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Cancer Chemotherapy and Pharmacology

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08.07.2019 | Original Article

Celastrol enhances TRAIL-induced apoptosis in human glioblastoma via the death receptor pathway

verfasst von: Zhe Cha, Jianzhang Cheng, Hui Xiang, Jingjing Qin, Yujia He, Zhiping Peng, Jianhua Jia, Huarong Yu

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 4/2019

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Abstract

Purpose

Glioblastoma is the most common, malignant and devastating type of primary brain tumor. Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) is characterized by its lethality to precancerous and cancerous cells. However, many kinds of tumor cells, including most glioma cells, tend to evade TRAIL-induced apoptosis. Celastrol is a pleiotropic compound from a traditional Chinese medicine that has proven to be useful as a sensitizer for TRAIL treatment. However, the underlying mechanism and role of celastrol in the sensitization of glioma cells remain to be elucidated.

Methods

The viability of glioma cell lines was examined by the CCK-8 assay. The expression of DR5 was detected by reverse transcriptase quantitative real-time PCR. The protein expression of DR5, cleaved caspase-8, cleaved caspase-3 and PARP were measured by western blot. The apoptosis rates and the sub-G1 population were detected by flow cytometry. The cellular morphological changes were assessed by TUNEL apoptosis and Hoechst 33258 staining assays. The knockdown of DR5 expression was conducted by siRNA.

Results

In this study, we observed that celastrol treatment inhibited cell viability in a dose-dependent manner, while glioma and normal human astroglial cell lines were resistant to TRAIL treatment. We also observed that the antiproliferative effects of TRAIL in combination with a noncytotoxic concentration of celastrol were significantly greater than those of celastrol or TRAIL alone. In addition, cell death induced by the combination treatment was apoptotic and occurred through the death receptor pathway via activation of caspase-8, caspase-3, and PARP. Furthermore, celastrol upregulated death receptor 5 (DR5) at the mRNA and protein levels, and siRNA-mediated DR5 knockdown reduced the killing effect of the combination drug treatment on glioma cells and reduced the activation of caspase-3, caspase-8 and PARP.

Conclusions

Taken together, the results of our study demonstrate that celastrol sensitizes glioma cells to TRAIL via the death receptor pathway and that DR5 plays an important role in the effects of this cotreatment. The results indicate that this cotreatment is a promising tumor-killing therapeutic strategy with high efficacy and low toxicity.

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Titel: Celastrol enhances TRAIL-induced apoptosis in human glioblastoma via the death receptor pathway
verfasst von: Zhe Cha
Jianzhang Cheng
Hui Xiang
Jingjing Qin
Yujia He
Zhiping Peng
Jianhua Jia
Huarong Yu
Publikationsdatum: 08.07.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 4/2019
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-019-03900-8

Springer Medizin

Celastrol enhances TRAIL-induced apoptosis in human glioblastoma via the death receptor pathway