The anti-malarial atovaquone selectively increases chemosensitivity in retinoblastoma via mitochondrial dysfunction-dependent oxidative damage and Akt/AMPK/mTOR inhibition
The anti-malarial atovaquone selectively increases chemosensitivity in retinoblastoma via mitochondrial dysfunction-dependent oxidative damage and Akt/AMPK/mTOR inhibition
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DOI：
10.1016/j.bbrc.2018.06.049
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发表时间：
2018-10-02
影响因子：
3.1
通讯作者：
Zuo, Zhigang
中科院分区：
文献类型：
--
作者：
Ke, Feng;Yu, Jinqiang;Zuo, Zhigang
线粒体已被确定为几种癌症中有希望的靶点。然而，很少有人知道靶向线粒体在视网膜母细胞瘤中的作用。在这项工作中，我们表明，抗疟疾阿托伐醌，在临床上可达到的浓度，表现出抑制作用，视网膜母细胞瘤细胞，在更大程度上比正常的视网膜细胞。阿托伐醌还显著增加视网膜母细胞瘤的化疗敏感性。重要的是，我们发现，视网膜母细胞瘤细胞具有较高水平的线粒体呼吸，膜电位，质量和ATP相比，正常视网膜细胞。虽然阿托伐醌以类似的方式显著抑制恶性和正常视网膜细胞中的线粒体呼吸并降低ATP水平，但阿托伐醌在视网膜母细胞瘤中比正常视网膜细胞诱导更多的氧化应激和损伤。这些表明正常视网膜细胞比视网膜母细胞瘤细胞更能耐受线粒体功能障碍。我们进一步证明阿托伐醌通过诱导线粒体功能障碍靶向Akt/AMPK/mTOR信号传导。我们的临床前工作证明了阿托伐醌作为视网膜母细胞瘤治疗药物的补充的转化潜力。我们的工作还证明了恶性与正常视网膜细胞中线粒体生物发生和功能的差异，这对于视网膜母细胞瘤的靶向治疗很重要。(C)2018爱思唯尔公司All rights reserved.
Mitochondria has been identified as a promising target in several cancers. However, little is known on the effects of targeting mitochondria in retinoblastoma. In this work, we show that anti-malarial atovaquone, at clinically achievable concentration, demonstrates inhibitory effects to retinoblastoma cells, to a more extent than in normal retinal cells. Atovaquone also significantly increases chemosensitivity in retinoblastoma. Importantly, we show that retinoblastoma cells have higher level of mitochondrial respiration, membrane potential, mass and ATP compared to normal retinal cells. Although atovaquone significantly inhibits mitochondrial respiration and decrease ATP level in both malignant and normal retinal cells in a similar manner, atovaquone induces much more oxidative stress and damage in retinoblastoma than normal retinal cells. These suggest that normal retinal cells are more tolerable to mitochondrial dysfunctions than retinoblastoma cells. We further demonstrate that atovaquone targets Akt/AMPK/mTOR signaling via inducing mitochondrial dysfunction. Our pre-clinical work demonstrates the translational potential of atovaquone as an addition to the treatment armamentarium for retinoblastoma. Our work also demonstrates the differences of mitochondrial biogenesis and function in malignant versus normal retinal cells which are important for the targeted therapy in retinoblastoma. (C) 2018 Elsevier Inc. All rights reserved.