Oncotarget

Research Papers:

OSI-027 inhibits pancreatic ductal adenocarcinoma cell proliferation and enhances the therapeutic effect of gemcitabine both in vitro and in vivo

Xiao Zhi, Wei Chen, Fei Xue, Chao Liang, Bryan Wei Chen, Yue Zhou, Liang Wen, Liqiang Hu, Jian Shen, Xueli Bai and Tingbo Liang _

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Oncotarget. 2015; 6:26230-26241. https://doi.org/10.18632/oncotarget.4579

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Abstract

Xiao Zhi1,*, Wei Chen1,*, Fei Xue1, Chao Liang1, Bryan Wei Chen1, Yue Zhou1, Liang Wen1, Liqiang Hu1, Jian Shen1, Xueli Bai1,2, Tingbo Liang1,2,3

1Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, P.R.China

2Key Laboratory of Cancer Prevention and Intervention, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P.R.China

3Collaborative Innovation Center for Cancer Medicine, Zhejiang University, Hangzhou, P.R.China

*These authors have contributed equally to this work

Correspondence to:

Tingbo Liang, e-mail: [email protected]

Xueli Bai, e-mail: [email protected]

Keywords: PDAC, mTOR, OSI-027, gemcitabine, multidrug resistance

Received: April 06, 2015     Accepted: July 10, 2015     Published: July 21, 2015

ABSTRACT

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.


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