文章：

mTOR1/2双重抑制剂AZD8055对犬肺癌的抗肿瘤作用

Antitumor Effect of mTOR1/2 Dual Inhibitor AZD8055 in Canine Pulmonary Carcinoma

原文发布日期：14 June 2025

DOI: 10.3390/cancers17121991

类型: Article

开放获取: 是

英文摘要：

Background/Objectives:Primary pulmonary carcinoma (PC) is a malignant neoplasm that occurs in humans, dogs, and other species. In canine PC, palliative care remains the most practical approach for dogs with inoperable PC.Methods:We investigated the effectiveness of mammalian target of rapamycin (mTOR) inhibitors in canine lung cancer upon PI3K/AKT/mTOR activation. Three canine PC cell lines (AZACL1, AZACL2, and cPAC-1) were treated with three mTOR inhibitors (AZD8055, temsirolimus, and everolimus). In vitro, sensitivity assays were conducted to evaluate proliferation and Western blotting was used to examine pathway activation and phosphorylation of mTOR-related protein.Results:AZD8055 had a stronger inhibitory effect on cell proliferation than temsirolimus and everolimus in all three PC cell lines. The IC50for AZD8055 in the AZACL1, AZACL2, and cPAC-1 cell lines were 23.8 μM, 95.8 nM, and 237 nM, for temsirolimus they were 34.6 μM, 11.5 μM, and 11.2 μM, and for everolims they were 36.6 μM, 33.4 μM, and 33.0 μM, respectively. Western blotting revealed PI3K/AKT/mTOR pathway activation and differential phosphorylation of mTOR signal-related proteins across the three PC cell lines. In xenograft mice injected with the AZACL1 and AZACL2 cell lines we showed that the AZD8055-treated group exhibited a significant reduction in tumor volume via the inhibition of tumor growth compared to the control group.Conclusions:These findings reveal that the PI3K/AKT/mTOR pathway plays a key role in canine PC and that AZD8055 may be a novel therapeutic agent for PC-bearing dogs.

摘要翻译： 

背景/目的：原发性肺癌是一种发生于人类、犬类及其他物种的恶性肿瘤。对于无法手术的犬类肺癌患者，姑息治疗仍是最为实用的临床策略。本研究旨在探究哺乳动物雷帕霉素靶蛋白抑制剂在PI3K/AKT/mTOR通路激活状态下对犬肺癌的治疗效果。方法：采用三种mTOR抑制剂（AZD8055、替西罗莫司和依维莫司）处理三种犬肺癌细胞系（AZACL1、AZACL2和cPAC-1）。通过体外敏感性实验评估细胞增殖情况，并运用蛋白质印迹法检测通路激活状态及mTOR相关蛋白磷酸化水平。结果：在所有三种肺癌细胞系中，AZD8055较替西罗莫司和依维莫司表现出更强的细胞增殖抑制作用。AZD8055在AZACL1、AZACL2和cPAC-1细胞系中的IC50值分别为23.8 μM、95.8 nM和237 nM；替西罗莫司对应值为34.6 μM、11.5 μM和11.2 μM；依维莫司则为36.6 μM、33.4 μM和33.0 μM。蛋白质印迹分析显示三种肺癌细胞系均存在PI3K/AKT/mTOR通路激活，且mTOR信号相关蛋白呈现差异化磷酸化状态。在接种AZACL1和AZACL2细胞系的异种移植小鼠模型中，AZD8055治疗组通过抑制肿瘤生长，较对照组表现出显著的肿瘤体积缩减。结论：本研究表明PI3K/AKT/mTOR通路在犬肺癌发生发展中起关键作用，AZD8055可能成为肺癌患犬的新型治疗药物。

原文链接：

Antitumor Effect of mTOR1/2 Dual Inhibitor AZD8055 in Canine Pulmonary Carcinoma