Inhibitory effects of valproic acid in DNA double-strand break repair after irradiation in esophageal squamous carcinoma cells
Radiation therapy is one of the most promising therapeutic strategies in unresectable esophageal squamous cell carcinoma (ESCC). The histone deacetylase (HDAC) inhibitor has been shown to enhance radiosensitivity. Valproic acid (VPA) is a well-known drug used to treat seizure disorders and epilepsy,...
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| Veröffentlicht in: | Oncology reports 2015-09, Vol.34 (3), p.1185-1192 |
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| creator | MAKITA, NAOKI NINOMIYA, ITASU TSUKADA, TOMOYA OKAMOTO, KOICHI HARADA, SHINICHI NAKANUMA, SHINICHI SAKAI, SEISHO MAKINO, ISAMU KINOSHITA, JUN HAYASHI, HIRONORI OYAMA, KATSUNOBU NAKAGAWARA, HISATOSHI MIYASHITA, TOMOHARU TAJIMA, HIDEHIRO TAKAMURA, HIROYUKI FUSHIDA, SACHIO OHTA, TETSUO |
| description | Radiation therapy is one of the most promising therapeutic strategies in unresectable esophageal squamous cell carcinoma (ESCC). The histone deacetylase (HDAC) inhibitor has been shown to enhance radiosensitivity. Valproic acid (VPA) is a well-known drug used to treat seizure disorders and epilepsy, and has been shown to inhibit HDACs. We recently reported that a clinically safe dose of VPA enhances radiation-induced cytotoxicity in human ESCC cells. However, the mechanism of radiosensitizing effect of VPA has not yet been confirmed. The present study examined the effect of VPA on DNA double-strand break (DSB) repair after radiation in the human ESCC cell lines KES, TE9 and TE11 by examining H2AX phosphorylation (γH2AX) levels as a marker of radiation-induced DSBs. The present study also examined whether VPA inhibited radiation-induced DNA DSB repair by suppressing non-homologous end joining (NHEJ), focusing particularly on the acetylation of Ku70. VPA was shown to prolong γH2AX levels after irradiation in all three ESCC cell lines. Moreover, prolonged γH2AX foci formation after irradiation was also observed by immunocytochemistry following VPA pretreatment in KES and TE9 cells. VPA was shown to induce Ku70 acetylation after irradiation in all three ESCC cell lines. Our results suggest that VPA prolonged radiation-induced DSBs by inhibiting NHEJ in DSB repair pathways in ESCC. VPA could therefore be used as an effective radiosensitizer in ESCC radiotherapy. |
| doi_str_mv | 10.3892/or.2015.4089 |
| format | Article |
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The histone deacetylase (HDAC) inhibitor has been shown to enhance radiosensitivity. Valproic acid (VPA) is a well-known drug used to treat seizure disorders and epilepsy, and has been shown to inhibit HDACs. We recently reported that a clinically safe dose of VPA enhances radiation-induced cytotoxicity in human ESCC cells. However, the mechanism of radiosensitizing effect of VPA has not yet been confirmed. The present study examined the effect of VPA on DNA double-strand break (DSB) repair after radiation in the human ESCC cell lines KES, TE9 and TE11 by examining H2AX phosphorylation (γH2AX) levels as a marker of radiation-induced DSBs. The present study also examined whether VPA inhibited radiation-induced DNA DSB repair by suppressing non-homologous end joining (NHEJ), focusing particularly on the acetylation of Ku70. VPA was shown to prolong γH2AX levels after irradiation in all three ESCC cell lines. Moreover, prolonged γH2AX foci formation after irradiation was also observed by immunocytochemistry following VPA pretreatment in KES and TE9 cells. VPA was shown to induce Ku70 acetylation after irradiation in all three ESCC cell lines. Our results suggest that VPA prolonged radiation-induced DSBs by inhibiting NHEJ in DSB repair pathways in ESCC. VPA could therefore be used as an effective radiosensitizer in ESCC radiotherapy.</description><identifier>ISSN: 1021-335X</identifier><identifier>EISSN: 1791-2431</identifier><identifier>DOI: 10.3892/or.2015.4089</identifier><identifier>PMID: 26135807</identifier><language>eng</language><publisher>Greece: D.A. Spandidos</publisher><subject>Apoptosis ; Ataxia ; Cancer therapies ; Carcinoma, Squamous Cell ; Care and treatment ; Cell cycle ; Cell Line, Tumor ; Chromatin ; Deoxyribonucleic acid ; Divalproex ; DNA ; DNA Breaks, Double-Stranded - drug effects ; DNA Breaks, Double-Stranded - radiation effects ; DNA repair ; DNA Repair - drug effects ; double-strand DNA breaks ; Esophageal cancer ; Esophageal Neoplasms ; Esophageal Squamous Cell Carcinoma ; Fluorescent Antibody Technique ; Health aspects ; histone deacetylase inhibitor ; Histones - biosynthesis ; Humans ; Kinases ; Ku70 ; Methods ; non-homologous DNA end joining ; Phosphorylation ; Proteins ; Radiation therapy ; Radiation Tolerance - drug effects ; Radiation-Sensitizing Agents - pharmacology ; Radiotherapy ; Squamous cell carcinoma ; Studies ; Valproic acid ; Valproic Acid - pharmacology</subject><ispartof>Oncology reports, 2015-09, Vol.34 (3), p.1185-1192</ispartof><rights>Copyright © 2015, Spandidos Publications</rights><rights>COPYRIGHT 2015 Spandidos Publications</rights><rights>Copyright Spandidos Publications UK Ltd. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c680t-4f7ffa436bea730c973e54aac00edc469db828e58ace0bf6270645f01c1900753</citedby><cites>FETCH-LOGICAL-c680t-4f7ffa436bea730c973e54aac00edc469db828e58ace0bf6270645f01c1900753</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26135807$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MAKITA, NAOKI</creatorcontrib><creatorcontrib>NINOMIYA, ITASU</creatorcontrib><creatorcontrib>TSUKADA, TOMOYA</creatorcontrib><creatorcontrib>OKAMOTO, KOICHI</creatorcontrib><creatorcontrib>HARADA, SHINICHI</creatorcontrib><creatorcontrib>NAKANUMA, SHINICHI</creatorcontrib><creatorcontrib>SAKAI, SEISHO</creatorcontrib><creatorcontrib>MAKINO, ISAMU</creatorcontrib><creatorcontrib>KINOSHITA, JUN</creatorcontrib><creatorcontrib>HAYASHI, HIRONORI</creatorcontrib><creatorcontrib>OYAMA, KATSUNOBU</creatorcontrib><creatorcontrib>NAKAGAWARA, HISATOSHI</creatorcontrib><creatorcontrib>MIYASHITA, TOMOHARU</creatorcontrib><creatorcontrib>TAJIMA, HIDEHIRO</creatorcontrib><creatorcontrib>TAKAMURA, HIROYUKI</creatorcontrib><creatorcontrib>FUSHIDA, SACHIO</creatorcontrib><creatorcontrib>OHTA, TETSUO</creatorcontrib><title>Inhibitory effects of valproic acid in DNA double-strand break repair after irradiation in esophageal squamous carcinoma cells</title><title>Oncology reports</title><addtitle>Oncol Rep</addtitle><description>Radiation therapy is one of the most promising therapeutic strategies in unresectable esophageal squamous cell carcinoma (ESCC). The histone deacetylase (HDAC) inhibitor has been shown to enhance radiosensitivity. Valproic acid (VPA) is a well-known drug used to treat seizure disorders and epilepsy, and has been shown to inhibit HDACs. We recently reported that a clinically safe dose of VPA enhances radiation-induced cytotoxicity in human ESCC cells. However, the mechanism of radiosensitizing effect of VPA has not yet been confirmed. The present study examined the effect of VPA on DNA double-strand break (DSB) repair after radiation in the human ESCC cell lines KES, TE9 and TE11 by examining H2AX phosphorylation (γH2AX) levels as a marker of radiation-induced DSBs. The present study also examined whether VPA inhibited radiation-induced DNA DSB repair by suppressing non-homologous end joining (NHEJ), focusing particularly on the acetylation of Ku70. VPA was shown to prolong γH2AX levels after irradiation in all three ESCC cell lines. Moreover, prolonged γH2AX foci formation after irradiation was also observed by immunocytochemistry following VPA pretreatment in KES and TE9 cells. VPA was shown to induce Ku70 acetylation after irradiation in all three ESCC cell lines. Our results suggest that VPA prolonged radiation-induced DSBs by inhibiting NHEJ in DSB repair pathways in ESCC. VPA could therefore be used as an effective radiosensitizer in ESCC radiotherapy.</description><subject>Apoptosis</subject><subject>Ataxia</subject><subject>Cancer therapies</subject><subject>Carcinoma, Squamous Cell</subject><subject>Care and treatment</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Chromatin</subject><subject>Deoxyribonucleic acid</subject><subject>Divalproex</subject><subject>DNA</subject><subject>DNA Breaks, Double-Stranded - drug effects</subject><subject>DNA Breaks, Double-Stranded - radiation effects</subject><subject>DNA repair</subject><subject>DNA Repair - drug effects</subject><subject>double-strand DNA breaks</subject><subject>Esophageal cancer</subject><subject>Esophageal Neoplasms</subject><subject>Esophageal Squamous Cell Carcinoma</subject><subject>Fluorescent Antibody Technique</subject><subject>Health aspects</subject><subject>histone deacetylase inhibitor</subject><subject>Histones - biosynthesis</subject><subject>Humans</subject><subject>Kinases</subject><subject>Ku70</subject><subject>Methods</subject><subject>non-homologous DNA end joining</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>Radiation therapy</subject><subject>Radiation Tolerance - drug effects</subject><subject>Radiation-Sensitizing Agents - pharmacology</subject><subject>Radiotherapy</subject><subject>Squamous cell carcinoma</subject><subject>Studies</subject><subject>Valproic acid</subject><subject>Valproic Acid - pharmacology</subject><issn>1021-335X</issn><issn>1791-2431</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNptkk1v1DAQhiMEoqVw44wsISEOZBl_JHGOq1KgUgUXkLhZE2fcdUnirZ0g9cJvr6OW0iLkg63RMzPvjN-ieMlhI3Ur3oe4EcCrjQLdPioOedPyUijJH-c3CF5KWf04KJ6ldAEgGqjbp8WBqLmsNDSHxe_Taec7P4d4xcg5snNiwbFfOOxj8Jah9T3zE_vwZcv6sHQDlWmOOPWsi4Q_WaQ9-sjQzRSZjxF7j7MP05pDKex3eE44sHS54BiWxCxG66cwIrM0DOl58cThkOjF7X1UfP948u34c3n29dPp8fastLWGuVSucQ6VrDvCRoJtG0mVQrQA1FtVt32nhaZKoyXoXL3OqSoH3PIWoKnkUfH2pm6e6nKhNJvRp1UBTpRlGd6AqCshOM_o63_Qi7DEKaszvJWi1lLpe9Q5DmT85ELeil2Lmq2SGZG1WNtu_kPl09PobZjI-Rx_kPDmXsIur27epTAs60rTQ_DdDWhjSCmSM_voR4xXhoNZfWFCNKsvzOqLjL-6HWrpRurv4D9G-Ns47fPn-j6kOybEUqoSZMm5ruQ1Z0W-Pg</recordid><startdate>20150901</startdate><enddate>20150901</enddate><creator>MAKITA, NAOKI</creator><creator>NINOMIYA, ITASU</creator><creator>TSUKADA, TOMOYA</creator><creator>OKAMOTO, KOICHI</creator><creator>HARADA, SHINICHI</creator><creator>NAKANUMA, SHINICHI</creator><creator>SAKAI, SEISHO</creator><creator>MAKINO, ISAMU</creator><creator>KINOSHITA, JUN</creator><creator>HAYASHI, HIRONORI</creator><creator>OYAMA, KATSUNOBU</creator><creator>NAKAGAWARA, HISATOSHI</creator><creator>MIYASHITA, TOMOHARU</creator><creator>TAJIMA, HIDEHIRO</creator><creator>TAKAMURA, HIROYUKI</creator><creator>FUSHIDA, SACHIO</creator><creator>OHTA, TETSUO</creator><general>D.A. Spandidos</general><general>Spandidos Publications</general><general>Spandidos Publications UK Ltd</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>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20150901</creationdate><title>Inhibitory effects of valproic acid in DNA double-strand break repair after irradiation in esophageal squamous carcinoma cells</title><author>MAKITA, NAOKI ; NINOMIYA, ITASU ; TSUKADA, TOMOYA ; OKAMOTO, KOICHI ; HARADA, SHINICHI ; NAKANUMA, SHINICHI ; SAKAI, SEISHO ; MAKINO, ISAMU ; KINOSHITA, JUN ; HAYASHI, HIRONORI ; OYAMA, KATSUNOBU ; NAKAGAWARA, HISATOSHI ; MIYASHITA, TOMOHARU ; TAJIMA, HIDEHIRO ; TAKAMURA, HIROYUKI ; FUSHIDA, SACHIO ; OHTA, TETSUO</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c680t-4f7ffa436bea730c973e54aac00edc469db828e58ace0bf6270645f01c1900753</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Apoptosis</topic><topic>Ataxia</topic><topic>Cancer therapies</topic><topic>Carcinoma, Squamous Cell</topic><topic>Care and treatment</topic><topic>Cell cycle</topic><topic>Cell Line, Tumor</topic><topic>Chromatin</topic><topic>Deoxyribonucleic acid</topic><topic>Divalproex</topic><topic>DNA</topic><topic>DNA Breaks, Double-Stranded - drug effects</topic><topic>DNA Breaks, Double-Stranded - radiation effects</topic><topic>DNA repair</topic><topic>DNA Repair - drug effects</topic><topic>double-strand DNA breaks</topic><topic>Esophageal cancer</topic><topic>Esophageal Neoplasms</topic><topic>Esophageal Squamous Cell Carcinoma</topic><topic>Fluorescent Antibody Technique</topic><topic>Health aspects</topic><topic>histone deacetylase inhibitor</topic><topic>Histones - biosynthesis</topic><topic>Humans</topic><topic>Kinases</topic><topic>Ku70</topic><topic>Methods</topic><topic>non-homologous DNA end joining</topic><topic>Phosphorylation</topic><topic>Proteins</topic><topic>Radiation therapy</topic><topic>Radiation Tolerance - drug effects</topic><topic>Radiation-Sensitizing Agents - pharmacology</topic><topic>Radiotherapy</topic><topic>Squamous cell carcinoma</topic><topic>Studies</topic><topic>Valproic acid</topic><topic>Valproic Acid - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MAKITA, NAOKI</creatorcontrib><creatorcontrib>NINOMIYA, ITASU</creatorcontrib><creatorcontrib>TSUKADA, TOMOYA</creatorcontrib><creatorcontrib>OKAMOTO, KOICHI</creatorcontrib><creatorcontrib>HARADA, SHINICHI</creatorcontrib><creatorcontrib>NAKANUMA, SHINICHI</creatorcontrib><creatorcontrib>SAKAI, SEISHO</creatorcontrib><creatorcontrib>MAKINO, ISAMU</creatorcontrib><creatorcontrib>KINOSHITA, JUN</creatorcontrib><creatorcontrib>HAYASHI, HIRONORI</creatorcontrib><creatorcontrib>OYAMA, KATSUNOBU</creatorcontrib><creatorcontrib>NAKAGAWARA, HISATOSHI</creatorcontrib><creatorcontrib>MIYASHITA, TOMOHARU</creatorcontrib><creatorcontrib>TAJIMA, HIDEHIRO</creatorcontrib><creatorcontrib>TAKAMURA, HIROYUKI</creatorcontrib><creatorcontrib>FUSHIDA, SACHIO</creatorcontrib><creatorcontrib>OHTA, TETSUO</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>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</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>British Nursing Database</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>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</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>Oncology reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MAKITA, NAOKI</au><au>NINOMIYA, ITASU</au><au>TSUKADA, TOMOYA</au><au>OKAMOTO, KOICHI</au><au>HARADA, SHINICHI</au><au>NAKANUMA, SHINICHI</au><au>SAKAI, SEISHO</au><au>MAKINO, ISAMU</au><au>KINOSHITA, JUN</au><au>HAYASHI, HIRONORI</au><au>OYAMA, KATSUNOBU</au><au>NAKAGAWARA, HISATOSHI</au><au>MIYASHITA, TOMOHARU</au><au>TAJIMA, HIDEHIRO</au><au>TAKAMURA, HIROYUKI</au><au>FUSHIDA, SACHIO</au><au>OHTA, TETSUO</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibitory effects of valproic acid in DNA double-strand break repair after irradiation in esophageal squamous carcinoma cells</atitle><jtitle>Oncology reports</jtitle><addtitle>Oncol Rep</addtitle><date>2015-09-01</date><risdate>2015</risdate><volume>34</volume><issue>3</issue><spage>1185</spage><epage>1192</epage><pages>1185-1192</pages><issn>1021-335X</issn><eissn>1791-2431</eissn><abstract>Radiation therapy is one of the most promising therapeutic strategies in unresectable esophageal squamous cell carcinoma (ESCC). The histone deacetylase (HDAC) inhibitor has been shown to enhance radiosensitivity. Valproic acid (VPA) is a well-known drug used to treat seizure disorders and epilepsy, and has been shown to inhibit HDACs. We recently reported that a clinically safe dose of VPA enhances radiation-induced cytotoxicity in human ESCC cells. However, the mechanism of radiosensitizing effect of VPA has not yet been confirmed. The present study examined the effect of VPA on DNA double-strand break (DSB) repair after radiation in the human ESCC cell lines KES, TE9 and TE11 by examining H2AX phosphorylation (γH2AX) levels as a marker of radiation-induced DSBs. The present study also examined whether VPA inhibited radiation-induced DNA DSB repair by suppressing non-homologous end joining (NHEJ), focusing particularly on the acetylation of Ku70. VPA was shown to prolong γH2AX levels after irradiation in all three ESCC cell lines. Moreover, prolonged γH2AX foci formation after irradiation was also observed by immunocytochemistry following VPA pretreatment in KES and TE9 cells. VPA was shown to induce Ku70 acetylation after irradiation in all three ESCC cell lines. Our results suggest that VPA prolonged radiation-induced DSBs by inhibiting NHEJ in DSB repair pathways in ESCC. VPA could therefore be used as an effective radiosensitizer in ESCC radiotherapy.</abstract><cop>Greece</cop><pub>D.A. Spandidos</pub><pmid>26135807</pmid><doi>10.3892/or.2015.4089</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1021-335X |
| ispartof | Oncology reports, 2015-09, Vol.34 (3), p.1185-1192 |
| issn | 1021-335X 1791-2431 |
| language | eng |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Apoptosis Ataxia Cancer therapies Carcinoma, Squamous Cell Care and treatment Cell cycle Cell Line, Tumor Chromatin Deoxyribonucleic acid Divalproex DNA DNA Breaks, Double-Stranded - drug effects DNA Breaks, Double-Stranded - radiation effects DNA repair DNA Repair - drug effects double-strand DNA breaks Esophageal cancer Esophageal Neoplasms Esophageal Squamous Cell Carcinoma Fluorescent Antibody Technique Health aspects histone deacetylase inhibitor Histones - biosynthesis Humans Kinases Ku70 Methods non-homologous DNA end joining Phosphorylation Proteins Radiation therapy Radiation Tolerance - drug effects Radiation-Sensitizing Agents - pharmacology Radiotherapy Squamous cell carcinoma Studies Valproic acid Valproic Acid - pharmacology |
| title | Inhibitory effects of valproic acid in DNA double-strand break repair after irradiation in esophageal squamous carcinoma cells |
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