<br>小分子 Molephantin 通过胶质母细胞瘤中 ROS 的产生诱导细胞凋亡和线粒体自噬通量阻断,Cancer Letters

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小分子 Molephantin 通过胶质母细胞瘤中 ROS 的产生诱导细胞凋亡和线粒体自噬通量阻断
Cancer Letters ( IF 9.1 ) Pub Date : 2024-05-01 , DOI: 10.1016/j.canlet.2024.216927
Zhipeng Ling ₁ , Junping Pan ₂ , Zhongfei Zhang ₃ , Guisi Chen ₄ , Jiayuan Geng ₅ , Qiang Lin ₆ , Tao Zhang ₇ , Shuqin Cao ₈ , Cheng Chen ₃ , Jinrong Lin ₃ , Hongyao Yuan ₃ , Weilong Ding ₄ , Fei Xiao ₄ , Xinke Xu ₃ , Fangcheng Li ₃ , Guocai Wang ₆ , Yubo Zhang ₁ , Junliang Li ₃

Affiliation

Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China; Department of Pharmacology, School of Medicine, and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China.
Guangdong Second Provincial General Hospital, Integrated Chinese and Western Medicine Postdoctoral Research Station, School of Medicine, Jinan University, Guangzhou, China.
Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou, China.
Department of Pharmacology, School of Medicine, and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China.
Department of Microbial and Biochemical Pharmacy, College of Pharmacy, Jinan University, Guangzhou, China.
Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China.
Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, 10330, Thailand.

胶质母细胞瘤（GBM）是世界上最恶性的脑肿瘤之一，治疗选择有限且生存率很低。迫切需要有效且安全的胶质母细胞瘤疾病缓解药物。在这里，我们鉴定了一种小分子 Molephantin (EM-5)，它能有效穿透血脑屏障 (BBB)，并表现出显着的抗 GBM 抗肿瘤作用，并且在体外和体内均具有良好的安全性。从机制上讲，EM-5不仅抑制GBM细胞的增殖和侵袭，还通过活性氧（ROS）介导的PI3K/Akt/mTOR通路诱导细胞凋亡。此外，EM-5 会导致线粒体功能障碍，并通过阻碍线粒体自噬体与溶酶体的融合来阻断线粒体自噬流。值得注意的是，EM-5 不会干扰自噬体形成或溶酶体功能的启动。此外，EM-5 引起的线粒体自噬通量阻断是由细胞内 ROS 的积累驱动的。在体内，EM-5 在异种移植模型中表现出显着的抑制肿瘤生长的功效。总的来说，我们的研究结果不仅确定了 EM-5 是一种有前途、有效且安全的治疗 GBM 的先导化合物，而且还从细胞凋亡和线粒体自噬的角度揭示了其潜在机制。

"点击查看英文标题和摘要"

Small-molecule Molephantin induces apoptosis and mitophagy flux blockage through ROS production in glioblastoma

Glioblastoma (GBM), one of the most malignant brain tumors in the world, has limited treatment options and a dismal survival rate. Effective and safe disease-modifying drugs for glioblastoma are urgently needed. Here, we identified a small molecule, Molephantin (EM-5), effectively penetrated the blood-brain barrier (BBB) and demonstrated notable antitumor effects against GBM with good safety profiles both in vitro and in vivo. Mechanistically, EM-5 not only inhibits the proliferation and invasion of GBM cells but also induces cell apoptosis through the reactive oxygen species (ROS)-mediated PI3K/Akt/mTOR pathway. Furthermore, EM-5 causes mitochondrial dysfunction and blocks mitophagy flux by impeding the fusion of mitophagosomes with lysosomes. It is noteworthy that EM-5 does not interfere with the initiation of autophagosome formation or lysosomal function. Additionally, the mitophagy flux blockage caused by EM-5 was driven by the accumulation of intracellular ROS. In vivo, EM-5 exhibited significant efficacy in suppressing tumor growth in a xenograft model. Collectively, our findings not only identified EM-5 as a promising, effective, and safe lead compound for treating GBM but also uncovered its underlying mechanisms from the perspective of apoptosis and mitophagy.

更新日期：2024-05-01

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