2. Academic Validation
  3. A novel L-shaped ortho-quinone analog suppresses glioblastoma progression by targeting acceleration of AR degradation and regulating PI3K/AKT pathway

A novel L-shaped ortho-quinone analog suppresses glioblastoma progression by targeting acceleration of AR degradation and regulating PI3K/AKT pathway

  • Biochem Pharmacol. 2024 Aug:226:116398. doi: 10.1016/j.bcp.2024.116398.
Tao Zhang 1,  Weidong Pan 2,  Xin Tan 2,  Jia Yu 2,  Sha Cheng 2,  Shinan Wei 2,  Kuan Fan 3,  Lu Wang 3,  Heng Luo 4,  Xiao Hu 5
Affiliations

Affiliations

  • 1 GuiZhou University Medical College, Guiyang 550025, Guizhou Province, China; State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, Guizhou Province, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, Guizhou Province, China; Department of Neurology, Guizhou Provincial People's Hospital, Guiyang 550002, Guizhou Province, China.
  • 2 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, Guizhou Province, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, Guizhou Province, China.
  • 3 Department of Neurology, Guizhou Provincial People's Hospital, Guiyang 550002, Guizhou Province, China.
  • 4 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, Guizhou Province, China; Natural Products Research Center of Guizhou Province, Guiyang 550014, Guizhou Province, China. Electronic address: luo_heng@gmc.edu.cn.
  • 5 GuiZhou University Medical College, Guiyang 550025, Guizhou Province, China; Department of Neurology, Guizhou Provincial People's Hospital, Guiyang 550002, Guizhou Province, China. Electronic address: huxiao@gz5055.com.
PMID: 38944395 DOI: 10.1016/j.bcp.2024.116398
Abstract

Glioblastoma (GBM) is a primary intracranial malignant tumor with the highest mortality and morbidity among all malignant central nervous system tumors. Tanshinone IIA is a fat-soluble active ingredient obtained from Salvia miltiorrhiza, which has an inhibitory effect against various cancers. We designed and synthesized a novel L-shaped ortho-quinone analog TE5 with tanshinone IIA as the lead compound and tested its antitumor activity against GBM. The results indicated that TE5 effectively inhibited the proliferation, migration, and invasion of GBM cells, and demonstrated low toxicity in vitro. We found that TE5 may bind to androgen receptors and promote their degradation through the Proteasome. Inhibition of the PI3K/Akt signaling pathway was also observed in TE5 treated GBM cells. Additionally, TE5 arrested the cell cycle at the G2/M phase and induced mitochondria-dependent Apoptosis. In vivo experiments further confirmed the anti-tumor activity, safety, and effect on Androgen Receptor level of TE5 in animal models of GBM. Our results suggest that TE5 may be a potential therapeutic drug to treat GBM.

Keywords

Androgen receptor; Apoptosis; G2/M phase; Glioblastoma; L-shaped ortho-quinone analog; Molecular docking.

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