The PI3K/mTOR dual inhibitor GSK458 potently impedes ovarian cancer tumorigenesis and metastasis
The PI3K/mTOR dual inhibitor GSK458 potently impedes ovarian cancer tumorigenesis and metastasis
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PI3K/mTOR双重抑制剂GSK458有效阻止卵巢癌肿瘤发生和转移
DOI：
10.1007/s13402-020-00514-8
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发表时间：
2020
影响因子：
6.6
通讯作者：
Zhang Rong
中科院分区：
文献类型：
--
作者：
Xiao Yangjiong;Yu Yang;Jiang Pengcheng;Li Yuhong;Wang Chao;Zhang Rong
目的PI3K/AKT/mTOR通路是晚期卵巢癌中最活跃的细胞信号通路之一。虽然已经开发出几种PI3K/AKT/mTOR抑制剂来治疗各种类型的癌症，但许多这些化合物对卵巢癌的抗肿瘤功效尚不清楚。方法对16种已进入临床试验的PI3K/AKT/mTOR抑制剂（XL765、米替福星、雷帕霉素、CCI-779、RAD001、FK506、XL147、GSK2110183、IPI-145、GSK2141795、BYL719、GSK458、cal101、XL765类似物SAR245409、tricribine和GDC0941）以及一线药物紫杉醇的抗肿瘤活性进行了检测和比较。体外和体内测定卵巢癌细胞系和患者源性卵巢原发肿瘤细胞系的抗肿瘤效果。结果我们发现PI3K/mTOR双抑制剂GSK458在所有细胞系中都是有效的增殖抑制剂，最大抑制浓度的一半（IC50）约为0.01-1µM，比其他PI3K/AKT/mTOR抑制剂低几十到几百倍。此外，GSK458对卵巢癌细胞迁移的抑制效果最高。GSK458还能抑制裸鼠腹腔内移植SKOV3细胞或患者来源的肿瘤细胞异种移植物（PDCX）的肿瘤生长和转移。重要的是，GSK458在体外对细胞增殖和迁移的抑制效率与紫杉醇相当。从机制上讲，GSK458的抗肿瘤活性与AKT和mTOR的失活以及诱导细胞周期阻滞在G0/G1期有关。基于我们的研究结果，我们得出结论，GSK458可能是治疗卵巢癌的一个有吸引力的候选药物。
PurposeThe PI3K/AKT/mTOR pathway is one of the most highly activated cellular signaling pathways in advanced ovarian cancer. Although several PI3K/AKT/mTOR inhibitors have been developed to treat various types of cancer, the antitumor efficacy of many of these compounds against ovarian cancer has remained unclear.MethodsHere, we tested and compared a panel of 16 PI3K/AKT/mTOR inhibitors (XL765, Miltefosine, Rapamycin, CCI-779, RAD001, FK506, XL147, GSK2110183, IPI-145, GSK2141795, BYL719, GSK458, CAL-101, XL765 analogue SAR245409, Triciribine, and GDC0941) that have entered clinical trials for antitumor activity against ovarian cancer, as well as the front line drug, paclitaxel. Antitumor efficacy was measured in both ovarian cancer cell lines and patient-derived ovarian primary tumor cell linesin vitroandin vivo.ResultsWe identified the PI3K/mTOR dual inhibitor GSK458 as a potent inhibitor of proliferation in all cell lines tested at half maximal inhibitory concentrations (IC50) of approximately 0.01-1 µM, a range tens to hundreds fold lower than that of the other PI3K/AKT/mTOR inhibitors tested. Additionally, GSK458 showed the highest inhibitory efficacy against ovarian cancer cell migration. GSK458 also inhibited tumor growth and metastasis in nude mice intraperitoneally engrafted with SKOV3 cells or a patient-derived tumor cell xenograft (PDCX). Importantly, the inhibitory efficiency of GSK458 on cell proliferation and migration bothin vitroandin vivowas comparable to that of paclitaxel. Mechanistically, the anti-tumor activity of GSK458 was found to be associated with inactivation of AKT and mTOR, and induction of cell cycle arrest at the G0/G1 phase.ConclusionsBased on our results, we conclude that GSK458 may serve as an attractive candidate to treat ovarian cancer.