文章：

生长激素释放激素（GHRH）拮抗肽联合PI3K亚型抑制剂增强前列腺癌细胞死亡

Growth Hormone-Releasing Hormone (GHRH) Antagonist Peptides Combined with PI3K Isoform Inhibitors Enhance Cell Death in Prostate Cancer

原文发布日期：13 May 2025

DOI: 10.3390/cancers17101643

类型: Article

开放获取: 是

英文摘要：

Background. Antagonists of GHRH have experimental therapeutic value, but as single agents are not likely to improve clinical outcomes, especially in advanced prostate cancer resistant to androgen deprivation therapy. Our objective is to identify anti-cancer drugs that, in combination with MIA-602 or -690 GHRH antagonists, increase cell death in all types of prostate cancer. Methods/Results. We identified inhibitors of PI3Kα or PI3Kβ that consistently increased cell death when combined with MIA-602/690. The PI3K family is critical in mediating upstream signals from receptors to downstream AKT/mTOR signaling pathways and has an important role in cancer progression. The results revealed that MIA-602/690 alone decreased androgen receptors and likely enhanced PI3K (negative feedback), which was then countered by the addition of PI3K inhibitors. Furthermore, the MIA-602/690 + PI3K inhibitor combination affected multiple signaling pathways, including apoptosis (anti-apoptotic Mcl-1L switching to pro-apoptotic Mcl-1S), proliferation (E2F1, cyclin A), PI3Kα/β, AKT, and ERK. Similar results were obtained with a more clinically relevant acetate salt form of MIA-602/690. The identification of PI3K as a drug target for prostate cancer is significant because PTEN (negative regulator of PI3K) loss of function occurs in 40–50% and PIK3CA mutation/amplification occurs in 60% of prostate cancer patients, leading to a poor prognosis. Conclusion. The ability of the MIA-602/690 + PI3K inhibitor combination to alter multiple signaling pathways may weaken the activation of adaptive mechanisms resulting from each drug and improve efficacy.

摘要翻译： 

背景：生长激素释放激素（GHRH）拮抗剂具有实验性治疗价值，但作为单一药物可能无法改善临床结局，尤其是在对雄激素剥夺疗法产生耐药性的晚期前列腺癌中。本研究旨在筛选与MIA-602或MIA-690型GHRH拮抗剂联用时可增强各类前列腺癌细胞死亡效应的抗癌药物。方法/结果：研究发现PI3Kα或PI3Kβ抑制剂与MIA-602/690联用能持续增强细胞死亡效应。PI3K家族在介导受体至下游AKT/mTOR信号通路的上游信号传导中起关键作用，对癌症进展具有重要影响。结果显示，单独使用MIA-602/690可降低雄激素受体水平并可能增强PI3K信号（负反馈效应），而联用PI3K抑制剂可抵消该效应。此外，MIA-602/690与PI3K抑制剂联用可影响多条信号通路，包括凋亡通路（抗凋亡蛋白Mcl-1L向促凋亡蛋白Mcl-1S转换）、增殖通路（E2F1、细胞周期蛋白A）、PI3Kα/β通路、AKT通路及ERK通路。使用临床相关性更高的MIA-602/690醋酸盐形式亦获得相似结果。将PI3K确定为前列腺癌药物靶点具有重要意义，因为在前列腺癌患者中，40-50%存在PI3K负调控因子PTEN功能缺失，60%存在PIK3CA突变/扩增，这些变异均导致不良预后。结论：MIA-602/690与PI3K抑制剂联用可通过改变多条信号通路，削弱各药物引发的适应性机制激活，从而提升治疗效果。

原文链接：

Growth Hormone-Releasing Hormone (GHRH) Antagonist Peptides Combined with PI3K Isoform Inhibitors Enhance Cell Death in Prostate Cancer