Synergistic antitumor activity of the combination of salubrinal and rapamycin against human cholangiocarcinoma cells
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...
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| Veröffentlicht in: | Oncotarget 2016-12, Vol.7 (51), p.85492-85501 |
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| creator | Zhao, Xiaofang Zhang, Chunyan Zhou, Hong Xiao, Bin Cheng, Ying Wang, Jinju Yao, Fuli Duan, Chunyan Chen, Run Liu, Youping Feng, Chunhong Li, Hong Li, Jing Dai, Rongyang |
| description | 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. |
| doi_str_mv | 10.18632/oncotarget.13408 |
| format | Article |
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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.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.13408</identifier><identifier>PMID: 27863431</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Animals ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; bcl-X Protein - metabolism ; Bile Duct Neoplasms - drug therapy ; Bile Duct Neoplasms - metabolism ; Bile Duct Neoplasms - pathology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cholangiocarcinoma - drug therapy ; Cholangiocarcinoma - metabolism ; Cholangiocarcinoma - pathology ; Cinnamates - pharmacology ; Drug Synergism ; Eukaryotic Initiation Factor-2 - antagonists & inhibitors ; Eukaryotic Initiation Factor-2 - metabolism ; Humans ; Male ; Mice, Nude ; Phosphorylation ; Proto-Oncogene Proteins c-akt - antagonists & inhibitors ; Proto-Oncogene Proteins c-akt - metabolism ; Research Paper ; Signal Transduction - drug effects ; Sirolimus - pharmacology ; Thiourea - analogs & derivatives ; Thiourea - pharmacology ; Time Factors ; TOR Serine-Threonine Kinases - antagonists & inhibitors ; TOR Serine-Threonine Kinases - metabolism ; Tumor Burden - drug effects ; Xenograft Model Antitumor Assays</subject><ispartof>Oncotarget, 2016-12, Vol.7 (51), p.85492-85501</ispartof><rights>Copyright: © 2016 Zhao et al. 2016</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-9ce3e8c237acc83e7162639691233ce68d0d5a3c2f935c9e60852621996195b93</citedby><cites>FETCH-LOGICAL-c356t-9ce3e8c237acc83e7162639691233ce68d0d5a3c2f935c9e60852621996195b93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356752/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356752/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27863431$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhao, Xiaofang</creatorcontrib><creatorcontrib>Zhang, Chunyan</creatorcontrib><creatorcontrib>Zhou, Hong</creatorcontrib><creatorcontrib>Xiao, Bin</creatorcontrib><creatorcontrib>Cheng, Ying</creatorcontrib><creatorcontrib>Wang, Jinju</creatorcontrib><creatorcontrib>Yao, Fuli</creatorcontrib><creatorcontrib>Duan, Chunyan</creatorcontrib><creatorcontrib>Chen, Run</creatorcontrib><creatorcontrib>Liu, Youping</creatorcontrib><creatorcontrib>Feng, Chunhong</creatorcontrib><creatorcontrib>Li, Hong</creatorcontrib><creatorcontrib>Li, Jing</creatorcontrib><creatorcontrib>Dai, Rongyang</creatorcontrib><title>Synergistic antitumor activity of the combination of salubrinal and rapamycin against human cholangiocarcinoma cells</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>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.</description><subject>Animals</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>bcl-X Protein - metabolism</subject><subject>Bile Duct Neoplasms - drug therapy</subject><subject>Bile Duct Neoplasms - metabolism</subject><subject>Bile Duct Neoplasms - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cholangiocarcinoma - drug therapy</subject><subject>Cholangiocarcinoma - metabolism</subject><subject>Cholangiocarcinoma - pathology</subject><subject>Cinnamates - pharmacology</subject><subject>Drug Synergism</subject><subject>Eukaryotic Initiation Factor-2 - antagonists & inhibitors</subject><subject>Eukaryotic Initiation Factor-2 - metabolism</subject><subject>Humans</subject><subject>Male</subject><subject>Mice, Nude</subject><subject>Phosphorylation</subject><subject>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Research Paper</subject><subject>Signal Transduction - drug effects</subject><subject>Sirolimus - pharmacology</subject><subject>Thiourea - analogs & derivatives</subject><subject>Thiourea - pharmacology</subject><subject>Time Factors</subject><subject>TOR Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>Tumor Burden - drug effects</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1LBDEMLaKo6P4AL9Kjl9VpO-1ML4KIXyB4UM8lm-3OVmbate0I---tun7lkpDkvZfwCDli1SlrleBnwWPIEDubT5moq3aL7DNd6ymXUmz_qffIJKWXqoSsm5brXbLHm8JQC7ZP8uPa29i5lB1S8NnlcQiRAmb35vKahgXNS0sxDDPnIbvgP1oJ-nEWS6MvmDmNsIJhjc5T6MD5lOlyHMBTXIYefOcCQizTMABF2_fpkOwsoE92sskH5Pn66unydnr_cHN3eXE_RSFVnmq0wrbIRQOIrbANU1wJrTTjQqBV7byaSxDIF1pI1FZVreSKM60V03KmxQE5_-JdjbPBztH6HKE3q-gGiGsTwJn_E--WpgtvRhb9RvJCcLIhiOF1tCmbwaWPF8DbMCbD2po1WlRNU1bZ1yrGkFK0ix8ZVplPw8yvYebTsII5_nvfD-LbHvEOMGaXrg</recordid><startdate>20161220</startdate><enddate>20161220</enddate><creator>Zhao, Xiaofang</creator><creator>Zhang, Chunyan</creator><creator>Zhou, Hong</creator><creator>Xiao, Bin</creator><creator>Cheng, Ying</creator><creator>Wang, Jinju</creator><creator>Yao, Fuli</creator><creator>Duan, Chunyan</creator><creator>Chen, Run</creator><creator>Liu, Youping</creator><creator>Feng, Chunhong</creator><creator>Li, Hong</creator><creator>Li, Jing</creator><creator>Dai, Rongyang</creator><general>Impact Journals LLC</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20161220</creationdate><title>Synergistic antitumor activity of the combination of salubrinal and rapamycin against human cholangiocarcinoma cells</title><author>Zhao, Xiaofang ; Zhang, Chunyan ; Zhou, Hong ; Xiao, Bin ; Cheng, Ying ; Wang, Jinju ; Yao, Fuli ; Duan, Chunyan ; Chen, Run ; Liu, Youping ; Feng, Chunhong ; Li, Hong ; Li, Jing ; Dai, Rongyang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-9ce3e8c237acc83e7162639691233ce68d0d5a3c2f935c9e60852621996195b93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Antineoplastic Combined Chemotherapy Protocols - pharmacology</topic><topic>bcl-X Protein - metabolism</topic><topic>Bile Duct Neoplasms - drug therapy</topic><topic>Bile Duct Neoplasms - metabolism</topic><topic>Bile Duct Neoplasms - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cholangiocarcinoma - drug therapy</topic><topic>Cholangiocarcinoma - metabolism</topic><topic>Cholangiocarcinoma - pathology</topic><topic>Cinnamates - pharmacology</topic><topic>Drug Synergism</topic><topic>Eukaryotic Initiation Factor-2 - antagonists & inhibitors</topic><topic>Eukaryotic Initiation Factor-2 - metabolism</topic><topic>Humans</topic><topic>Male</topic><topic>Mice, Nude</topic><topic>Phosphorylation</topic><topic>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Research Paper</topic><topic>Signal Transduction - drug effects</topic><topic>Sirolimus - pharmacology</topic><topic>Thiourea - analogs & derivatives</topic><topic>Thiourea - pharmacology</topic><topic>Time Factors</topic><topic>TOR Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><topic>Tumor Burden - drug effects</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>online_resources</toplevel><creatorcontrib>Zhao, Xiaofang</creatorcontrib><creatorcontrib>Zhang, Chunyan</creatorcontrib><creatorcontrib>Zhou, Hong</creatorcontrib><creatorcontrib>Xiao, Bin</creatorcontrib><creatorcontrib>Cheng, Ying</creatorcontrib><creatorcontrib>Wang, Jinju</creatorcontrib><creatorcontrib>Yao, Fuli</creatorcontrib><creatorcontrib>Duan, Chunyan</creatorcontrib><creatorcontrib>Chen, Run</creatorcontrib><creatorcontrib>Liu, Youping</creatorcontrib><creatorcontrib>Feng, Chunhong</creatorcontrib><creatorcontrib>Li, Hong</creatorcontrib><creatorcontrib>Li, Jing</creatorcontrib><creatorcontrib>Dai, Rongyang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhao, Xiaofang</au><au>Zhang, Chunyan</au><au>Zhou, Hong</au><au>Xiao, Bin</au><au>Cheng, Ying</au><au>Wang, Jinju</au><au>Yao, Fuli</au><au>Duan, Chunyan</au><au>Chen, Run</au><au>Liu, Youping</au><au>Feng, Chunhong</au><au>Li, Hong</au><au>Li, Jing</au><au>Dai, Rongyang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synergistic antitumor activity of the combination of salubrinal and rapamycin against human cholangiocarcinoma cells</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2016-12-20</date><risdate>2016</risdate><volume>7</volume><issue>51</issue><spage>85492</spage><epage>85501</epage><pages>85492-85501</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><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.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>27863431</pmid><doi>10.18632/oncotarget.13408</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antineoplastic Combined Chemotherapy Protocols - pharmacology bcl-X Protein - metabolism Bile Duct Neoplasms - drug therapy Bile Duct Neoplasms - metabolism Bile Duct Neoplasms - pathology Cell Line, Tumor Cell Proliferation - drug effects Cholangiocarcinoma - drug therapy Cholangiocarcinoma - metabolism Cholangiocarcinoma - pathology Cinnamates - pharmacology Drug Synergism Eukaryotic Initiation Factor-2 - antagonists & inhibitors Eukaryotic Initiation Factor-2 - metabolism Humans Male Mice, Nude Phosphorylation Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - metabolism Research Paper Signal Transduction - drug effects Sirolimus - pharmacology Thiourea - analogs & derivatives Thiourea - pharmacology Time Factors TOR Serine-Threonine Kinases - antagonists & inhibitors TOR Serine-Threonine Kinases - metabolism Tumor Burden - drug effects Xenograft Model Antitumor Assays |
| title | Synergistic antitumor activity of the combination of salubrinal and rapamycin against human cholangiocarcinoma cells |
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