ABSTRACT

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.

Abbreviations

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.

中文翻译：

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盐酸硫利达嗪：一种抗精神病药，通过诱导 G0/G1 期阻滞和细胞凋亡抑制三阴性乳腺癌的肿瘤生长和肺转移

摘要

三阴性乳腺癌 (TNBC) 是最具侵袭性的乳腺癌类型，仍然缺乏可用的靶向治疗方案。盐酸硫利达嗪 (Thi-hyd) 是一种常见的吩噻嗪类抗精神病药物，已在多种类型的癌细胞中显示出巨大的肿瘤抑制潜力。在这项研究中，我们探讨了三氢大麻酚对 TNBC 的抗肿瘤作用。Thi-hyd在体外显着抑制了 TNBC 细胞的活力和迁移。PI3K/AKT信号通路被证实与Thi-hyd诱导的肿瘤抑制有关。用 Thi-hyd 处理后观察到 G0/G1 细胞周期停滞和细胞凋亡。细胞周期停滞伴随着 CDK4/细胞周期蛋白 D1 的下调和 p21 和 p27 的上调。细胞凋亡伴随着线粒体功能障碍。体内, Thi-hyd 显着抑制了肿瘤的生长，显示出 63.73% 的肿瘤重量抑制率。Thi-hyd 治疗也有效地防止了自发性肺转移，抑制率为 72.58%。免疫组织学分析显示，在 Thi-hyd 处理的小鼠中，Ki67 表达增加，裂解的 caspase-3 表达减少。根据血液测试和 H&E 染色结果，没有观察到明显的副作用。总的来说，我们的结果表明 Thi-hyd 可用作 TNBC 治疗的潜在药物，并为其临床评估和研究奠定基础。

缩写

CCK8：细胞计数试剂盒-8；CDK：细胞周期蛋白依赖性激酶；DRD2：多巴胺D2受体；ERK1/2：细胞外信号调节激酶 1/2；GAPDH：3-磷酸甘油醛脱氢酶；H&E：苏木精和伊红；MMP：膜电位；NAC：N-乙酰基-L-半胱氨酸；PI：碘化丙啶；Rh123：罗丹明-123；ROS：活性氧；TBST：含有 0.1% Tween 20 TNBC 的 Tris 缓冲盐水：三阴性乳腺癌；Thi-hyd：盐酸硫利达嗪。