Zhi Xiao, Chen Wei, Xue Fei, Liang Chao, Chen Bryan Wei, Zhou Yue, Wen Liang, Hu Liqiang, Shen Jian, Bai Xueli, Liang Tingbo
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R.China.
Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P.R.China.
Oncotarget. 2015 Sep 22;6(28):26230-41. doi: 10.18632/oncotarget.4579.
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.
尽管胰腺导管腺癌（PDAC）相对罕见，但在癌症死亡中占很大比例。在本研究中，我们研究了雷帕霉素复合物1（mTORC1）和mTORC2的选择性抑制剂OSI-027单独治疗PDAC细胞系以及与吉西他滨（GEM）联合使用时的体外疗效。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疗效。OSI-027显著使细胞周期停滞在G0/G1期，抑制Panc-1、BxPC-3和CFPAC-1细胞的增殖，并下调这些细胞中的mTORC1、mTORC2、磷酸化Akt、磷酸化p70S6K、磷酸化4E-BP1、细胞周期蛋白D1和细胞周期蛋白依赖性激酶4（CDK4）。此外，OSI-027还下调多药耐药（MDR）- 1，其与PDAC细胞的化疗耐药有关，并增强了吉西他滨在三种PDAC细胞系中诱导的细胞凋亡。联合使用时，OSI-027与吉西他滨在体外和体内均显示出协同细胞毒性作用。这是OSI-027在PDAC中疗效的首个证据，可能为新的临床PDAC治疗奠定基础。
