1. Academic Validation
  2. Daurisoline suppress glioma progression by inhibiting autophagy through PI3K/AKT/mTOR pathway and increases TMZ sensitivity

Daurisoline suppress glioma progression by inhibiting autophagy through PI3K/AKT/mTOR pathway and increases TMZ sensitivity

  • Biochem Pharmacol. 2024 Mar 7:116113. doi: 10.1016/j.bcp.2024.116113.
Hai-Tang Yin 1 Hui-Lu 1 Ji-Hong Yang 2 Qin Li 3 Ming Li 1 Qing-Qing Zhao 4 Zhi-Peng Wen 5
Affiliations

Affiliations

  • 1 Department of Pharmacy, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, PR China; College of Pharmacy, Guizhou Medical University, Guiyang, Guizhou Province, PR China.
  • 2 Department of Pharmacy, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, PR China; College of Pharmacy, Guizhou Medical University, Guiyang, Guizhou Province, PR China. Electronic address: 2391490225@qq.com.
  • 3 Centre of Clinical Trials, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, PR China.
  • 4 Clinical Research Center, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, PR China.
  • 5 Department of Pharmacy, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, PR China; College of Pharmacy, Guizhou Medical University, Guiyang, Guizhou Province, PR China. Electronic address: wenzhipeng@gmc.edu.cn.
Abstract

Glioma is one of the most common primary malignant tumors of the central nervous system. Temozolomide (TMZ) is the only effective chemotherapeutic agent, but it easily develops resistance and has unsatisfactory efficacy. Consequently, there is an urgent need to develop safe and effective compounds for glioma treatment. The cytotoxicity of 30 candidate compounds to glioma cells was detected by the CCK-8 assay. Daurisoline (DAS) was selected for further investigation due to its potent anti-glioma effects. Our study revealed that DAS induced glioma cell Apoptosis through increasing Caspase-3/6/9 activity. DAS significantly inhibited the proliferation of glioma cells by inducing G1-phase cell cycle arrest. Meanwhile, DAS remarkably suppressed the migration and invasion of glioma cells by regulating epithelial-mesenchymal transition. Mechanistically, our results revealed that DAS impaired the autophagic flux of glioma cells at a late stage by mediating the PI3K/Akt/mTOR pathway. DAS could inhibit TMZ-induced Autophagy and then significantly promote TMZ chemosensitivity. Nude mice xenograft model revealed that DAS could restrain glioma proliferation and promote TMZ chemosensitivity. Thus, DAS is a potential anti-glioma drug that can improve glioma sensitivity to TMZ and provide a new therapeutic strategy for glioma in chemoresistance.

Keywords

Apoptosis; Autophagy; Daurisoline; Glioma; Temozolomide.

Figures
Products