Zhu Min, Li Youkong, Zhou Zhifang
Department of Urology, JingZhou Central Hospital, The Second Clinical Medical College, Yangtze University, JingZhou, People's Republic of China.
Department of Oncology, JingZhou Central Hospital, The Second Clinical Medical College, Yangtze University, JingZhou, People's Republic of China.
Biochem Biophys Res Commun. 2017 Oct 21;492(3):373-378. doi: 10.1016/j.bbrc.2017.08.097. Epub 2017 Aug 25.
Renal cell carcinoma (RCC) is the most aggressive type of genitourinary cancer and highly resistant to current available therapies. In this work, we investigated the effects and mechanism of anti-parasitic agent ivermectin in RCC. We show that ivermectin significantly inhibits proliferation and induces apoptosis in multiple RCC cell lines that represent different histological subtypes and various mutation status. Importantly, ivermectin is significantly less or ineffective in normal kidney cells compared with RCC cells, demonstrating the preferential toxicity of ivermectin to RCC. Ivermectin also significantly inhibits RCC tumor growth in vivo. Mechanistically, ivermectin induces mitochondrial dysfunction via decreasing mitochondrial membrane potential, mitochondrial respiration and ATP production. As a consequence of mitochondrial dysfunction, oxidative stress and damage is detected in ivermectin treated RCC cells and xenograft mouse model. The rescue of ivermectin's effect by acetyl-l-Carnitine (ALCAR, a mitochondrial fuel) or antioxidant N-acetyl-l-cysteine (NAC) confirms mitochondria as the target of ivermectin in RCC cells. Compared to normal kidney cells, RCC cells have higher mitochondrial mass and respiration, and ATP production, which might explain the preferential toxicity of ivermectin to RCC. Our work suggest that ivermectin is a promising candidate for RCC treatment and targeting mitochondrial metabolism is an alternative therapeutic strategy for RCC.
肾细胞癌（RCC）是最具侵袭性的泌尿生殖系统癌症类型，对目前可用的治疗方法具有高度抗性。在这项研究中，我们调查了抗寄生虫药物伊维菌素在肾细胞癌中的作用及机制。我们发现，伊维菌素能显著抑制多种代表不同组织学亚型和各种突变状态的肾细胞癌细胞系的增殖并诱导其凋亡。重要的是，与肾细胞癌细胞相比，伊维菌素对正常肾细胞的作用显著较小或无效，这表明伊维菌素对肾细胞癌具有选择性毒性。伊维菌素在体内也能显著抑制肾细胞癌肿瘤的生长。从机制上来说，伊维菌素通过降低线粒体膜电位、线粒体呼吸和ATP生成来诱导线粒体功能障碍。由于线粒体功能障碍，在经伊维菌素处理的肾细胞癌细胞和异种移植小鼠模型中检测到氧化应激和损伤。用乙酰左旋肉碱（ALCAR，一种线粒体燃料）或抗氧化剂N-乙酰-L-半胱氨酸（NAC）挽救伊维菌素的作用，证实线粒体是伊维菌素在肾细胞癌细胞中的作用靶点。与正常肾细胞相比，肾细胞癌细胞具有更高的线粒体质量、呼吸和ATP生成，这可能解释了伊维菌素对肾细胞癌的选择性毒性。我们的研究表明，伊维菌素是肾细胞癌治疗的一个有前景的候选药物，靶向线粒体代谢是肾细胞癌的一种替代治疗策略。
