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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
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.
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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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