OSI-027 inhibits pancreatic ductal adenocarcinoma cell proliferation and enhances the therapeutic effect of gemcitabine both in vitro and in vivo.
OSI-027 inhibits pancreatic ductal adenocarcinoma cell proliferation and enhances the therapeutic effect of gemcitabine both in vitro and in vivo.
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OSI-027 抑制胰腺导管腺癌细胞增殖并增强吉西他滨的体外和体内治疗效果。
DOI：
10.18632/oncotarget.4579
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发表时间：
2015-09-22
期刊：
影响因子：
--
通讯作者：
Liang T
中科院分区：
文献类型：
--
作者：
Zhi X;Chen W;Xue F;Liang C;Chen BW;Zhou Y;Wen L;Hu L;Shen J;Bai X;Liang T
尽管相对罕见，胰腺导管腺癌（PDAC）占癌症死亡的很大比例。在本研究中，我们研究了哺乳动物雷帕霉素靶点复合物1 （mTORC1）和mTORC2选择性抑制剂osii -027对PDAC细胞系的体外治疗效果，以及与吉西他滨（GEM）联合治疗的效果。同样，我们在PDAC的异种移植小鼠模型中测试了这两种化合物的功效。OSI-027在G0/G1期显著阻滞细胞周期，抑制Panc-1、BxPC-3和CFPAC-1细胞的增殖，下调mTORC1、mTORC2、phospho-Akt、phospho-p70S6K、phospho-4E-BP1、cyclin D1和cyclin依赖性激酶4 （CDK4）的表达。此外，OSI-027还下调了PDAC细胞的多药耐药(MDR)-1，这与3种PDAC细胞系的化疗耐药和GEM诱导的细胞凋亡增强有关。在体外和体内，OSI-027与GEM联用均表现出协同的细胞毒作用。这是OSI-027对PDAC疗效的第一个证据，可能为新的临床PDAC治疗提供基础。
Despite its relative rarity, pancreatic ductal adenocarcinoma (PDAC) accounts for a large percentage of cancer deaths. In this study, we investigated the in vitro efficacy of OSI-027, a selective inhibitor of mammalian target of rapamycin complex 1 (mTORC1) and mTORC2, to treat PDAC cell lines alone, and in combination with gemcitabine (GEM). Similarly, we tested the efficacy of these two compounds in a xenograft mouse model of PDAC. OSI-027 significantly arrested cell cycle in G0/G1 phase, inhibited the proliferation of Panc-1, BxPC-3, and CFPAC-1 cells, and downregulated mTORC1, mTORC2, phospho-Akt, phospho-p70S6K, phospho-4E-BP1, cyclin D1, and cyclin-dependent kinase 4 (CDK4) in these cells. Moreover, OSI-027 also downregulated multidrug resistance (MDR)-1, which has been implicated in chemotherapy resistance in PDAC cells and enhanced apoptosis induced by GEM in the three PDAC cell lines. When combined, OSI-027 with GEM showed synergistic cytotoxic effects both in vitro and in vivo. This is the first evidence of the efficacy of OSI-027 in PDAC and may provide the groundwork for a new clinical PDAC therapy.