Roles of dopamine receptors and their antagonist thioridazine in hepatoma metastasis.
Roles of dopamine receptors and their antagonist thioridazine in hepatoma metastasis.
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多巴胺受体及其拮抗剂硫利达嗪在肝癌转移中的作用
DOI：
10.2147/ott.s77373
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发表时间：
2015
影响因子：
4
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Lu M;Li J;Luo Z;Zhang S;Xue S;Wang K;Shi Y;Zhang C;Chen H;Li Z
肿瘤转移是癌症患者死亡和预后不良的最常见原因。预防肿瘤转移的疗法是延长癌症患者寿命的关键。癌症干细胞被认为在转移过程中至关重要。最近，针对癌症干细胞的药物筛选报告显示，抗精神病药物显示出潜在的抗癌活性。硫利达嗪是一种作用于多巴胺受体（DRs）的抗精神病药物，已表明它可诱导白血病和乳腺癌中的癌症干细胞分化，但尚不清楚该药物是否会影响肝癌。在本研究中，DR5在肿瘤中的表达高于癌旁非肿瘤组织，而DR1在人肝细胞癌（HCC）中的表达低于癌旁组织。其他多巴胺受体的表达量很低或无法检测到。用硫利达嗪处理肝癌细胞在肝癌细胞系SNU449、LM3和Huh7中呈现出剂量依赖性反应。硫利达嗪处理通过诱导G0/G1细胞周期阻滞以及抑制干性基因CD133、OCT4和EpCam，降低了肝癌细胞系的细胞活力和球体形成。它还通过抑制上皮 - 间质转化（EMT）相关基因如twist2和E - 钙黏蛋白来抑制细胞迁移。经硫利达嗪预处理的LM3细胞降低了裸鼠的肿瘤发生能力。综上所述，我们的数据表明硫利达嗪可能在肝癌治疗中具有潜在作用。
Tumor metastasis is the most common cause of death and poor prognosis for cancer patients. Therapeutics that prevent tumor metastasis are the key to prolonging the lifespan of cancer patients. Cancer stem cells are believed to be critical in the metastatic process. Recently, drug screening for cancer stem cells reports that antipsychotic drugs displayed potential anticancer activity. Thioridazine, one of the antipsychotic drugs for dopamine receptors (DRs), is shown to induce the differentiation of cancer stem cells in leukemic disease and breast cancer, but it is not known if this drug would affect liver cancer. In this study, expression of DR5 was higher in tumors than in nontumor adjacent tissues, while DR1 was lower in human hepatocellular carcinoma (HCC) than those in the adjacent tissues. Other DRs were very low or undetectable. Treatment of HCC cells with thioridazine displays a dose-dependent response in HCC cell lines SNU449, LM3, and Huh7. Thioridazine treatment reduced cell viability and sphere formation of HCC cell lines through induction of G0/G1 cell cycle arrest and suppression of stemness genes CD133, OCT4, and EpCam. It also inhibited cell migration via suppression of epithelial–mesenchymal transition (EMT)-related genes such as twist2 and E-cadherin. Thioridazine-pretreated LM3 cells decreased the capacity of tumorigenesis in nude mice. Taken together, our data suggest that thioridazine may have the potential role in treatment of HCC.