Thioridazine hydrochloride is a phenothiazine antipsychotic agent with dopamine-receptor antagonistic activity[1]. Thioridazine hydrochloride inhibits dopamine D2 receptor (D2DR), dopamine D4 receptor (D4DR), and calcium channels and modulates autophagy, apoptosis, and vascular endothelial growth factor receptor 2 (VEGFR-2)/phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) signaling in cancer-cell models[1-3]. Thioridazine hydrochloride is used in research on dopamine-receptor signaling, glioma stem-like cells, autophagy, apoptosis, angiogenesis, and tumor-xenograft biology[1-5].
In vitro, Thioridazine hydrochloride (5μM, 7.5μM, 10μM, and 15μM; 24h) activated caspases, promoted poly(adenosine diphosphate-ribose) polymerase (PARP) cleavage, increased microtubule-associated protein 1 light chain 3-II (LC3-II) accumulation, and reduced stem-like properties in U87MG and GBM8401 glioblastoma cells[1].
In vivo, Thioridazine hydrochloride (25mg/kg; oral administration every 3 days for 27 days) reduced tumor growth by approximately fivefold and decreased tumor weight and phosphorylation of VEGFR-2, PI3K, and mTOR in nude mice bearing 2774 ovarian cancer xenografts[3].
References：[1] Cheng HW, Liang YH, Kuo YL, Chuu CP, Lin CY, Lee MH, et al. Identification of thioridazine, an antipsychotic drug, as an antiglioblastoma and anticancer stem cell agent using public gene expression data. Cell Death Dis. 2015;6:e1753. doi:10.1038/cddis.2015.77.
[2] Chu CW, Ko HJ, Chou CH, Cheng TS, Cheng HW, Liang YH, et al. Thioridazine enhances P62-mediated autophagy and apoptosis through Wnt/β-catenin signaling pathway in glioma cells. Int J Mol Sci. 2019;20(3):473. doi:10.3390/ijms20030473.
[3] Park MS, Dong SM, Kim BR, Seo SH, Kang S, Lee EJ, et al. Thioridazine inhibits angiogenesis and tumor growth by targeting the VEGFR-2/PI3K/mTOR pathway in ovarian cancer xenografts. Oncotarget. 2014;5(13):4929-4934. doi:10.18632/oncotarget.2063.
[4] Yong M, Yu T, Tian S, Liu S, Xu J, Hu J, et al. DR2 blocker thioridazine: a promising drug for ovarian cancer therapy. Oncol Lett. 2017;14(6):8171-8177. doi:10.3892/ol.2017.7184.
[5] Colturato-Kido C, Salerno AG, Cardoso BA, Panepucci RA, Covas DT, Souto EX, et al. Inhibition of autophagy enhances the antitumor effect of thioridazine in acute lymphoblastic leukemia. Life (Basel). 2021;11(4):365. doi:10.3390/life11040365.