雄激素受体抑制剂联合顺铂治疗膀胱癌有效。

Combination of androgen receptor inhibitor and cisplatin, an effective treatment strategy for urothelial carcinoma of the bladder.

机构信息

Department of Urology, University of Louisville, Louisville, KY.

Department of Pathology, University of Louisville, Louisville, KY.

出版信息

Urol Oncol. 2019 Jul;37(7):492-502. doi: 10.1016/j.urolonc.2019.03.008. Epub 2019 Apr 18.

DOI:10.1016/j.urolonc.2019.03.008

PMID:31006613

Abstract

PURPOSE

The role of androgen receptor (AR) signaling in bladder cancer (BCa) is not fully characterized. This study aimed to delineate the role of AR signaling in BCa and to determine whether the combination of AR inhibitor, Enzalutamide (Enz), and Cisplatin (Cis) efficiently inhibit the growth of BCa cells.

METHODS

AR expression was determined in 89 human urothelial BCa specimens by immunohistochemistry. A panel of BCa cell lines was treated with Cis, Enz, or a combination of both (Enz + Cis). We determined the expression of AR, changes in apoptotic signaling, DNA damage, and analyzed effect on epithelial mesenchymal transformation markers.

RESULT

AR expression was detected in 61.4% of tumors from male BCa patients. Inhibition of AR signaling by Enz effectively inhibited the growth of AR BCa cells by inducing apoptosis (26%) in AR TCCSUP (P = 0.0201) and J82 (15%, P = 0.0386) cells. Interestingly, Enz + Cis synergistically inhibited the proliferation of BCa cells even at low concentrations by inducing proapoptotic signaling in AR BCa cells. Invasive and migratory potential of TCCSUP and J82 cells were reduced with Enz + Cis treatment, and associated with down-regulation of mesenchymal markers.

CONCLUSIONS

A high percentage of the bladder tumors from male patients in our cohort expressed AR. The combination of Enz and Cis synergistically inhibited growth of BCa cells more efficiently than single agent alone. This supports the rationale for future investigation of AR antagonists in combination with standard chemotherapy in MIBC.

摘要

目的

雄激素受体（AR）信号在膀胱癌（BCa）中的作用尚未完全阐明。本研究旨在阐明 AR 信号在 BCa 中的作用，并确定 AR 抑制剂恩杂鲁胺（Enz）与顺铂（Cis）联合应用是否能有效抑制 BCa 细胞的生长。

方法

通过免疫组织化学法检测 89 例人尿路上皮 BCa 标本中 AR 的表达。用 Cis、Enz 或两者联合（Enz+Cis）处理一组 BCa 细胞系。我们测定了 AR 的表达、凋亡信号的变化、DNA 损伤，并分析了对上皮间质转化标志物的影响。

结果

从男性 BCa 患者的肿瘤中检测到 61.4%的肿瘤表达 AR。AR 信号的抑制通过诱导 AR TCCSUP（P=0.0201）和 J82（15%，P=0.0386）细胞中的凋亡（26%）有效地抑制了 AR BCa 细胞的生长。有趣的是，即使在低浓度下，Enz+Cis 也能通过诱导 AR BCa 细胞中的促凋亡信号协同抑制 BCa 细胞的增殖。TCCSUP 和 J82 细胞的侵袭和迁移能力在 Enz+Cis 治疗后降低，与间充质标志物的下调有关。