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

• Published in: Biochemical pharmacology 2024-08, Vol.226, p.116398, Article 116398
• Main Authors: Zhang, Tao, Pan, Weidong, Tan, Xin, Yu, Jia, Cheng, Sha, Wei, Shinan, Fan, Kuan, Wang, Lu, Luo, Heng, Hu, Xiao
• Format: Article
• Language: English
• Subjects: Abietanes - pharmacology; Androgen receptor; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Disease Progression; G2/M phase; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; L-shaped ortho-quinone analog; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular docking; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Quinones - chemical synthesis; Quinones - chemistry; Quinones - pharmacology; Receptors, Androgen - metabolism; Signal Transduction - drug effects; Xenograft Model Antitumor Assays - methods
• ISSN: 0006-2952; 1873-2968; 1873-2968
• DOI: 10.1016/j.bcp.2024.116398

[Display omitted] 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.