Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling
| Autor: | Lu Wang, Ningning Zhou, Weiming Zheng, Jianglong Lu, Fugen Shangguan, Qiumei Jin, Lingyan Chen, Lin Cai, Chengde Wang, Junwan Lu, Shengnan Han, Shiyi Yu, Xiaohe Tian, Yongzhang Liu, Zhipeng Su, Bin Lu, Qun Li |
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| Rok vydání: | 2021 |
| Předmět: |
Male
MAPK/ERK pathway Cancer Research p38 mitogen-activated protein kinases Immunology Antifungal drug Mice Nude Apoptosis Drug development p38 Mitogen-Activated Protein Kinases Oxidative Phosphorylation Article Bortezomib Cellular and Molecular Neuroscience Cell Movement Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans Neoplasm Invasiveness lcsh:QH573-671 Protein kinase A Cell Proliferation Mice Inbred BALB C lcsh:Cytology Brain Neoplasms Chemistry Kinase JNK Mitogen-Activated Protein Kinases NF-kappa B Drug Synergism Cell Biology Ciclopirox Xenograft Model Antitumor Assays Cancer metabolism Tumor Burden Proteasome inhibitor Cancer research Glioblastoma Reactive Oxygen Species Signal Transduction medicine.drug |
| Zdroj: | Cell Death & Disease Cell Death and Disease, Vol 12, Iss 3, Pp 1-13 (2021) |
| ISSN: | 2041-4889 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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