Oncolytic virotherapy promotes radiosensitivity in soft tissue sarcoma by suppressing anti-apoptotic MCL1 expression
Soft tissue sarcoma (STS) is a rare cancer that develops from soft tissues in any part of the body. Despite major advances in the treatment of STS, patients are often refractory to conventional radiotherapy, leading to poor prognosis. Enhancement of sensitivity to radiotherapy would therefore improv...
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| Veröffentlicht in: | PloS one 2021-04, Vol.16 (4), p.e0250643-e0250643, Article 0250643 |
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| creator | Omori, Toshinori Tazawa, Hiroshi Yamakawa, Yasuaki Osaki, Shuhei Hasei, Joe Sugiu, Kazuhisa Komatsubara, Tadashi Fujiwara, Tomohiro Yoshida, Aki Kunisada, Toshiyuki Urata, Yasuo Kagawa, Shunsuke Ozaki, Toshifumi Fujiwara, Toshiyoshi |
| description | Soft tissue sarcoma (STS) is a rare cancer that develops from soft tissues in any part of the body. Despite major advances in the treatment of STS, patients are often refractory to conventional radiotherapy, leading to poor prognosis. Enhancement of sensitivity to radiotherapy would therefore improve the clinical outcome of STS patients. We previously revealed that the tumor-specific, replication-competent oncolytic adenovirus OBP-301 kills human sarcoma cells. In this study, we investigated the radiosensitizing effect of OBP-301 in human STS cells. The in vitro antitumor effect of OBP-301 and ionizing radiation in monotherapy or combination therapy was assessed using highly radiosensitive (RD-ES and SK-ES-1) and moderately radiosensitive (HT1080 and NMS-2) STS cell lines. The expression of markers for apoptosis and DNA damage were evaluated in STS cells after treatment. The therapeutic potential of combination therapy was further analyzed using SK-ES-1 and HT1080 cells in subcutaneous xenograft tumor models. The combination of OBP-301 and ionizing radiation showed a synergistic antitumor effect in all human STS cell lines tested, including those that show different radiosensitivity. OBP-301 was found to enhance irradiation-induced apoptosis and DNA damage via suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1), which was expressed at higher levels in moderately radiosensitive cell lines. The combination of OBP-301 and ionizing radiation showed a more profound antitumor effect compared to monotherapy in SK-ES-1 (highly radiosensitive) and HT1080 (moderately radiosensitive) subcutaneous xenograft tumors. OBP-301 is a promising antitumor reagent to improve the therapeutic potential of radiotherapy by increasing radiation-induced apoptosis in STS. |
| doi_str_mv | 10.1371/journal.pone.0250643 |
| format | Article |
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Despite major advances in the treatment of STS, patients are often refractory to conventional radiotherapy, leading to poor prognosis. Enhancement of sensitivity to radiotherapy would therefore improve the clinical outcome of STS patients. We previously revealed that the tumor-specific, replication-competent oncolytic adenovirus OBP-301 kills human sarcoma cells. In this study, we investigated the radiosensitizing effect of OBP-301 in human STS cells. The in vitro antitumor effect of OBP-301 and ionizing radiation in monotherapy or combination therapy was assessed using highly radiosensitive (RD-ES and SK-ES-1) and moderately radiosensitive (HT1080 and NMS-2) STS cell lines. The expression of markers for apoptosis and DNA damage were evaluated in STS cells after treatment. The therapeutic potential of combination therapy was further analyzed using SK-ES-1 and HT1080 cells in subcutaneous xenograft tumor models. The combination of OBP-301 and ionizing radiation showed a synergistic antitumor effect in all human STS cell lines tested, including those that show different radiosensitivity. OBP-301 was found to enhance irradiation-induced apoptosis and DNA damage via suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1), which was expressed at higher levels in moderately radiosensitive cell lines. The combination of OBP-301 and ionizing radiation showed a more profound antitumor effect compared to monotherapy in SK-ES-1 (highly radiosensitive) and HT1080 (moderately radiosensitive) subcutaneous xenograft tumors. OBP-301 is a promising antitumor reagent to improve the therapeutic potential of radiotherapy by increasing radiation-induced apoptosis in STS.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0250643</identifier><identifier>PMID: 33886686</identifier><language>eng</language><publisher>SAN FRANCISCO: Public Library Science</publisher><subject>Adenoviruses ; Apoptosis ; Auroral kilometric radiation ; Biology and life sciences ; Biotechnology ; Bone cancer ; Cancer ; Care and treatment ; Chemotherapy ; Clinical medicine ; Data analysis ; Dentistry ; Deoxyribonucleic acid ; DNA ; DNA damage ; DNA repair ; Dosage ; Drug dosages ; Editing ; Ewings sarcoma ; Fibrosarcoma ; Genetic aspects ; Graduate schools ; Graduate studies ; Infections ; Ionizing radiation ; Lymphoma ; Mcl-1 protein ; Medical materials ; Medicine ; Medicine and Health Sciences ; Metastases ; Methodology ; Multidisciplinary Sciences ; Oncolysis ; Orthopedics ; Patients ; Pharmaceutical sciences ; Pharmaceuticals ; Pharmacology ; Physical Sciences ; Physiological aspects ; Proteins ; Radiation ; Radiation dosage ; Radiation therapy ; Radiosensitivity ; Research and analysis methods ; Sarcoma ; Science & Technology ; Science & Technology - Other Topics ; Sensitivity enhancement ; Soft tissue sarcoma ; Soft tissues ; Surgery ; Telomerase ; Tissues ; Tumors ; University graduates</subject><ispartof>PloS one, 2021-04, Vol.16 (4), p.e0250643-e0250643, Article 0250643</ispartof><rights>COPYRIGHT 2021 Public Library of Science</rights><rights>2021 Omori et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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Despite major advances in the treatment of STS, patients are often refractory to conventional radiotherapy, leading to poor prognosis. Enhancement of sensitivity to radiotherapy would therefore improve the clinical outcome of STS patients. We previously revealed that the tumor-specific, replication-competent oncolytic adenovirus OBP-301 kills human sarcoma cells. In this study, we investigated the radiosensitizing effect of OBP-301 in human STS cells. The in vitro antitumor effect of OBP-301 and ionizing radiation in monotherapy or combination therapy was assessed using highly radiosensitive (RD-ES and SK-ES-1) and moderately radiosensitive (HT1080 and NMS-2) STS cell lines. The expression of markers for apoptosis and DNA damage were evaluated in STS cells after treatment. The therapeutic potential of combination therapy was further analyzed using SK-ES-1 and HT1080 cells in subcutaneous xenograft tumor models. The combination of OBP-301 and ionizing radiation showed a synergistic antitumor effect in all human STS cell lines tested, including those that show different radiosensitivity. OBP-301 was found to enhance irradiation-induced apoptosis and DNA damage via suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1), which was expressed at higher levels in moderately radiosensitive cell lines. The combination of OBP-301 and ionizing radiation showed a more profound antitumor effect compared to monotherapy in SK-ES-1 (highly radiosensitive) and HT1080 (moderately radiosensitive) subcutaneous xenograft tumors. OBP-301 is a promising antitumor reagent to improve the therapeutic potential of radiotherapy by increasing radiation-induced apoptosis in STS.</description><subject>Adenoviruses</subject><subject>Apoptosis</subject><subject>Auroral kilometric radiation</subject><subject>Biology and life sciences</subject><subject>Biotechnology</subject><subject>Bone cancer</subject><subject>Cancer</subject><subject>Care and treatment</subject><subject>Chemotherapy</subject><subject>Clinical medicine</subject><subject>Data analysis</subject><subject>Dentistry</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA repair</subject><subject>Dosage</subject><subject>Drug dosages</subject><subject>Editing</subject><subject>Ewings sarcoma</subject><subject>Fibrosarcoma</subject><subject>Genetic aspects</subject><subject>Graduate schools</subject><subject>Graduate studies</subject><subject>Infections</subject><subject>Ionizing 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Shuhei</au><au>Hasei, Joe</au><au>Sugiu, Kazuhisa</au><au>Komatsubara, Tadashi</au><au>Fujiwara, Tomohiro</au><au>Yoshida, Aki</au><au>Kunisada, Toshiyuki</au><au>Urata, Yasuo</au><au>Kagawa, Shunsuke</au><au>Ozaki, Toshifumi</au><au>Fujiwara, Toshiyoshi</au><au>Ulasov, Ilya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Oncolytic virotherapy promotes radiosensitivity in soft tissue sarcoma by suppressing anti-apoptotic MCL1 expression</atitle><jtitle>PloS one</jtitle><stitle>PLOS ONE</stitle><addtitle>PLoS One</addtitle><date>2021-04-22</date><risdate>2021</risdate><volume>16</volume><issue>4</issue><spage>e0250643</spage><epage>e0250643</epage><pages>e0250643-e0250643</pages><artnum>0250643</artnum><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Soft tissue sarcoma (STS) is a rare cancer that develops from soft tissues in any part of the body. Despite major advances in the treatment of STS, patients are often refractory to conventional radiotherapy, leading to poor prognosis. Enhancement of sensitivity to radiotherapy would therefore improve the clinical outcome of STS patients. We previously revealed that the tumor-specific, replication-competent oncolytic adenovirus OBP-301 kills human sarcoma cells. In this study, we investigated the radiosensitizing effect of OBP-301 in human STS cells. The in vitro antitumor effect of OBP-301 and ionizing radiation in monotherapy or combination therapy was assessed using highly radiosensitive (RD-ES and SK-ES-1) and moderately radiosensitive (HT1080 and NMS-2) STS cell lines. The expression of markers for apoptosis and DNA damage were evaluated in STS cells after treatment. The therapeutic potential of combination therapy was further analyzed using SK-ES-1 and HT1080 cells in subcutaneous xenograft tumor models. The combination of OBP-301 and ionizing radiation showed a synergistic antitumor effect in all human STS cell lines tested, including those that show different radiosensitivity. OBP-301 was found to enhance irradiation-induced apoptosis and DNA damage via suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1), which was expressed at higher levels in moderately radiosensitive cell lines. The combination of OBP-301 and ionizing radiation showed a more profound antitumor effect compared to monotherapy in SK-ES-1 (highly radiosensitive) and HT1080 (moderately radiosensitive) subcutaneous xenograft tumors. OBP-301 is a promising antitumor reagent to improve the therapeutic potential of radiotherapy by increasing radiation-induced apoptosis in STS.</abstract><cop>SAN FRANCISCO</cop><pub>Public Library Science</pub><pmid>33886686</pmid><doi>10.1371/journal.pone.0250643</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-4028-0786</orcidid><orcidid>https://orcid.org/0000-0003-4658-1050</orcidid><orcidid>https://orcid.org/0000-0002-4790-933X</orcidid><orcidid>https://orcid.org/0000-0002-5377-6051</orcidid><orcidid>https://orcid.org/0000-0002-1775-850X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2021-04, Vol.16 (4), p.e0250643-e0250643, Article 0250643 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2516827173 |
| source | DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adenoviruses Apoptosis Auroral kilometric radiation Biology and life sciences Biotechnology Bone cancer Cancer Care and treatment Chemotherapy Clinical medicine Data analysis Dentistry Deoxyribonucleic acid DNA DNA damage DNA repair Dosage Drug dosages Editing Ewings sarcoma Fibrosarcoma Genetic aspects Graduate schools Graduate studies Infections Ionizing radiation Lymphoma Mcl-1 protein Medical materials Medicine Medicine and Health Sciences Metastases Methodology Multidisciplinary Sciences Oncolysis Orthopedics Patients Pharmaceutical sciences Pharmaceuticals Pharmacology Physical Sciences Physiological aspects Proteins Radiation Radiation dosage Radiation therapy Radiosensitivity Research and analysis methods Sarcoma Science & Technology Science & Technology - Other Topics Sensitivity enhancement Soft tissue sarcoma Soft tissues Surgery Telomerase Tissues Tumors University graduates |
| title | Oncolytic virotherapy promotes radiosensitivity in soft tissue sarcoma by suppressing anti-apoptotic MCL1 expression |
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