التفاصيل البيبلوغرافية
| العنوان: |
Novel Targeting of Transcription and Metabolism in Glioblastoma |
| المؤلفون: |
Chunzhang Yang, Dragan Maric, Jing Wu, Li-Yuan Chen, Herui Wang, Kristan Meetze, Wei Zhang, Zhengping Zhuang, Mioara Larion, Hallie Lappin, Gabriel Vasconcelos, Adrian Lita, Mones Abu-Asab, Mark R. Gilbert, Yu-Ting Su, Hua Song, Tomas Estok, Qi Zhang, Orieta Celiku, Aiguo Li, Robert T. Chen |
| المصدر: |
Clin Cancer Res |
| سنة النشر: |
2017 |
| مصطلحات موضوعية: |
0301 basic medicine, Cancer Research, Programmed cell death, Transcription, Genetic, Drug Evaluation, Preclinical, Apoptosis, Biology, Heterocyclic Compounds, 4 or More Rings, Article, 03 medical and health sciences, Mice, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, medicine, Temozolomide, Animals, Humans, Cytotoxicity, Cell Proliferation, Cell growth, Brain Neoplasms, Brain, Drug Synergism, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Cell killing, Oncology, Cell culture, Cancer cell, Cancer research, Energy Metabolism, Glioblastoma, medicine.drug |
| الوصف: |
Purpose: Glioblastoma (GBM) is highly resistant to treatment, largely due to disease heterogeneity and resistance mechanisms. We sought to investigate a promising drug that can inhibit multiple aspects of cancer cell survival mechanisms and become an effective therapeutic for GBM patients. Experimental Design: To investigate TG02, an agent with known penetration of the blood–brain barrier, we examined the effects as single agent and in combination with temozolomide, a commonly used chemotherapy in GBM. We used human GBM cells and a syngeneic mouse orthotopic GBM model, evaluating survival and the pharmacodynamics of TG02. Mechanistic studies included TG02-induced transcriptional regulation, apoptosis, and RNA sequencing in treated GBM cells as well as the investigation of mitochondrial and glycolytic function assays. Results: We demonstrated that TG02 inhibited cell proliferation, induced cell death, and synergized with temozolomide in GBM cells with different genetic background but not in astrocytes. TG02-induced cytotoxicity was blocked by the overexpression of phosphorylated CDK9, suggesting a CDK9-dependent cell killing. TG02 suppressed transcriptional progression of antiapoptotic proteins and induced apoptosis in GBM cells. We further demonstrated that TG02 caused mitochondrial dysfunction and glycolytic suppression and ultimately ATP depletion in GBM. A prolonged survival was observed in GBM mice receiving combined treatment of TG02 and temozolomide. The TG02-induced decrease of CDK9 phosphorylation was confirmed in the brain tumor tissue. Conclusions: TG02 inhibits multiple survival mechanisms and synergistically decreases energy production with temozolomide, representing a promising therapeutic strategy in GBM, currently under investigation in an ongoing clinical trial. Clin Cancer Res; 24(5); 1124–37. ©2017 AACR. |
| اللغة: |
English |
| الوصول الحر: |
https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2c3bdab4cdbaa22e54c0ad3b91504c74Test
https://europepmc.org/articles/PMC8108069Test/ |
| حقوق: |
OPEN |
| رقم الانضمام: |
edsair.doi.dedup.....2c3bdab4cdbaa22e54c0ad3b91504c74 |
| قاعدة البيانات: |
OpenAIRE |
