Melanoma therapy by TRAIL and KATP channel inhibitors

本研究项目的主要发现是：（1）KATP通道抑制剂增强细胞凋亡是不同来源的癌细胞（包括白血病和肺癌细胞）中的普遍现象;（2）这些通道抑制剂的作用（包括去极化诱导）是肿瘤选择性的;（3）细胞凋亡的增强通过上调TRAIL受体-1/2和增加线粒体和内质网死亡途径发生;（4）细胞凋亡的增强通过上调TRAIL受体-1/2和增加线粒体和内质网死亡途径发生。（4）线粒体活性氧（ROS）介导死亡信号通路的激活，去极化与ROS相互调节。这些发现提供了联合使用TRAIL和KATP通道抑制剂治疗TRAIL耐药癌细胞的分子基础，这与新出现的概念有关，即氧化应激是线粒体和内质网功能障碍的关键介质，并作为癌症治疗中的肿瘤选择性靶点。

The major findings of this research project are that:(1) the potentiation of the apoptosis by KATP channel inhibitors is a general phenomenon among cancer cells with different origins, including leukemia and lung cancer cells; (2) the effects of these channel inhibitors including depolarization induction are tumor-selective; (3) the potentiation of apoptosis occurs through upregulation of TRAIL receptors-1/2 and increased mitochondrial and endoplasmic reticulum death pathways; (4) mitochondrial reactive oxygen species (ROS) mediate the activation of death signaling pathways, and depolarization and ROS mutually regulate one another. The findings provide a molecular basis of the combined use of TRAIL and KATP channel inhibitors in the treatment of TRAIL-resistant cancer cells in connection with the emerging concept that oxidative stress is a critical mediator of mitochondrial and endoplasmic reticulum dysfunctions and serves as a tumor-selective target in cancer treatment.