Simvastatin enhances radiation sensitivity of colorectal cancer cells
Introduction Neoadjuvant chemoradiation (CRT) for rectal cancer induces variable responses, and better response has been associated with improved oncologic outcomes. Our group has previously shown that the administration of HMG-CoA reductase inhibitors, commonly known as statins, is associated with...
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| description | Introduction
Neoadjuvant chemoradiation (CRT) for rectal cancer induces variable responses, and better response has been associated with improved oncologic outcomes. Our group has previously shown that the administration of HMG-CoA reductase inhibitors, commonly known as statins, is associated with improved response to neoadjuvant CRT in rectal cancer patients. The purpose of this study was to study the effects of simvastatin on colorectal cancer cells and explore its potential as a radiation-sensitizer in vitro.
Methods
Four colorectal cancer cell lines (SW480, DLD1, SW837, and HRT18) were used to test the effects of simvastatin alone, radiation alone, and combination therapy. Outcome measures included ATP-based cell viability, colony formation, and protein (immunoblot) assays.
Results
The combination of radiation and simvastatin inhibited colony formation and cell viability of all four CRC lines, to a greater degree than either treatment alone (
p
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| doi_str_mv | 10.1007/s00464-017-5841-1 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1940052309</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1999910515</sourcerecordid><originalsourceid>FETCH-LOGICAL-c372t-4114d4e1f1fd5e20ca06ee1b0307f3c264a0032809e878237b5afdb00a9b82cd3</originalsourceid><addsrcrecordid>eNp1kE1LxDAQhoMo7rr6A7xIwYuX6kw--nEUWT9gwYN6Dmmaapc2XZN2Yf-9KV1FBHMZSJ55M_MQco5wjQDpjQfgCY8B01hkHGM8IHPkjMaUYnZI5pAziGma8xk58X4NAc9RHJMZzXJMci7mZPlSt1vle9XXNjL2Q1ltfORUWYebzkbeWF_39bbud1FXRbprOmd0r5pIj6iLtGkaf0qOKtV4c7avC_J2v3y9e4xXzw9Pd7erWLOU9jFH5CU3WGFVCkNBK0iMwQIYpBXTNOEKgNEMcpOlGWVpIVRVFgAqLzKqS7YgV1PuxnWfg_G9bGs_TqCs6QYvMecAgrKw-IJc_kHX3eBsmC5Q4SAIFIHCidKu896ZSm5c3Sq3kwhydCwnxzI4lqNjiaHnYp88FK0pfzq-pQaAToAPT_bduF9f_5v6BZimhiQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1999910515</pqid></control><display><type>article</type><title>Simvastatin enhances radiation sensitivity of colorectal cancer cells</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Karagkounis, Georgios ; DeVecchio, Jennifer ; Ferrandon, Sylvain ; Kalady, Matthew F.</creator><creatorcontrib>Karagkounis, Georgios ; DeVecchio, Jennifer ; Ferrandon, Sylvain ; Kalady, Matthew F.</creatorcontrib><description>Introduction
Neoadjuvant chemoradiation (CRT) for rectal cancer induces variable responses, and better response has been associated with improved oncologic outcomes. Our group has previously shown that the administration of HMG-CoA reductase inhibitors, commonly known as statins, is associated with improved response to neoadjuvant CRT in rectal cancer patients. The purpose of this study was to study the effects of simvastatin on colorectal cancer cells and explore its potential as a radiation-sensitizer in vitro.
Methods
Four colorectal cancer cell lines (SW480, DLD1, SW837, and HRT18) were used to test the effects of simvastatin alone, radiation alone, and combination therapy. Outcome measures included ATP-based cell viability, colony formation, and protein (immunoblot) assays.
Results
The combination of radiation and simvastatin inhibited colony formation and cell viability of all four CRC lines, to a greater degree than either treatment alone (
p
< 0.01). In addition, the effects of simvastatin in this combination therapy were dose dependent, with increased concentrations resulting in more potentiated inhibitory effects. The radiosensitizing effects of simvastatin on cell viability were negated by the presence of exogenous GGPP in the media. On protein analyses of irradiated cells, simvastatin treatment inhibited phosphorylation of ERK1/2, in a dose-dependent manner, while the total levels of ERK1/2 remained stable. In addition, the combined treatment resulted in increased levels of cleaved caspase 3, indicating greater apoptotic activity in the cells treated with radiation and simvastatin together.
Conclusions
Treatment with simvastatin hindered CRC cell viability and enhanced radiation sensitivity in vitro. These effects were tied to the depletion of GGPP and the decreased phosphorylation of ERK1/2, suggesting a prominent role for the EGFR-RAS-ERK1/2 pathway, through which statin enhances radiation sensitivity.</description><identifier>ISSN: 0930-2794</identifier><identifier>EISSN: 1432-2218</identifier><identifier>DOI: 10.1007/s00464-017-5841-1</identifier><identifier>PMID: 28916945</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Abdominal Surgery ; Apoptosis ; Cancer therapies ; Caspase 3 - metabolism ; Cell Line, Tumor ; Cell Survival ; Chemoradiotherapy - methods ; Colorectal cancer ; Colorectal Neoplasms - metabolism ; Colorectal Neoplasms - therapy ; Gastroenterology ; Gynecology ; Hepatology ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use ; Immunoblotting ; MAP Kinase Signaling System ; Medicine ; Medicine & Public Health ; Neoadjuvant Therapy ; Phosphorylation ; Proctology ; Radiation Tolerance - drug effects ; Radiation-Sensitizing Agents - therapeutic use ; Simvastatin - therapeutic use ; Statins ; Stem Cells ; Surgery</subject><ispartof>Surgical endoscopy, 2018-03, Vol.32 (3), p.1533-1539</ispartof><rights>Springer Science+Business Media, LLC 2017</rights><rights>Surgical Endoscopy is a copyright of Springer, (2017). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c372t-4114d4e1f1fd5e20ca06ee1b0307f3c264a0032809e878237b5afdb00a9b82cd3</citedby><cites>FETCH-LOGICAL-c372t-4114d4e1f1fd5e20ca06ee1b0307f3c264a0032809e878237b5afdb00a9b82cd3</cites><orcidid>0000-0003-0759-8108</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00464-017-5841-1$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00464-017-5841-1$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28916945$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Karagkounis, Georgios</creatorcontrib><creatorcontrib>DeVecchio, Jennifer</creatorcontrib><creatorcontrib>Ferrandon, Sylvain</creatorcontrib><creatorcontrib>Kalady, Matthew F.</creatorcontrib><title>Simvastatin enhances radiation sensitivity of colorectal cancer cells</title><title>Surgical endoscopy</title><addtitle>Surg Endosc</addtitle><addtitle>Surg Endosc</addtitle><description>Introduction
Neoadjuvant chemoradiation (CRT) for rectal cancer induces variable responses, and better response has been associated with improved oncologic outcomes. Our group has previously shown that the administration of HMG-CoA reductase inhibitors, commonly known as statins, is associated with improved response to neoadjuvant CRT in rectal cancer patients. The purpose of this study was to study the effects of simvastatin on colorectal cancer cells and explore its potential as a radiation-sensitizer in vitro.
Methods
Four colorectal cancer cell lines (SW480, DLD1, SW837, and HRT18) were used to test the effects of simvastatin alone, radiation alone, and combination therapy. Outcome measures included ATP-based cell viability, colony formation, and protein (immunoblot) assays.
Results
The combination of radiation and simvastatin inhibited colony formation and cell viability of all four CRC lines, to a greater degree than either treatment alone (
p
< 0.01). In addition, the effects of simvastatin in this combination therapy were dose dependent, with increased concentrations resulting in more potentiated inhibitory effects. The radiosensitizing effects of simvastatin on cell viability were negated by the presence of exogenous GGPP in the media. On protein analyses of irradiated cells, simvastatin treatment inhibited phosphorylation of ERK1/2, in a dose-dependent manner, while the total levels of ERK1/2 remained stable. In addition, the combined treatment resulted in increased levels of cleaved caspase 3, indicating greater apoptotic activity in the cells treated with radiation and simvastatin together.
Conclusions
Treatment with simvastatin hindered CRC cell viability and enhanced radiation sensitivity in vitro. These effects were tied to the depletion of GGPP and the decreased phosphorylation of ERK1/2, suggesting a prominent role for the EGFR-RAS-ERK1/2 pathway, through which statin enhances radiation sensitivity.</description><subject>Abdominal Surgery</subject><subject>Apoptosis</subject><subject>Cancer therapies</subject><subject>Caspase 3 - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival</subject><subject>Chemoradiotherapy - methods</subject><subject>Colorectal cancer</subject><subject>Colorectal Neoplasms - metabolism</subject><subject>Colorectal Neoplasms - therapy</subject><subject>Gastroenterology</subject><subject>Gynecology</subject><subject>Hepatology</subject><subject>Humans</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use</subject><subject>Immunoblotting</subject><subject>MAP Kinase Signaling System</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Neoadjuvant Therapy</subject><subject>Phosphorylation</subject><subject>Proctology</subject><subject>Radiation Tolerance - drug effects</subject><subject>Radiation-Sensitizing Agents - therapeutic use</subject><subject>Simvastatin - therapeutic use</subject><subject>Statins</subject><subject>Stem Cells</subject><subject>Surgery</subject><issn>0930-2794</issn><issn>1432-2218</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp1kE1LxDAQhoMo7rr6A7xIwYuX6kw--nEUWT9gwYN6Dmmaapc2XZN2Yf-9KV1FBHMZSJ55M_MQco5wjQDpjQfgCY8B01hkHGM8IHPkjMaUYnZI5pAziGma8xk58X4NAc9RHJMZzXJMci7mZPlSt1vle9XXNjL2Q1ltfORUWYebzkbeWF_39bbud1FXRbprOmd0r5pIj6iLtGkaf0qOKtV4c7avC_J2v3y9e4xXzw9Pd7erWLOU9jFH5CU3WGFVCkNBK0iMwQIYpBXTNOEKgNEMcpOlGWVpIVRVFgAqLzKqS7YgV1PuxnWfg_G9bGs_TqCs6QYvMecAgrKw-IJc_kHX3eBsmC5Q4SAIFIHCidKu896ZSm5c3Sq3kwhydCwnxzI4lqNjiaHnYp88FK0pfzq-pQaAToAPT_bduF9f_5v6BZimhiQ</recordid><startdate>20180301</startdate><enddate>20180301</enddate><creator>Karagkounis, Georgios</creator><creator>DeVecchio, Jennifer</creator><creator>Ferrandon, Sylvain</creator><creator>Kalady, Matthew F.</creator><general>Springer US</general><general>Springer Nature B.V</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>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-0759-8108</orcidid></search><sort><creationdate>20180301</creationdate><title>Simvastatin enhances radiation sensitivity of colorectal cancer cells</title><author>Karagkounis, Georgios ; DeVecchio, Jennifer ; Ferrandon, Sylvain ; Kalady, Matthew F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c372t-4114d4e1f1fd5e20ca06ee1b0307f3c264a0032809e878237b5afdb00a9b82cd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Abdominal Surgery</topic><topic>Apoptosis</topic><topic>Cancer therapies</topic><topic>Caspase 3 - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival</topic><topic>Chemoradiotherapy - methods</topic><topic>Colorectal cancer</topic><topic>Colorectal Neoplasms - metabolism</topic><topic>Colorectal Neoplasms - therapy</topic><topic>Gastroenterology</topic><topic>Gynecology</topic><topic>Hepatology</topic><topic>Humans</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use</topic><topic>Immunoblotting</topic><topic>MAP Kinase Signaling System</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Neoadjuvant Therapy</topic><topic>Phosphorylation</topic><topic>Proctology</topic><topic>Radiation Tolerance - drug effects</topic><topic>Radiation-Sensitizing Agents - therapeutic use</topic><topic>Simvastatin - therapeutic use</topic><topic>Statins</topic><topic>Stem Cells</topic><topic>Surgery</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Karagkounis, Georgios</creatorcontrib><creatorcontrib>DeVecchio, Jennifer</creatorcontrib><creatorcontrib>Ferrandon, Sylvain</creatorcontrib><creatorcontrib>Kalady, Matthew F.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Surgical endoscopy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Karagkounis, Georgios</au><au>DeVecchio, Jennifer</au><au>Ferrandon, Sylvain</au><au>Kalady, Matthew F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Simvastatin enhances radiation sensitivity of colorectal cancer cells</atitle><jtitle>Surgical endoscopy</jtitle><stitle>Surg Endosc</stitle><addtitle>Surg Endosc</addtitle><date>2018-03-01</date><risdate>2018</risdate><volume>32</volume><issue>3</issue><spage>1533</spage><epage>1539</epage><pages>1533-1539</pages><issn>0930-2794</issn><eissn>1432-2218</eissn><abstract>Introduction
Neoadjuvant chemoradiation (CRT) for rectal cancer induces variable responses, and better response has been associated with improved oncologic outcomes. Our group has previously shown that the administration of HMG-CoA reductase inhibitors, commonly known as statins, is associated with improved response to neoadjuvant CRT in rectal cancer patients. The purpose of this study was to study the effects of simvastatin on colorectal cancer cells and explore its potential as a radiation-sensitizer in vitro.
Methods
Four colorectal cancer cell lines (SW480, DLD1, SW837, and HRT18) were used to test the effects of simvastatin alone, radiation alone, and combination therapy. Outcome measures included ATP-based cell viability, colony formation, and protein (immunoblot) assays.
Results
The combination of radiation and simvastatin inhibited colony formation and cell viability of all four CRC lines, to a greater degree than either treatment alone (
p
< 0.01). In addition, the effects of simvastatin in this combination therapy were dose dependent, with increased concentrations resulting in more potentiated inhibitory effects. The radiosensitizing effects of simvastatin on cell viability were negated by the presence of exogenous GGPP in the media. On protein analyses of irradiated cells, simvastatin treatment inhibited phosphorylation of ERK1/2, in a dose-dependent manner, while the total levels of ERK1/2 remained stable. In addition, the combined treatment resulted in increased levels of cleaved caspase 3, indicating greater apoptotic activity in the cells treated with radiation and simvastatin together.
Conclusions
Treatment with simvastatin hindered CRC cell viability and enhanced radiation sensitivity in vitro. These effects were tied to the depletion of GGPP and the decreased phosphorylation of ERK1/2, suggesting a prominent role for the EGFR-RAS-ERK1/2 pathway, through which statin enhances radiation sensitivity.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>28916945</pmid><doi>10.1007/s00464-017-5841-1</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0003-0759-8108</orcidid></addata></record> |
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| subjects | Abdominal Surgery Apoptosis Cancer therapies Caspase 3 - metabolism Cell Line, Tumor Cell Survival Chemoradiotherapy - methods Colorectal cancer Colorectal Neoplasms - metabolism Colorectal Neoplasms - therapy Gastroenterology Gynecology Hepatology Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use Immunoblotting MAP Kinase Signaling System Medicine Medicine & Public Health Neoadjuvant Therapy Phosphorylation Proctology Radiation Tolerance - drug effects Radiation-Sensitizing Agents - therapeutic use Simvastatin - therapeutic use Statins Stem Cells Surgery |
| title | Simvastatin enhances radiation sensitivity of colorectal cancer cells |
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