Preclinical evaluation of Mito-LND, a targeting mitochondrial metabolism inhibitor, for glioblastoma treatment

  • J Transl Med. 2023 Aug 7;21(1):532. doi: 10.1186/s12967-023-04332-y.
Tongxuan Guo  #  1  2 ,  Changyong Wu  #  1  2 ,  Lingni Zhou  #  1  2 ,  Junhao Zhang  1 ,  Wanzhou Wang  1 ,  Yang Shen  1 ,  Ludong Zhang  1 ,  Mingshan Niu  3 ,  Xu Zhang  4  5 ,  Rutong Yu  6  7 ,  Xuejiao Liu  8  9
Affiliations
  • 1. Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 2. Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 3. Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 4. Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China. [email protected].
  • 5. Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China. [email protected].
  • 6. Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China. [email protected].
  • 7. Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China. [email protected].
  • 8. Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China. [email protected].
  • 9. Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China. [email protected].
  • # Contributed equally.
PMID: 37550679 DOI: 10.1186/s12967-023-04332-y
Abstract

Background: 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.

Methods: The present study evaluated the inhibitory effect of Mito-LND on the growth of GBM cells and elucidated its potential mechanism.

Results: 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.

Conclusion: 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.

Keywords
GBM; Mito-LND; Mitochondrial metabolism; Raf/MEK/ERK signaling pathway; Tumor cell proliferation.
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