Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling
Ciclopirox (CPX) is an antifungal drug that has recently been reported to act as a potential anticancer drug. However, the effects and underlying molecular mechanisms of CPX on glioblastoma multiforme (GBM) remain unknown. Bortezomib (BTZ) is the first proteasome inhibitor-based anticancer drug appr...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935936/ https://www.ncbi.nlm.nih.gov/pubmed/33674562 http://dx.doi.org/10.1038/s41419-021-03535-9 |
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author | Su, Zhipeng Han, Shengnan Jin, Qiumei Zhou, Ningning Lu, Junwan Shangguan, Fugen Yu, Shiyi Liu, Yongzhang Wang, Lu Lu, Jianglong Li, Qun Cai, Lin Wang, Chengde Tian, Xiaohe Chen, Lingyan Zheng, Weiming Lu, Bin |
author_facet | Su, Zhipeng Han, Shengnan Jin, Qiumei Zhou, Ningning Lu, Junwan Shangguan, Fugen Yu, Shiyi Liu, Yongzhang Wang, Lu Lu, Jianglong Li, Qun Cai, Lin Wang, Chengde Tian, Xiaohe Chen, Lingyan Zheng, Weiming Lu, Bin |
author_sort | Su, Zhipeng |
collection | PubMed |
description | Ciclopirox (CPX) is an antifungal drug that has recently been reported to act as a potential anticancer drug. However, the effects and underlying molecular mechanisms of CPX on glioblastoma multiforme (GBM) remain unknown. Bortezomib (BTZ) is the first proteasome inhibitor-based anticancer drug approved to treat multiple myeloma and mantle cell lymphoma, as BTZ exhibits toxic effects on diverse tumor cells. Herein, we show that CPX displays strong anti-tumorigenic activity on GBM. Mechanistically, CPX inhibits GBM cellular migration and invasion by reducing N-Cadherin, MMP9 and Snail expression. Further analysis revealed that CPX suppresses the expression of several key subunits of mitochondrial enzyme complex, thus leading to the disruption of mitochondrial oxidative phosphorylation (OXPHOS) in GBM cells. In combination with BTZ, CPX promotes apoptosis in GBM cells through the induction of reactive oxygen species (ROS)-mediated c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) signaling. Moreover, CPX and BTZ synergistically activates nuclear factor kappa B (NF-κB) signaling and induces cellular senescence. Our findings suggest that a combination of CPX and BTZ may serve as a novel therapeutic strategy to enhance the anticancer activity of CPX against GBM. |
format | Online Article Text |
id | pubmed-7935936 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-79359362021-03-19 Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling Su, Zhipeng Han, Shengnan Jin, Qiumei Zhou, Ningning Lu, Junwan Shangguan, Fugen Yu, Shiyi Liu, Yongzhang Wang, Lu Lu, Jianglong Li, Qun Cai, Lin Wang, Chengde Tian, Xiaohe Chen, Lingyan Zheng, Weiming Lu, Bin Cell Death Dis Article Ciclopirox (CPX) is an antifungal drug that has recently been reported to act as a potential anticancer drug. However, the effects and underlying molecular mechanisms of CPX on glioblastoma multiforme (GBM) remain unknown. Bortezomib (BTZ) is the first proteasome inhibitor-based anticancer drug approved to treat multiple myeloma and mantle cell lymphoma, as BTZ exhibits toxic effects on diverse tumor cells. Herein, we show that CPX displays strong anti-tumorigenic activity on GBM. Mechanistically, CPX inhibits GBM cellular migration and invasion by reducing N-Cadherin, MMP9 and Snail expression. Further analysis revealed that CPX suppresses the expression of several key subunits of mitochondrial enzyme complex, thus leading to the disruption of mitochondrial oxidative phosphorylation (OXPHOS) in GBM cells. In combination with BTZ, CPX promotes apoptosis in GBM cells through the induction of reactive oxygen species (ROS)-mediated c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) signaling. Moreover, CPX and BTZ synergistically activates nuclear factor kappa B (NF-κB) signaling and induces cellular senescence. Our findings suggest that a combination of CPX and BTZ may serve as a novel therapeutic strategy to enhance the anticancer activity of CPX against GBM. Nature Publishing Group UK 2021-03-05 /pmc/articles/PMC7935936/ /pubmed/33674562 http://dx.doi.org/10.1038/s41419-021-03535-9 Text en © The Author(s) 2021 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 Su, Zhipeng Han, Shengnan Jin, Qiumei Zhou, Ningning Lu, Junwan Shangguan, Fugen Yu, Shiyi Liu, Yongzhang Wang, Lu Lu, Jianglong Li, Qun Cai, Lin Wang, Chengde Tian, Xiaohe Chen, Lingyan Zheng, Weiming Lu, Bin Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling |
title | Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling |
title_full | Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling |
title_fullStr | Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling |
title_full_unstemmed | Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling |
title_short | Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling |
title_sort | ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing jnk/p38 mapk and nf-κb signaling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935936/ https://www.ncbi.nlm.nih.gov/pubmed/33674562 http://dx.doi.org/10.1038/s41419-021-03535-9 |
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