期刊
CANCER RESEARCH AND TREATMENT
卷 53, 期 2, 页码 367-377出版社
KOREAN CANCER ASSOCIATION
DOI: 10.4143/crt.2020.506
关键词
Isocitrate dehydrogenase 1; Temozolomide; Glioma; Ataxia telangiectasia mutated
类别
资金
- China Postdoctoral Science Foundation [2018M640305, 2019M660074]
- Chinese Society of Neurooncology, CACA Foundation [CSNO-2016-MSD12]
- Hei-longjiang Postdoctoral Science Foundation [LBH-Z18103]
- Heilongjiang Health and Family Planning Commission Foundation [2017201, 2019-102]
- Harbin Medical University Scientific Research Innovation Fund [2017LCZX46]
The study found that gliomas with IDH1 mutations are more sensitive to TMZ both in vitro and in vivo compared to wild type, with TMZ significantly inhibiting proliferation and inducing more DNA damage and apoptosis in IDH1 mutant cells. The ATM-associated DNA repair signal was impaired in IDH1 mutant cells, and inhibiting the ATM/CHK2 DNA repair pathway further sensitized IDH1 mutant glioma cells to chemotherapy. IDH1 mutation significantly inhibited tumor growth in vivo, and the combination of TMZ and ATM inhibitor enhanced the antitumor effect in IDH1 mutant gliomas.
Purpose Isocitrate dehydrogenase 1 (IDH1) mutations are the most common genetic abnormalities in low-grade gliomas and secondary glioblastomas. Glioma patients with these mutations had better clinical outcomes. However, the effect of IDH1 mutation on drug sensitivity is still under debate. Materials and Methods IDH1-R132H mutant cells were established by lentivirus. IDH1-R132H protein expression was confirmed by western blot. The expression of ataxia telangiectasia mutated (ATM) signaling pathway and apoptosis-related proteins were detected by immunofluorescence and western blot. Temozolomide (TMZ) induced cell apoptosis was detected by flow cytometry. Tumor cell proliferation was detected by Cell Counting Kit-8. In vivo nude mice were used to confirm the in vitro roles of IDH1 mutation. Results We established glioma cell lines that expressed IDH1-R132H mutation stably. We found that TMZ inhibited glioma cells proliferation more significantly in IDH1 mutant cells compared to wild type. The IC50 of TMZ in IDH1-R132H mutant group was less than half that of wild-type group (p < 0.01). TMZ significantly induced more DNA damage (quantification of gamma H2AX expression in IDH1 mutation vs. wild type, p < 0.05) and apoptosis (quantification of AnnexinV(+)propidium iodide-cells in IDH1 mutation versus wild type, p < 0.01) in IDH1 mutant gliomas compared to wild-type gliomas. The ATM-associated DNA repair signal was impaired in IDH1 mutant cells. Inhibiting the ATM/checkpoint kinase 2DNA repair pathway further sensitized IDH1 mutant glioma cells to chemotherapy. We found that IDH1 mutation significantly inhibited tumor growth in vivo (the tumor size was analyzed statistically, p < 0.05). Moreover, we confirmed that gliomas with IDH1 mutation were more sensitive to TMZ in vivo compared to wild type significantly and the results were consistent with the in vitro experiment. Conclusion These results provide evidence that combination of TMZ and ATM inhibitor enhances the antitumor effect in IDH1 mutant gliomas.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据