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DNA-PK inhibition synergizes with oncolytic virus M1 by inhibiting antiviral response and potentiating DNA damage

Oncolytic virotherapy is a promising therapeutic strategy that uses replication-competent viruses to selectively destroy malignancies. However, the therapeutic effect of certain oncolytic viruses (OVs) varies among cancer patients. Thus, it is necessary to overcome resistance to OVs through rational...

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Autores principales: Xiao, Xiao, Liang, Jiankai, Huang, Chunlong, Li, Kai, Xing, Fan, Zhu, Wenbo, Lin, Ziqing, Xu, Wencang, Wu, Guangen, Zhang, Jifu, Lin, Xi, Tan, Yaqian, Cai, Jing, Hu, Jun, Chen, Xueqin, Huang, Youwei, Qin, Zixi, Qiu, Pengxin, Su, Xingwen, Chen, Lijun, Lin, Yuan, Zhang, Haipeng, Yan, Guangmei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194050/
https://www.ncbi.nlm.nih.gov/pubmed/30337542
http://dx.doi.org/10.1038/s41467-018-06771-4
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author Xiao, Xiao
Liang, Jiankai
Huang, Chunlong
Li, Kai
Xing, Fan
Zhu, Wenbo
Lin, Ziqing
Xu, Wencang
Wu, Guangen
Zhang, Jifu
Lin, Xi
Tan, Yaqian
Cai, Jing
Hu, Jun
Chen, Xueqin
Huang, Youwei
Qin, Zixi
Qiu, Pengxin
Su, Xingwen
Chen, Lijun
Lin, Yuan
Zhang, Haipeng
Yan, Guangmei
author_facet Xiao, Xiao
Liang, Jiankai
Huang, Chunlong
Li, Kai
Xing, Fan
Zhu, Wenbo
Lin, Ziqing
Xu, Wencang
Wu, Guangen
Zhang, Jifu
Lin, Xi
Tan, Yaqian
Cai, Jing
Hu, Jun
Chen, Xueqin
Huang, Youwei
Qin, Zixi
Qiu, Pengxin
Su, Xingwen
Chen, Lijun
Lin, Yuan
Zhang, Haipeng
Yan, Guangmei
author_sort Xiao, Xiao
collection PubMed
description Oncolytic virotherapy is a promising therapeutic strategy that uses replication-competent viruses to selectively destroy malignancies. However, the therapeutic effect of certain oncolytic viruses (OVs) varies among cancer patients. Thus, it is necessary to overcome resistance to OVs through rationally designed combination strategies. Here, through an anticancer drug screening, we show that DNA-dependent protein kinase (DNA-PK) inhibition sensitizes cancer cells to OV M1 and improves therapeutic effects in refractory cancer models in vivo and in patient tumour samples. Infection of M1 virus triggers the transcription of interferons (IFNs) and the activation of the antiviral response, which can be abolished by pretreatment of DNA-PK inhibitor (DNA-PKI), resulting in selectively enhanced replication of OV M1 within malignancies. Furthermore, DNA-PK inhibition promotes the DNA damage response induced by M1 virus, leading to increased tumour cell apoptosis. Together, our study identifies the combination of DNA-PKI and OV M1 as a potential treatment for cancers.
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spelling pubmed-61940502018-10-22 DNA-PK inhibition synergizes with oncolytic virus M1 by inhibiting antiviral response and potentiating DNA damage Xiao, Xiao Liang, Jiankai Huang, Chunlong Li, Kai Xing, Fan Zhu, Wenbo Lin, Ziqing Xu, Wencang Wu, Guangen Zhang, Jifu Lin, Xi Tan, Yaqian Cai, Jing Hu, Jun Chen, Xueqin Huang, Youwei Qin, Zixi Qiu, Pengxin Su, Xingwen Chen, Lijun Lin, Yuan Zhang, Haipeng Yan, Guangmei Nat Commun Article Oncolytic virotherapy is a promising therapeutic strategy that uses replication-competent viruses to selectively destroy malignancies. However, the therapeutic effect of certain oncolytic viruses (OVs) varies among cancer patients. Thus, it is necessary to overcome resistance to OVs through rationally designed combination strategies. Here, through an anticancer drug screening, we show that DNA-dependent protein kinase (DNA-PK) inhibition sensitizes cancer cells to OV M1 and improves therapeutic effects in refractory cancer models in vivo and in patient tumour samples. Infection of M1 virus triggers the transcription of interferons (IFNs) and the activation of the antiviral response, which can be abolished by pretreatment of DNA-PK inhibitor (DNA-PKI), resulting in selectively enhanced replication of OV M1 within malignancies. Furthermore, DNA-PK inhibition promotes the DNA damage response induced by M1 virus, leading to increased tumour cell apoptosis. Together, our study identifies the combination of DNA-PKI and OV M1 as a potential treatment for cancers. Nature Publishing Group UK 2018-10-18 /pmc/articles/PMC6194050/ /pubmed/30337542 http://dx.doi.org/10.1038/s41467-018-06771-4 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Xiao, Xiao
Liang, Jiankai
Huang, Chunlong
Li, Kai
Xing, Fan
Zhu, Wenbo
Lin, Ziqing
Xu, Wencang
Wu, Guangen
Zhang, Jifu
Lin, Xi
Tan, Yaqian
Cai, Jing
Hu, Jun
Chen, Xueqin
Huang, Youwei
Qin, Zixi
Qiu, Pengxin
Su, Xingwen
Chen, Lijun
Lin, Yuan
Zhang, Haipeng
Yan, Guangmei
DNA-PK inhibition synergizes with oncolytic virus M1 by inhibiting antiviral response and potentiating DNA damage
title DNA-PK inhibition synergizes with oncolytic virus M1 by inhibiting antiviral response and potentiating DNA damage
title_full DNA-PK inhibition synergizes with oncolytic virus M1 by inhibiting antiviral response and potentiating DNA damage
title_fullStr DNA-PK inhibition synergizes with oncolytic virus M1 by inhibiting antiviral response and potentiating DNA damage
title_full_unstemmed DNA-PK inhibition synergizes with oncolytic virus M1 by inhibiting antiviral response and potentiating DNA damage
title_short DNA-PK inhibition synergizes with oncolytic virus M1 by inhibiting antiviral response and potentiating DNA damage
title_sort dna-pk inhibition synergizes with oncolytic virus m1 by inhibiting antiviral response and potentiating dna damage
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194050/
https://www.ncbi.nlm.nih.gov/pubmed/30337542
http://dx.doi.org/10.1038/s41467-018-06771-4
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