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

Publication Information

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

Author(s):Zhi-Peng Ling^#, Jun-Ping Pan^#, Zhong-Fei Zhang^#, Gui-Si Chen, Jia-Yuan Geng, Qiang Lin, Tao Zhang, Shu-Qin Cao, Cheng Chen, Jin-Rong Lin, Hong-Yao Yuan, Wei-Long Ding, Fei Xiao, Xin-Ke Xu, Fang-Cheng Li, Guo-Cai Wang*,Yu-Bo Zhang*, Jun-Liang Li*.

‌Journal Name, Year, Volume(Issue): Page range:

Cancer Letters2024, 592: 216927.

DOI: https://doi.org/10.1016/j.canlet.2024.216927

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.

First Page of Article: