1. Small-molecule Molephantin induces apoptosis and mitophagy flux blockage through ROS production in glioblastoma.
- Author
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Ling Z, Pan J, Zhang Z, Chen G, Geng J, Lin Q, Zhang T, Cao S, Chen C, Lin J, Yuan H, Ding W, Xiao F, Xu X, Li F, Wang G, Zhang Y, and Li J
- Subjects
- Humans, Animals, Cell Line, Tumor, Mice, Signal Transduction drug effects, Mitochondria drug effects, Mitochondria metabolism, Lysosomes drug effects, Lysosomes metabolism, Mice, Nude, TOR Serine-Threonine Kinases metabolism, Blood-Brain Barrier metabolism, Blood-Brain Barrier drug effects, Proto-Oncogene Proteins c-akt metabolism, Glioblastoma drug therapy, Glioblastoma pathology, Glioblastoma metabolism, Reactive Oxygen Species metabolism, Mitophagy drug effects, Apoptosis drug effects, Brain Neoplasms drug therapy, Brain Neoplasms pathology, Brain Neoplasms metabolism, Xenograft Model Antitumor Assays, Cell Proliferation drug effects
- Abstract
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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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