依西美坦与恩杂鲁胺联合应用对去势抵抗性前列腺癌具有协同作用。

IU1 and enzalutamide combination yields synergistic effects on castration-resistant prostate cancer.

机构信息

Department of Urology, Nanfang Hospital, Southern Medical University, Guangdong, Guangzhou, China.

出版信息

Prostate. 2023 Nov;83(15):1446-1457. doi: 10.1002/pros.24607. Epub 2023 Aug 7.

DOI:10.1002/pros.24607

PMID:37545197

Abstract

BACKGROUND

Androgen deprivation therapy (ADT) is one of the main treatment modalities for prostate cancer (PCa); however, almost all patients treated with ADT eventually progress into castration-resistant PCa (CRPC). Although second-generation androgen receptor (AR) antagonists, such as enzalutamide, have been approved for CRPC treatment, AR signaling in CRPC cells is reactivated through multiple mechanisms, resulting in resistance to treatment and tumor progression with a very poor prognosis. The present study aimed to explore the anticancer effect of a treatment combining AR antagonist enzalutamide with AR degrader IU1 on PCa cells.

METHODS

The joint effects of enzalutamide and IU1 on PCa cell proliferation and apoptosis and associated cell signaling were evaluated in vitro. Mechanistically, the ubiquitination level and half-life of AR were examined under the combination treatment. The binding of IU1 and enzalutamide to AR was further verified using cellular thermal shift analysis and isothermal dose-response curve fingerprinting.

RESULTS

The combination of IU1 and three AR antagonists showed synergistic effects in different prostate cell lines. IU1 and enzalutamide synergistically promoted the degradation of AR and AR-V7 proteins, as well as suppressed the expression levels of AR and AR-V7 downstream target genes at the transcriptional and protein levels. The combination also synergistically blocked the PCa cell cycle and promoted apoptosis in PCa cell lines. Mechanistically, the combination promoted increased levels of AR ubiquitination. In CRPC cell lines and in the presence of increased androgen concentrations, enzalutamide was still able to bind AR competitively with androgens, reducing the stability of AR and thus promoting the degradation effect of IU1 on AR, synergistically producing an inhibitory effect on PCa cells.

CONCLUSION

Taken together, our findings suggest that the combination of AR degrader and enzalutamide potentially represents a new therapeutic strategy for CRPC.

摘要

背景

雄激素剥夺疗法（ADT）是前列腺癌（PCa）的主要治疗方式之一；然而，几乎所有接受 ADT 治疗的患者最终都会进展为去势抵抗性前列腺癌（CRPC）。尽管第二代雄激素受体（AR）拮抗剂，如恩扎卢胺，已被批准用于 CRPC 治疗，但 CRPC 细胞中的 AR 信号通过多种机制被重新激活，导致对治疗产生耐药性，肿瘤进展，并预后极差。本研究旨在探讨 AR 拮抗剂恩扎卢胺与 AR 降解剂 IU1 联合治疗对 PCa 细胞的抗癌作用。

方法

在体外评估恩扎卢胺和 IU1 联合对 PCa 细胞增殖和凋亡及相关细胞信号的影响。从机制上研究了联合治疗下 AR 的泛素化水平和半衰期。进一步使用细胞热转移分析和等温剂量反应曲线指纹图谱验证了 IU1 和恩扎卢胺与 AR 的结合。

结果

IU1 与三种 AR 拮抗剂联合在不同的前列腺细胞系中表现出协同作用。IU1 和恩扎卢胺协同促进 AR 和 AR-V7 蛋白的降解，并在转录和蛋白水平上抑制 AR 和 AR-V7 下游靶基因的表达水平。该联合还协同阻断 PCa 细胞周期并促进 PCa 细胞系中的细胞凋亡。从机制上讲，联合治疗促进了 AR 泛素化水平的增加。在 CRPC 细胞系中并存在增加的雄激素浓度下，恩扎卢胺仍然能够与雄激素竞争性结合 AR，降低 AR 的稳定性，从而促进 IU1 对 AR 的降解作用，协同产生对 PCa 细胞的抑制作用。