4.7 Article

S670, an amide derivative of 3-O-acetyl-11-keto-β-boswellic acid, induces ferroptosis in human glioblastoma cells by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome

期刊

ACTA PHARMACOLOGICA SINICA
卷 -, 期 -, 页码 -

出版社

NATURE PUBL GROUP
DOI: 10.1038/s41401-023-01157-9

关键词

glioblastoma; 3-O-acetyl-11-keto-beta-boswellic acid; S670; ferroptosis; fusion of autophagosome and lysosome; STX17

向作者/读者索取更多资源

Glioblastoma (GBM) is a common malignant brain tumor with limited treatment options. This study showed that S670, a synthesized amide derivative of AKBA, inhibits GBM cell proliferation and induces cell death through the generation of ROS and modulation of ROS-mediated signaling pathways. Treatment with S670 also effectively inhibits tumor growth in a mouse model. These findings suggest that S670 may be a promising drug candidate for GBM treatment.
Glioblastoma (GBM) is the most common malignant tumor in the brain with temozolomide (TMZ) as the only approved chemotherapy agent. GBM is characterized by susceptibility to radiation and chemotherapy resistance and recurrence as well as low immunological response. There is an urgent need for new therapy to improve the outcome of GBM patients. We previously reported that 3-O-acetyl-11-keto-beta-boswellic acid (AKBA) inhibited the growth of GBM. In this study we characterized the anti-GBM effect of S670, a synthesized amide derivative of AKBA, and investigated the underlying mechanisms. We showed that S670 dose-dependently inhibited the proliferation of human GBM cell lines U87 and U251 with IC50 values of around 6 mu M. Furthermore, we found that S670 (6 mu M) markedly stimulated mitochondrial ROS generation and induced ferroptosis in the GBM cells. Moreover, S670 treatment induced ROS-mediated Nrf2 activation and TFEB nuclear translocation, promoting protective autophagosome and lysosome biogenesis in the GBM cells. On the other hand, S670 treatment significantly inhibited the expression of SXT17, thus impairing autophagosome-lysosome fusion and blocking autophagy flux, which exacerbated ROS accumulation and enhanced ferroptosis in the GBM cells. Administration of S670 (50 mg.kg(-1).d(-1), i.g.) for 12 days in a U87 mouse xenograft model significantly inhibited tumor growth with reduced Ki67 expression and increased LC3 and LAMP2 expression in the tumor tissues. Taken together, S670 induces ferroptosis by generating ROS and inhibiting STX17-mediated fusion of autophagosome and lysosome in GBM cells. S670 could serve as a drug candidate for the treatment of GBM.

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。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据