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硫唑嘌呤可拮抗胶质母细胞瘤中异常升高的脂质代谢并诱导其凋亡。

Azathioprine antagonizes aberrantly elevated lipid metabolism and induces apoptosis in glioblastoma.

作者信息

Nam Hye Jin, Kim Young Eun, Moon Byoung-San, Kim Hyun Young, Jung Daeyoung, Choi Seungho, Jang Jeong Woon, Nam Do-Hyun, Cho Heeyeong

机构信息

Drug Discovery Platform Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.

Department of Biotechnology, Chonnam National University, Yeosu 59626, Republic of Korea.

出版信息

iScience. 2021 Feb 26;24(3):102238. doi: 10.1016/j.isci.2021.102238. eCollection 2021 Mar 19.

DOI:10.1016/j.isci.2021.102238
PMID:33748720
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7957120/
Abstract

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.

摘要

多形性胶质母细胞瘤（GBM）是最具侵袭性的脑肿瘤类型，生存率低。替莫唑胺（TMZ）用作治疗GBM的标准化疗药物，但大量患者反应不佳和/或长期使用后产生耐药性，这凸显了开发具有新作用机制的有效药物的必要性。在此，我们通过高通量化合物筛选（HTS）发现，免疫抑制剂硫唑嘌呤是治疗TMZ耐药GBM的一种有前景的治疗药物。通过综合全基因组分析和全局蛋白质组分析，我们发现硫唑嘌呤抑制了可能由于EGFR/AKT/SREBP-1信号过度活跃导致的脂质代谢升高。硫唑嘌呤还促进内质网应激诱导的细胞凋亡。对注射了患者来源GBM细胞的原位异种移植模型的分析显示，硫唑嘌呤和TMZ联合治疗后肿瘤体积减小，细胞凋亡增加。这些数据表明，硫唑嘌呤可能是TMZ耐药GBM患者的一种有效治疗选择。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2da/7957120/57ace932f1ae/gr7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2da/7957120/e64a55904365/gr3.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2da/7957120/7b3ee0c9edb3/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2da/7957120/16f6a6b5f915/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2da/7957120/57ace932f1ae/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2da/7957120/03077d425464/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2da/7957120/f8866cd802d0/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2da/7957120/4c5bce8682a9/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2da/7957120/e64a55904365/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2da/7957120/dffd445bd58e/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2da/7957120/7b3ee0c9edb3/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2da/7957120/16f6a6b5f915/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2da/7957120/57ace932f1ae/gr7.jpg

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