title: Synergistic antitumor activity of the combination of salubrinal and rapamycin against human cholangiocarcinoma cells.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Molecular Biology, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xiao
authors.affiliation: Department of Biochemistry and Molecular Biology, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Hepatobiliary Surgery of the Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Jinju
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Fuli
authors.initials: F
authors.lastname: Yao
authors.affiliation: Department of Biochemistry and Molecular Biology, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Duan
authors.affiliation: Department of Public Health, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Run
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Hepatobiliary Surgery of the Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Youping
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery of the Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Feng
authors.affiliation: Department of Biochemistry and Molecular Biology, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery of the Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Southwest Medical University, Luzhou, Sichuan, China.
authors.forename: Rongyang
authors.initials: R
authors.lastname: Dai
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002934:Cinnamates / Q000494:pharmacology*; D004357:Drug Synergism; D015852:Eukaryotic Initiation Factor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008297:Male; D008819:Mice, Nude; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; D051020:bcl-X Protein; C496827:salubrinal; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D013890:Thiourea; D020123:Sirolimus
keywords: Akt; Bcl-xL; cholangiocarcinoma; rapamycin; salubrinal