加。在前列腺癌的晚期阶段，AR 显着上调参与 DNA 修复的基因的表达。碱基切除修复（BER）相关基因表达上调与患者生存率低相关。因此，抑制 BER 通路可能被证明是治疗前列腺癌的有效方法。使用高通量 BER 容量筛选试验，我们试图找出可以与去势疗法协同作用的 BER 抑制剂。使用适合 HTS 的基于荧光的测定法对 FDA 批准的药物库进行筛选，以鉴定 BER 抑制剂。基于凝胶的二次测定证实了初级筛选中鉴定的化合物降低了 BER 容量。然后选择五种化合物在独立衍生的雄激素依赖性前列腺癌细胞系 LNCaP 和 LAPC4 以及非恶性前列腺衍生细胞系 PNT1A 和 RWPE1 中进行进一步测试。进一步的分析确定了一种先导化合物游霉素，它是 BER 关键酶 DNA 聚合酶 β (pol β) 和 DNA 连接酶 I (LIG I) 的有效抑制剂。1 μM 浓度的纳他霉素可显着抑制雄激素耗尽环境中 PCa 细胞的增殖，但非恶性前列腺细胞系并未出现生长抑制，表明 BER 抑制可提高去势疗法的疗效。