Department of Biology, University of Padova, viale G. Colombo 3, 35121 Padova, Italy.
Department of Chemical Sciences, University of Padova, via F. Marzolo 1, 35121 Padova, Italy.
Cancer Cell. 2017 Apr 10;31(4):516-531.e10. doi: 10.1016/j.ccell.2017.03.003.
The potassium channel Kv1.3 is highly expressed in the mitochondria of various cancerous cells. Here we show that direct inhibition of Kv1.3 using two mitochondria-targeted inhibitors alters mitochondrial function and leads to reactive oxygen species (ROS)-mediated death of even chemoresistant cells independently of p53 status. These inhibitors killed 98% of ex vivo primary chronic B-lymphocytic leukemia tumor cells while sparing healthy B cells. In orthotopic mouse models of melanoma and pancreatic ductal adenocarcinoma, the compounds reduced tumor size by more than 90% and 60%, respectively, while sparing immune and cardiac functions. Our work provides direct evidence that specific pharmacological targeting of a mitochondrial potassium channel can lead to ROS-mediated selective apoptosis of cancer cells in vivo, without causing significant side effects.
钾通道 Kv1.3 在各种癌细胞的线粒体中高度表达。在这里，我们表明，使用两种靶向线粒体的抑制剂直接抑制 Kv1.3 会改变线粒体功能，并导致即使在 p53 状态下，也会导致化学抗性细胞发生活性氧 (ROS) 介导的死亡。这些抑制剂杀死了 98%的体外原发性慢性 B 淋巴细胞白血病肿瘤细胞，而对健康 B 细胞没有影响。在黑色素瘤和胰腺导管腺癌的原位小鼠模型中，这些化合物分别使肿瘤缩小了 90%以上和 60%，同时保留了免疫和心脏功能。我们的工作提供了直接证据，表明特定的线粒体钾通道药理学靶向可以导致体内 ROS 介导的癌细胞选择性凋亡，而不会引起明显的副作用。
