Dual PI3K/mTOR Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma
Dual PI3K/mTOR Inhibitors, GSK2126458 and PKI-587, Suppress Tumor Progression and Increase Radiosensitivity in Nasopharyngeal Carcinoma
复制标题
PI3K/mTOR 双重抑制剂 GSK2126458 和 PKI-587 可抑制肿瘤进展并增加鼻咽癌的放射敏感性
DOI：
10.1158/1535-7163.mct-14-0548
复制
发表时间：
2015-02-01
影响因子：
5.7
通讯作者：
Wang, Wei
中科院分区：
文献类型：
--
作者：
Liu, Tongxin;Sun, Quanquan;Wang, Wei
虽然联合放化疗已经为鼻咽癌（NPC）提供了相当大的改善，但复发和转移仍然很频繁。PI3K/Akt/mTOR通路在辐射诱导DNA损伤后的肿瘤形成和肿瘤细胞存活中起关键作用。在本研究中，我们评估了两种新型双抑制剂GSK2126458和PKI-587对PI3K/mTOR的抑制是否可以抑制肿瘤进展并使鼻咽癌细胞对辐射敏感。采用4株鼻鼻癌细胞系（CNE-1、CNE-2、5-8F和6-10B）分析GSK216458和pk587对辐射后细胞增殖、迁移、侵袭、克隆存活、γ-H2AX残灶数量、细胞周期和凋亡的影响。采用5-8F异种移植物模型评价两种化合物与电离辐射（IR）联合作用的体内效应。GSK216458和pk587均能有效抑制鼻鼻癌细胞的增殖和运动，并以浓度和时间依赖性的方式抑制Akt、mTOR、S6和4EBP1蛋白的磷酸化。此外，这两种化合物通过增加DNA损伤、增强G2-M细胞周期延迟和诱导细胞凋亡，使鼻咽癌细胞对IR敏感。在体内，IR与GSK2126458或PKI-587联合使用可显著抑制肿瘤生长。抗肿瘤作用与诱导细胞凋亡和抑制mTOR、Akt和4EBP1的磷酸化有关。这些新发现提示PI3K/mTOR双重抑制在抗肿瘤和放射增敏方面的有效性。IR联合双PI3K/mTOR抑制剂GSK2126458或PKI-587可能是一种很有前景的鼻咽癌治疗策略。巨蟹座；14 (2);429 - 39。AACR©2014。
Although combined chemoradiotherapy has provided considerable improvements for nasopharyngeal carcinoma (NPC), recurrence and metastasis are still frequent. The PI3K/Akt/mTOR pathway plays a critical role in tumor formation and tumor cell survival after radiation-induced DNA damage. In the present study, we evaluated whether inhibition of PI3K/mTOR by two novel dual inhibitors, GSK2126458 and PKI-587, could suppress tumor progression and sensitize NPC cells to radiation. Four NPC cell lines (CNE-1, CNE-2, 5-8F, and 6-10B) were used to analyze the effects of GSK216458 and PKI-587 on cell proliferation, migration, invasion, clonogenic survival, amount of residual γ-H2AX foci, cell cycle, and apoptosis after radiation. A 5-8F xenograft model was used to evaluate the in vivo effects of the two compounds in combination with ionizing radiation (IR). Both GSK216458 and PKI-587 effectively inhibited cell proliferation and motility in NPC cells and suppressed phosphorylation of Akt, mTOR, S6, and 4EBP1 proteins in a concentration- and time-dependent manner. Moreover, both compounds sensitized NPC cells to IR by increasing DNA damage, enhancing G2–M cell-cycle delay, and inducing apoptosis. In vivo, the combination of IR with GSK2126458 or PKI-587 significantly inhibited tumor growth. Antitumor effect was correlated with induction of apoptosis and suppression of the phosphorylation of mTOR, Akt, and 4EBP1. These new findings suggest the usefulness of PI3K/mTOR dual inhibition for antitumor and radiosensitizing. The combination of IR with a dual PI3K/mTOR inhibitor, GSK2126458 or PKI-587, might be a promising therapeutic strategy for NPC. Mol Cancer Ther; 14(2); 429–39. ©2014 AACR.