Melanoma therapy by TRAIL and KATP channel inhibitors

TRAIL 和 KATP 通道抑制剂治疗黑色素瘤

• 批准号: 23591631
• 负责人: SUZUKI Yoshihiro
• 金额: $ 3.33万
• 依托单位: Nihon University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23591631/
• 关键词: TRAIL; ATP感受性カリウムチャネル; メラノーマ; アポトーシス; ミトコンドリア; 活性酸素; melanoma; KATP; endoplasmic reticulum; ROS

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.

本课题的主要研究发现：(1)KATP通道抑制剂对细胞凋亡的促进作用是不同来源的肿瘤细胞的普遍现象，包括白血病和肺癌细胞；(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)凋亡的增强是通过TRAIL受体1/2的上调和线粒体和内质网死亡途径的增加而发生的；(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。这些发现为联合使用TRAIL和KATP通道抑制剂治疗TRAIL耐药癌细胞提供了分子基础，并与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这一新兴概念相关联。

项目成果

Depolarization controls TRAIL sensitization and selective killing of cancer cells : crosstalk with ROS

去极化控制 TRAIL 致敏和选择性杀死癌细胞：与 ROS 的串扰

• 发表时间: 2014
• 期刊: Frontiers Oncol
• 作者: Suzuki-Karasaki Y;Suzuki-Karasaki M;Uchida M;Ochiai T
• 通讯作者: Ochiai T

H2O2 acts as a tumor-selective cytotoxic agent

H2O2 作为肿瘤选择性细胞毒剂

• 发表时间: 2012
• 作者: 棚橋華奈;杉浦一充;室慶直;秋山真志;松尾裕彰;Suzuki Y et al
• 通讯作者: Suzuki Y et al

Autoimmunity-inducing metals

诱导自身免疫的金属

• 发表时间: 2011
• 期刊: Curr Pharm Design
• 影响因子: 3.1
• 作者: Suzuki Y;Inoue T;Ra C
• 通讯作者: Ra C

Hydrogen peroxide induces cell death in human TRAIL-resistant melanoma through intracellular superoxide generation

• DOI: 10.3892/ijo.2013.1769
• 发表时间: 2013-03-01
• 期刊: INTERNATIONAL JOURNAL OF ONCOLOGY
• 影响因子: 5.2
• 作者: Tochigi, Mizuki;Inoue, Toshio;Suzuki-Karasaki, Yoshihiro
• 通讯作者: Suzuki-Karasaki, Yoshihiro

Calcium Signaling

• DOI: 10.1007/978-94-007-2888-2
• 发表时间: 2012
• 期刊: Cold Spring Harbor perspectives in biology
• 影响因子: 7.2
• 作者: M. Bootman