Hellsten Rebecka, Stiehm Anna, Palominos Macarena, Persson Margareta, Bjartell Anders
Department of Translational Medicine, Lund University, Scheelevägen 8, Building 404:A3, Lund SE-223 63, Sweden.
Department of Translational Medicine, Lund University, Scheelevägen 8, Building 404:A3, Lund SE-223 63, Sweden.
Transl Oncol. 2022 Oct;24:101495. doi: 10.1016/j.tranon.2022.101495. Epub 2022 Jul 30.
Enzalutamide is a second-generation anti-androgen which has shown increased survival in patients with metastatic prostate cancer. However, some patients do not respond to this therapy or will develop resistance to treatment over time. Signal Transducer and Activator of Transcription 3 (STAT3) is known to be involved in castration-resistant prostate cancer and to interact with androgen receptor (AR)-signaling. This study aims to investigate the combination enzalutamide and the small molecule STAT3 inhibitor GPB730 for enhanced therapeutic effect in advanced prostate cancer in vitro. The prostate cancer cell lines LNCaP (androgen dependent) and C4-2 (androgen insensitive) were used. The effect of enzalutamide and GPB730, alone and in combination, was investigated on viability and IC values calculated. Enzalutamide and GPB730 treated LNCaP and C4-2 cells were subjected to western blot and QPCR analyses in order to investigate the expression of AR, STAT3 and down-stream targets. C4-2 were less sensitive to growth inhibition by enzalutamide than LNCaP cells. GPB730 enhanced the growth inhibitory effect of enzalutamide in LNCaP and C4-2 cells. The addition of GPB730 to enzalutamide decreased the IC values for enzalutamide by 3.3-fold for LNCaP and by 12-fold for C4-2. In C4-2 cells, GPB730 alone decreased PSA expression and enhanced the enzalutamide induced decrease in NKX3.1 expression. GPB730 and enzalutamide in combination enhanced inhibition of c-myc and survivin expression. This study suggests that enzalutamide may be combined with the STAT3 inhibitor GPB730 in order to enhance the efficacy of enzalutamide, offering a new therapeutic approach in advanced prostate cancer.
恩杂鲁胺是一种第二代抗雄激素药物，已显示可提高转移性前列腺癌患者的生存率。然而，一些患者对这种治疗没有反应，或者随着时间的推移会对治疗产生耐药性。已知信号转导和转录激活因子3（STAT3）参与去势抵抗性前列腺癌，并与雄激素受体（AR）信号通路相互作用。本研究旨在探讨恩杂鲁胺与小分子STAT3抑制剂GPB730联合使用对晚期前列腺癌体外治疗效果的增强作用。使用了前列腺癌细胞系LNCaP（雄激素依赖性）和C4-2（雄激素不敏感）。研究了恩杂鲁胺和GPB730单独及联合使用对细胞活力和计算所得IC值的影响。对经恩杂鲁胺和GPB730处理的LNCaP和C4-2细胞进行蛋白质免疫印迹和定量聚合酶链反应分析，以研究AR、STAT3及其下游靶点的表达。C4-2细胞对恩杂鲁胺生长抑制的敏感性低于LNCaP细胞。GPB730增强了恩杂鲁胺对LNCaP和C4-2细胞的生长抑制作用。在恩杂鲁胺中添加GPB730可使LNCaP细胞的恩杂鲁胺IC值降低3.3倍，使C4-2细胞的IC值降低12倍。在C4-2细胞中，单独使用GPB730可降低前列腺特异性抗原（PSA）表达，并增强恩杂鲁胺诱导的NKX3.1表达降低。GPB730与恩杂鲁胺联合使用可增强对c-myc和生存素表达的抑制作用。本研究表明，恩杂鲁胺可与STAT3抑制剂GPB730联合使用，以增强恩杂鲁胺的疗效，为晚期前列腺癌提供一种新的治疗方法。
