Zhao Juan, He Qiushan, Gong Zhimin, Chen Sen, Cui Long
Department of Oncology, Xiangyang Central Hospital, The Affiliated Hospital of Hubei College of Arts and Science, Xiangyang, 441021 People's Republic of China.
Department of Academic Affairs, Hubei University of Medicine, Shiyan, 441021 People's Republic of China.
Springerplus. 2016 Aug 30;5(1):1436. doi: 10.1186/s40064-016-3153-x. eCollection 2016.
To investigate the effects of anthelminthic drug niclosamide in renal cell carcinoma (RCC) and the underlying mechanisms of its action.
The effects of niclosamide on the proliferation and apoptosis of RCC cells were examined in vitro and in vivo by using MTS, colony formation assay, flow cytometry and xenograft cancer mouse model. Mechanism studies were performed by analyzing Wnt/β-catenin signaling and mitochondrial functions in a panel of RCC cell lines.
We show that niclosamide effectively targets two RCC cell lines through inhibiting proliferation and anchorage-independent colony formation, and inducing apoptosis. It also enhances the inhibitory effects of chemotherapeutic drug cisplatin in two independent in vivo RCC xenograft mouse models. Mechanistically, niclosamide decreases β-catenin levels and therefore suppresses Wnt/β-catenin activities. Overexpression of β-catenin partially reverses the inhibitory effects of niclosamide in RCC cells, demonstrating that besides β-catenin, other mechanisms are involved in niclosamide's anti-cancer activity. Indeed, we further show that niclosamide induces mitochondrial dysfunctions as shown by the decreased level of mitochondrial membrane potential and respiration, resulting in decreased ATP levels and increased reactive oxygen species (ROS) levels.
Our findings support the inhibitory effects of niclosamide in cancer and provide better understanding on its underlying mechanism. Our data suggests that niclosamide is a useful addition to the treatment armamentarium for RCC.
研究抗蠕虫药物氯硝柳胺对肾细胞癌（RCC）的作用及其潜在作用机制。
采用MTS法、集落形成试验、流式细胞术和异种移植癌小鼠模型，在体外和体内检测氯硝柳胺对RCC细胞增殖和凋亡的影响。通过分析一组RCC细胞系中的Wnt/β-连环蛋白信号通路和线粒体功能进行机制研究。
我们发现氯硝柳胺通过抑制增殖和非锚定依赖性集落形成以及诱导凋亡，有效作用于两种RCC细胞系。在两个独立的体内RCC异种移植小鼠模型中，它还增强了化疗药物顺铂的抑制作用。机制上，氯硝柳胺降低β-连环蛋白水平，从而抑制Wnt/β-连环蛋白活性。β-连环蛋白的过表达部分逆转了氯硝柳胺对RCC细胞的抑制作用，表明除β-连环蛋白外，其他机制也参与了氯硝柳胺的抗癌活性。事实上，我们进一步表明，氯硝柳胺诱导线粒体功能障碍，表现为线粒体膜电位和呼吸水平降低，导致ATP水平降低和活性氧（ROS）水平升高。
我们的研究结果支持氯硝柳胺对癌症的抑制作用，并为其潜在机制提供了更好的理解。我们的数据表明，氯硝柳胺是RCC治疗药物库中的一种有用补充。
