Cassane diterpenoid derivative induces apoptosis in IDH1 mutant glioma cells through the inhibition of glutaminase in vitro and in vivo
Cassane diterpenoid derivative induces apoptosis in IDH1 mutant glioma cells through the inhibition of glutaminase in vitro and in vivo
复制标题
卡桑二萜衍生物通过体内外抑制谷氨酰胺酶诱导 IDH1 突变胶质瘤细胞凋亡
DOI：
10.1016/j.phymed.2020.153434
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发表时间：
2021-01-30
期刊：
影响因子：
7.9
通讯作者：
Chen, Lei
中科院分区：
文献类型：
--
作者：
Huang, Guo-dong;Chen, Fan-fan;Chen, Lei
背景：多形性胶质母细胞瘤（GBM）是成人中枢神经系统最常见、最致命、最具侵袭性的肿瘤。基于异柠檬酸脱氢酶（IDH）突变体表型和分类的新型抗GBM药物的发现引起了广泛的关注。目的：二萜类化合物是一类天然存在的20-碳类异戊二烯化合物，许多科学报道显示其对多种人类肿瘤具有高细胞毒性。本研究共鉴定出4种类型的31个卡桑二萜类化合物，即丁内酯类（I）（1-10）、三环类（II）（11-15）、聚氧丁内酯类（III）（16-23）和稠合呋喃环类（IV）（24-31），基于原代GBM细胞培养物和人少突胶质细胞瘤（HOG）细胞系的IDH 1突变体表型，测试它们的抗胶质母细胞瘤活性和潜在机制。我们证实，三环型（II）和化合物13（Caesalpin A，CSA）在IDH 1突变型胶质瘤细胞中显示出最好的抗肿瘤效力，与其他类型和化合物相比。此外，结构关系分析表明，在C-12位的羰基和α，β-不饱和酮单元从根本上有助于增强抗胶质瘤活性。研究其机制的研究表明，CSA通过引起谷胱甘肽还原和负性调节谷胱甘肽转移酶（GLS）激活NOS来诱导氧化应激，这被证明高度依赖于IDH突变型胶质母细胞瘤。GLS过表达逆转了CsA诱导的HOG-IDH 1-mu细胞的体外和体内抗胶质瘤效应，表明GLS的减少参与了CsA诱导的HOG-IDH 1-mu细胞增殖抑制和凋亡。因此，本研究结果表明，与其他二萜类化合物相比，三环型二萜类化合物可能是通过负调节GLS治疗继发性IDH 1突变型胶质母细胞瘤的靶向候选药物。
Background: Glioblastoma multiforme (GBM) is the most frequent, lethal and aggressive tumour of the central nervous system in adults. The discovery of novel anti-GBM agents based on the isocitrate dehydrogenase (IDH) mutant phenotypes and classifications have attracted comprehensive attention.Purpose: Diterpenoids are a class of naturally occurring 20-carbon isoprenoid compounds, and have previously been shown to possess high cytotoxicity for a variety of human tumours in many scientific reports. In the present study, 31 cassane diterpenoids of four types, namely, butanolide lactone cassane diterpenoids (I) (1-10), tricyclic cassane diterpenoids (II) (11-15), polyoxybutanolide lactone cassane diterpenoids (III) (16-23), and fused furan ring cassane diterpenoids (IV) (24-31), were tested for their anti-glioblastoma activity and mechanism underlying based on IDH1 mutant phenotypes of primary GBM cell cultures and human oligodendroglioma (HOG) cell lines.Results: We confirmed that tricyclic-type (II) and compound 13 (Caesalpin A, CSA) showed the best antineoplastic potencies in IDH1 mutant glioma cells compared with the other types and compounds. Furthermore, the structure-relationship analysis indicated that the carbonyl group at C-12 and an alpha, beta-unsaturated ketone unit fundamentally contributed to enhancing the anti-glioma activity. Studies investigating the mechanism demonstrated that CSA induced oxidative stress via causing glutathione reduction and NOS activation by negatively regulating glutaminase (GLS), which proved to be highly dependent on IDH mutant type glioblastoma. Finally, GLS overexpression reversed the CSA-induced anti-glioma effects in vitro and in vivo, which indicated that the reduction of GLS contributed to the CSA-induced proliferation inhibition and apoptosis in HOG-IDH1-mu cells.Conclusion: Therefore, the present results demonstrated that compared with other diterpenoids, tricyclic-type diterpenoids could be a targeted drug candidate for the treatment of secondary IDH1 mutant type glioblastoma through negatively regulating GLS.