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Irinotecan Induces Autophagy-Dependent Apoptosis and Positively Regulates ROS-Related JNK- and P38-MAPK Pathways in Gastric Cancer Cells
BACKGROUND: Irinotecan (IRI) is considered an option for second-line treatment of advanced gastric cancer; however, acquired drug resistance currently limits its clinical application. Recently, many researchers have shown that autophagy plays a crucial role in the resistance of tumor cells to chemot...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135144/ https://www.ncbi.nlm.nih.gov/pubmed/32308415 http://dx.doi.org/10.2147/OTT.S240803 |
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author | Zhu, Qingyun Guo, Yuehui Chen, Shiwei Fu, Daiquan Li, Yanxiang Li, Zhi Ni, Caifang |
author_facet | Zhu, Qingyun Guo, Yuehui Chen, Shiwei Fu, Daiquan Li, Yanxiang Li, Zhi Ni, Caifang |
author_sort | Zhu, Qingyun |
collection | PubMed |
description | BACKGROUND: Irinotecan (IRI) is considered an option for second-line treatment of advanced gastric cancer; however, acquired drug resistance currently limits its clinical application. Recently, many researchers have shown that autophagy plays a crucial role in the resistance of tumor cells to chemotherapy and radiotherapy. In this study, we investigated the relationship between autophagy and antitumor activity of IRI in gastric cancer cells. METHODS: We used MTT assay, flow cytometry and immunofluorescence staining to detect viability, apoptosis and autophagy in gastric cancer. Western blotting assay was used to determine the expression of LC3, Beclin-1, P62, cleaved PARP and Caspase 3. In vivo animal study was performed finally. RESULTS: We found that IRI treatment dose- and time-dependently inhibited growth and induced apoptosis in gastric cancer cells. Moreover, IRI treatment caused autophagy in these cells, whereas autophagy inhibitors—3-methyladenine (3-MA), chloroquine (CQ), and Beclin-1 small interfering RNA (siRNA)—suppressed cytotoxicity of IRI. A mechanistic analysis showed that IRI-induced autophagy and apoptosis were related to increased reactive oxygen species (ROS) accumulation and activation of the JNK- and p38-MAPK pathways. Further in vivo experiments revealed that IRI suppressed tumor growth, induced autophagy, and stimulated the JNK- and p38-MAPK pathways, whereas 3-MA attenuated these effects. CONCLUSION: Taken together, these results indicate that IRI stimulates the ROS-related JNK- and p38-MAPK pathways to promote autophagy-dependent apoptosis. Thus, a combination of IRI with a pharmacological autophagy enhancer may be a promising therapeutic strategy against gastric cancer. |
format | Online Article Text |
id | pubmed-7135144 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Dove |
record_format | MEDLINE/PubMed |
spelling | pubmed-71351442020-04-17 Irinotecan Induces Autophagy-Dependent Apoptosis and Positively Regulates ROS-Related JNK- and P38-MAPK Pathways in Gastric Cancer Cells Zhu, Qingyun Guo, Yuehui Chen, Shiwei Fu, Daiquan Li, Yanxiang Li, Zhi Ni, Caifang Onco Targets Ther Original Research BACKGROUND: Irinotecan (IRI) is considered an option for second-line treatment of advanced gastric cancer; however, acquired drug resistance currently limits its clinical application. Recently, many researchers have shown that autophagy plays a crucial role in the resistance of tumor cells to chemotherapy and radiotherapy. In this study, we investigated the relationship between autophagy and antitumor activity of IRI in gastric cancer cells. METHODS: We used MTT assay, flow cytometry and immunofluorescence staining to detect viability, apoptosis and autophagy in gastric cancer. Western blotting assay was used to determine the expression of LC3, Beclin-1, P62, cleaved PARP and Caspase 3. In vivo animal study was performed finally. RESULTS: We found that IRI treatment dose- and time-dependently inhibited growth and induced apoptosis in gastric cancer cells. Moreover, IRI treatment caused autophagy in these cells, whereas autophagy inhibitors—3-methyladenine (3-MA), chloroquine (CQ), and Beclin-1 small interfering RNA (siRNA)—suppressed cytotoxicity of IRI. A mechanistic analysis showed that IRI-induced autophagy and apoptosis were related to increased reactive oxygen species (ROS) accumulation and activation of the JNK- and p38-MAPK pathways. Further in vivo experiments revealed that IRI suppressed tumor growth, induced autophagy, and stimulated the JNK- and p38-MAPK pathways, whereas 3-MA attenuated these effects. CONCLUSION: Taken together, these results indicate that IRI stimulates the ROS-related JNK- and p38-MAPK pathways to promote autophagy-dependent apoptosis. Thus, a combination of IRI with a pharmacological autophagy enhancer may be a promising therapeutic strategy against gastric cancer. Dove 2020-04-02 /pmc/articles/PMC7135144/ /pubmed/32308415 http://dx.doi.org/10.2147/OTT.S240803 Text en © 2020 Zhu et al. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). |
spellingShingle | Original Research Zhu, Qingyun Guo, Yuehui Chen, Shiwei Fu, Daiquan Li, Yanxiang Li, Zhi Ni, Caifang Irinotecan Induces Autophagy-Dependent Apoptosis and Positively Regulates ROS-Related JNK- and P38-MAPK Pathways in Gastric Cancer Cells |
title | Irinotecan Induces Autophagy-Dependent Apoptosis and Positively Regulates ROS-Related JNK- and P38-MAPK Pathways in Gastric Cancer Cells |
title_full | Irinotecan Induces Autophagy-Dependent Apoptosis and Positively Regulates ROS-Related JNK- and P38-MAPK Pathways in Gastric Cancer Cells |
title_fullStr | Irinotecan Induces Autophagy-Dependent Apoptosis and Positively Regulates ROS-Related JNK- and P38-MAPK Pathways in Gastric Cancer Cells |
title_full_unstemmed | Irinotecan Induces Autophagy-Dependent Apoptosis and Positively Regulates ROS-Related JNK- and P38-MAPK Pathways in Gastric Cancer Cells |
title_short | Irinotecan Induces Autophagy-Dependent Apoptosis and Positively Regulates ROS-Related JNK- and P38-MAPK Pathways in Gastric Cancer Cells |
title_sort | irinotecan induces autophagy-dependent apoptosis and positively regulates ros-related jnk- and p38-mapk pathways in gastric cancer cells |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135144/ https://www.ncbi.nlm.nih.gov/pubmed/32308415 http://dx.doi.org/10.2147/OTT.S240803 |
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