PMID- 31281953 OWN - NLM STAT- MEDLINE DCOM- 20200512 LR - 20230907 IS - 1432-0843 (Electronic) IS - 0344-5704 (Linking) VI - 84 IP - 4 DP - 2019 Oct TI - Celastrol enhances TRAIL-induced apoptosis in human glioblastoma via the death receptor pathway. PG - 719-728 LID - 10.1007/s00280-019-03900-8 [doi] AB - 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. FAU - Cha, Zhe AU - Cha Z AD - Research Center of Neuroscience, Chongqing Medical University, No. 1 of Yixueyuan Road, Yuzhong District, Chongqing, 400016, China. FAU - Cheng, Jianzhang AU - Cheng J AD - Research Center of Neuroscience, Chongqing Medical University, No. 1 of Yixueyuan Road, Yuzhong District, Chongqing, 400016, China. FAU - Xiang, Hui AU - Xiang H AD - Research Center of Neuroscience, Chongqing Medical University, No. 1 of Yixueyuan Road, Yuzhong District, Chongqing, 400016, China. FAU - Qin, Jingjing AU - Qin J AD - Research Center of Neuroscience, Chongqing Medical University, No. 1 of Yixueyuan Road, Yuzhong District, Chongqing, 400016, China. FAU - He, Yujia AU - He Y AD - Laboratory of Radiological Medicine, Chongqing Medical University, Chongqing, 400016, China. FAU - Peng, Zhiping AU - Peng Z AD - Laboratory of Radiological Medicine, Chongqing Medical University, Chongqing, 400016, China. FAU - Jia, Jianhua AU - Jia J AD - Laboratory of Radiological Medicine, Chongqing Medical University, Chongqing, 400016, China. FAU - Yu, Huarong AU - Yu H AUID- ORCID: 0000-0002-0763-8379 AD - Research Center of Neuroscience, Chongqing Medical University, No. 1 of Yixueyuan Road, Yuzhong District, Chongqing, 400016, China. yuhuarong@cqmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190708 PL - Germany TA - Cancer Chemother Pharmacol JT - Cancer chemotherapy and pharmacology JID - 7806519 RN - 0 (Antineoplastic Agents) RN - 0 (Drugs, Chinese Herbal) RN - 0 (Pentacyclic Triterpenes) RN - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand) RN - 0 (TNF-Related Apoptosis-Inducing Ligand) RN - 0 (Triterpenes) RN - L8GG98663L (celastrol) SB - IM MH - Antineoplastic Agents/pharmacokinetics MH - Apoptosis/*drug effects MH - Brain Neoplasms/drug therapy/metabolism/pathology MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Cell Survival/*drug effects MH - Drug Synergism MH - Drugs, Chinese Herbal/pharmacokinetics MH - Glioblastoma/drug therapy/metabolism/pathology MH - Humans MH - Pentacyclic Triterpenes MH - Receptors, TNF-Related Apoptosis-Inducing Ligand/*metabolism MH - *TNF-Related Apoptosis-Inducing Ligand/metabolism/pharmacology MH - Tripterygium MH - Triterpenes/*pharmacokinetics MH - Up-Regulation OTO - NOTNLM OT - Apoptosis OT - Celastrol OT - DR5 OT - TRAIL OT - U87-MG EDAT- 2019/07/10 06:00 MHDA- 2020/05/19 06:00 CRDT- 2019/07/09 06:00 PHST- 2019/02/20 00:00 [received] PHST- 2019/06/18 00:00 [accepted] PHST- 2019/07/10 06:00 [pubmed] PHST- 2020/05/19 06:00 [medline] PHST- 2019/07/09 06:00 [entrez] AID - 10.1007/s00280-019-03900-8 [pii] AID - 10.1007/s00280-019-03900-8 [doi] PST - ppublish SO - Cancer Chemother Pharmacol. 2019 Oct;84(4):719-728. doi: 10.1007/s00280-019-03900-8. Epub 2019 Jul 8.