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

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

  • Cancer Lett. 2024 Jun 28:592:216927. 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 9,  Yubo Zhang 10,  Junliang Li 11
Affiliations

Affiliations

  • 1 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.
  • 2 Guangdong Second Provincial General Hospital, Integrated Chinese and Western Medicine Postdoctoral Research Station, School of Medicine, Jinan University, Guangzhou, China.
  • 3 Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou, China.
  • 4 Department of Pharmacology, School of Medicine, and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China.
  • 5 Department of Microbial and Biochemical Pharmacy, College of Pharmacy, Jinan University, Guangzhou, China.
  • 6 Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China.
  • 7 Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 8 Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, 10330, Thailand.
  • 9 Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China. Electronic address: twangguocai@jnu.edu.cn.
  • 10 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. Electronic address: ybzhang99@126.com.
  • 11 Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou, China. Electronic address: junliangli@aliyun.com.
PMID: 38697460 DOI: 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.

Keywords

Apoptosis; EM-5; Glioblastoma; Mitophagy flux; ROS.

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