Synergistic antitumor activity of the combination of salubrinal and rapamycin against human cholangiocarcinoma cells
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Xiaofang Zhao1,*, Chunyan Zhang1,*, Hong Zhou1,*, Bin Xiao1, Ying Cheng1, Jinju Wang2, Fuli Yao1, Chunyan Duan1, Run Chen3, Youping Liu2, Chunhong Feng2, Hong Li1, Jing Li2, Rongyang Dai1
1Department of Biochemistry and Molecular Biology, Southwest Medical University, Luzhou, Sichuan, China
2Department of Hepatobiliary Surgery of the Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
3Department of Public Health, Southwest Medical University, Luzhou, Sichuan, China
*These authors have contributed equally to this work
Rongyang Dai, email: [email protected]
Jing Li, email: [email protected]
Keywords: salubrinal, rapamycin, cholangiocarcinoma, Akt, Bcl-xL
Received: August 20, 2016 Accepted: October 27, 2016 Published: November 16, 2016
Less is known about the roles of eukaryotic initiation factor alpha (eIF2α) in cholangiocarcinoma (CCA). Here, we report that eIF2α inhibitor salubrinal inhibits the proliferation of human CCA cells. Clinical application of mammalian target of rapamycin (mTOR) inhibitors only has moderate antitumor efficacy. Therefore, combination approaches may be required for effective clinical use of mTOR inhibitors. Here, we investigated the efficacy of the combination of salubrinal and rapamycin in the treatment of CCA. Our data demonstrate a synergistic antitumor effect of the combination of salubrinal and rapamycin against CCA cells. Rapamycin significantly inhibits the proliferation of CCA cells. However, rapamycin initiates a negative feedback activation of Akt. Inhibition of Akt by salubrinal potentiates the efficacy of rapamycin both in vitro and in vivo. Additionally, rapamycin treatment results in the up-regulation of Bcl-xL in a xenograft mouse model. It is notable that salubrinal inhibits rapamycin-induced Bcl-xL up-regulation in vivo. Taken together, our data suggest that salubrinal and rapamycin combination might be a new and effective strategy for the treatment of CCA.
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