Preclinical evaluation of Mito-LND, a targeting mitochondrial metabolism inhibitor, for glioblastoma treatment.
Preclinical evaluation of Mito-LND, a targeting mitochondrial metabolism inhibitor, for glioblastoma treatment.
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DOI：
10.1186/s12967-023-04332-y
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发表时间：
2023-08-07
影响因子：
7.4
通讯作者：
Liu, Xuejiao
中科院分区：
文献类型：
--
作者：
Guo, Tongxuan;Wu, Changyong;Zhou, Lingni;Zhang, Junhao;Wang, Wanzhou;Shen, Yang;Zhang, Ludong;Niu, Mingshan;Zhang, Xu;Yu, Rutong;Liu, Xuejiao
胶质母细胞瘤（GBM）是中枢神经系统中恶性程度最高、预后最差的脑肿瘤。线粒体代谢在肿瘤的发生、发展中起着重要作用，为肿瘤的治疗提供了重要的物质支持。Mito-LND是一种选择性抑制肿瘤细胞能量代谢的新型小分子抑制剂。然而，Mito-LND对GBM的治疗效果仍不清楚。本研究旨在探讨Mito-LND对GBM细胞生长的抑制作用及其可能的作用机制。结果表明，Mito-LND可抑制GBM细胞的存活、增殖和集落形成。此外，Mito-LND诱导细胞周期阻滞和凋亡。在机制上，Mito-LND抑制线粒体呼吸链复合物I的活性，降低线粒体膜电位，从而促进ROS的产生。Mito-LND可通过阻断Raf/MEK/ERK信号通路抑制GBM恶性增殖。体内实验表明，Mito-LND可抑制小鼠移植性GBM的生长，显著延长荷瘤小鼠的生存时间。因此，靶向线粒体代谢可能成为GBM治疗的一个潜在的、有前景的策略，这将为将来Mito-LND的进一步临床试验奠定理论基础。在线版本包含补充材料，可通过10.1186/s12967-023-04332-y获得。
Glioblastoma (GBM) is a brain tumor with the highest level of malignancy and the worst prognosis in the central nervous system. Mitochondrial metabolism plays a vital role in the occurrence and development of cancer, which provides critical substances to support tumor anabolism. Mito-LND is a novel small-molecule inhibitor that can selectively inhibit the energy metabolism of tumor cells. However, the therapeutic effect of Mito-LND on GBM remains unclear. The present study evaluated the inhibitory effect of Mito-LND on the growth of GBM cells and elucidated its potential mechanism. The results showed that Mito-LND could inhibit the survival, proliferation and colony formation of GBM cells. Moreover, Mito-LND induced cell cycle arrest and apoptosis. Mechanistically, Mito-LND inhibited the activity of mitochondrial respiratory chain complex I and reduced mitochondrial membrane potential, thus promoting ROS generation. Importantly, Mito-LND could inhibit the malignant proliferation of GBM by blocking the Raf/MEK/ERK signaling pathway. In vivo experiments showed that Mito-LND inhibited the growth of GBM xenografts in mice and significantly prolonged the survival time of tumor-bearing mice. Taken together, the current findings support that targeting mitochondrial metabolism may be as a potential and promising strategy for GBM therapy, which will lay the theoretical foundation for further clinical trials on Mito-LND in the future. The online version contains supplementary material available at 10.1186/s12967-023-04332-y.
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DOI：
10.1074/jbc.m115.697516
发表时间：
2016-01-01
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Guo L;Shestov AA;Worth AJ;Nath K;Nelson DS;Leeper DB;Glickson JD;Blair IA
通讯作者：
Blair IA
影响因子：
7.3
作者：
Klein K;He K;Younes AI;Barsoumian HB;Chen D;Ozgen T;Mosaffa S;Patel RR;Gu M;Novaes J;Narayanan A;Cortez MA;Welsh JW
通讯作者：
Welsh JW
影响因子：
2.2
作者：
Awuah, Wireko Andrew;Toufik, Abdul-Rahman;Yarlagadda, Rohan;Mikhailova, Tatiana;Mehta, Aashna;Huang, Helen;Kundu, Mrinmoy;Lopes, Leilani;Benson, Sylvester;Mykola, Lyndin;Vladyslav, Sikora;Alexiou, Athanasios;Alghamdi, Badrah S.;Hashem, Anwar M.;Ashraf, Ghulam Md
通讯作者：
Ashraf, Ghulam Md
影响因子：
5.2
作者：
通讯作者：
--
影响因子：
14.5
作者：
Halcrow PW;Lynch ML;Geiger JD;Ohm JE
通讯作者：
Ohm JE