期刊
ISCIENCE
卷 24, 期 3, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.isci.2021.102238
关键词
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资金
- Korea Research Institute of Chemical Technology [SI-2031-50]
- Bio & Medical Technology Development Program of the National Research Foundation (NRF) - Ministry of Science ICT [2020M3A9I4036072]
- National Research Foundation of Korea [2020M3A9I4036072] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Azathioprine is a promising therapeutic agent for treating TMZ-resistant GBM by inhibiting hyperactive EGFR/AKT/SREBP-1 signaling and promoting ER stress-induced apoptosis.
Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor with poor survival rate. Temozolomide (TMZ) is used as standard chemotherapy to treat GBM, but a large number of patients either respond poorly and/or develop resistance after long-term use, emphasizing the need to develop potent drugs with novel mechanisms of action. Here, using high-throughput compound screening (HTS), we found that azathioprine, an immunosuppressant, is a promising therapeutic agent to treat TMZ-resistant GBM. Through integrative genome-wide analysis and global proteomic analysis, we found that elevated lipid metabolism likely due to hyperactive EGFR/AKT/SREBP-1 signaling was inhibited by azathioprine. Azathioprine also promoted ER stress-induced apoptosis. Analysis of orthotopic xenograft models injected with patient-derived GBM cells revealed reduced tumor volume and increased apoptosis after azathioprine and TMZ co-treatment. These data indicate that azathioprine could be a powerful therapeutic option for TMZ-resistant GBM patients.
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