Thioridazine hydrochloride: an antipsychotic agent that inhibits tumor growth and lung metastasis in triple-negative breast cancer via inducing G0/G1 arrest and apoptosis

• Published in: Cell cycle (Georgetown, Tex.) Tex.), 2020-12, Vol.19 (24), p.3521-3533
• Main Authors: Song, Yanlin, Li, Lu, Chen, Jiao, Chen, Hongli, Cui, Bomiao, Feng, Yun, Zhang, Ping, Zhang, Qiangsheng, Xia, Yong, Luo, Min
• Format: Article
• Language: English
• Subjects: Animals; antipsychotic agent; Antipsychotic Agents - pharmacology; Antipsychotic Agents - therapeutic use; Apoptosis - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Female; G1 Phase Cell Cycle Checkpoints - drug effects; Humans; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Membrane Potential, Mitochondrial - drug effects; Mice; Mice, Inbred BALB C; PI3K/AKT pathway; Reactive Oxygen Species - metabolism; Research Paper; Resting Phase, Cell Cycle - drug effects; Signal Transduction - drug effects; Thioridazine - pharmacology; Thioridazine - therapeutic use; Thioridazine hydrochloride; Treatment Outcome; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; triple-negative breast cancer; Xenograft Model Antitumor Assays
• ISSN: 1538-4101; 1551-4005
• DOI: 10.1080/15384101.2020.1850969

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer and still lacks available targeted therapy options. Thioridazine hydrochloride (Thi-hyd), a common phenothiazine antipsychotic drug, has shown great tumor-suppressive potential in several types of cancer cells. In this study, we explored the anti-tumor effects of Thi-hyd on TNBC. Thi-hyd significantly inhibited the viability and migration of TNBC cells in vitro. PI3K/AKT signaling pathway was verified to be related to Thi-hyd-induced tumor inhibition. G0/G1 cell cycle arrest and apoptosis were observed after treatment with Thi-hyd. The cell cycle arrest was accompanied by down-regulation of CDK4/cyclin D1 and up-regulation of p21 and p27. The apoptosis was accompanied by mitochondrial dysfunction. In vivo, Thi-hyd significantly suppressed the growth of tumors showing a 63.73% inhibition rate in tumor weight. Spontaneous lung metastasis was also efficiently prevented by Thi-hyd treatment, with a 72.58% inhibition rate. Immunohistological analysis showed increased Ki67 expression and reduced cleaved caspase-3 expression in Thi-hyd-treated mice. No apparent side effects were observed according to blood test and H&E staining results. Collectively, our results show that Thi-hyd can be used as a potential drug for TNBC treatment and set the basis for its clinical evaluation and investigation. CCK8: Cell Counting Kit-8; CDK: cyclin-dependent kinase; DRD2: dopamine D2 receptor; ERK1/2: extracellular signal-regulated kinase 1/2; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; H&E: hematoxylin and eosin; MMP: membrane potential; NAC: N-acetyl-L-cysteine; PI: Propidium iodide; Rh123: rhodamine-123; ROS: reactive oxygen species; TBST: tris-buffered saline containing 0.1% Tween 20 TNBC: Triple-negative breast cancer; Thi-hyd: Thioridazine hydrochloride.