Ciclopirox and bortezomib synergistically inhibits glioblastoma multiforme growth via simultaneously enhancing JNK/p38 MAPK and NF-κB signaling

Abstract

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.

Glutathione S-Transferases S1, Z1 and A1 Serve as Prognostic Factors in Glioblastoma and Promote Drug Resistance through Antioxidant Pathways

“…The GSH redox system plays an important role in cell survival and apoptosis [ 52 , 53 , 54 ], and inhibition of HPGDS was found to result in a downregulation of the GSH levels and a reduction in cellular drug resistance. Considering that the JNK pathway plays an important role in promoting apoptosis in glioma, and a variety of GSTs can regulate the activation of the JNK signaling pathway [ 42 , 55 , 56 ], we speculate that the resistance-promoting function of HPGDS is partly attributable to the inhibition of apoptosis resulting from downregulated activation of the JNK pathway. In this study, inhibition of HPGDS led to significant activation of JNK phosphorylation, and interference with the activation of the JNK pathway reversed the reduction in cell drug resistance caused by inhibition of HPGDS, indicating that HPGDS functions similarly to other GSTs in regulating the activation level of apoptotic pathways.…”

Ciclopirox drives growth arrest and autophagic cell death through STAT3 in gastric cancer cells

“…CPX, an antifungal agent off-patent for several decades, was recently found to have remarkable antitumor effects via growth arrest or cell death induction in various cancers [ 8 , 9 , 25 , 40 ]. Here, we demonstrated the role of CPX in regulating proliferation inhibition and autophagic death of GC cells.…”

“…CPX has been considered a potential antitumor agent due to its therapeutic potential in preclinical models of various cancers. For instance, CPX inhibits tumorigenesis by inducing apoptosis and protective autophagy in multiple cancers, such as colorectal cancer, glioma, and cervical carcinoma [ 7 , 9 , 25 , 41 ]. However, our study showed that CPX triggers autophagic death rather than apoptotic death in GC cells.…”

Hesperidin Protects SH−SY5Y Neuronal Cells against High Glucose−Induced Apoptosis via Regulation of MAPK Signaling

“…The MAPK pathway has been reported to participate in cell proliferation, senescence, and apoptosis [ 48 ]. The other two studies also showed that a high glucose level triggered DNA damage response and dysregulated MAPK via excessive ROS in hyperglycemia, and an unfolded protein response in ER stress could regulate phosphorylation of JNK causing apoptosis [ 5 , 49 ].…”