Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.
Cell Death Dis. 2020 Sep 1;11(8):712. doi: 10.1038/s41419-020-02885-0.
Utilizing oxidative stress has recently been regarded as a potential strategy for tumor therapy. The NUAK family SNF1-like kinase 1 (NUAK1) is a critical component of the antioxidant defense system and is necessary for the survival of tumors. Therefore, NUAK1 is considered an attractive therapeutic target in cancer. However, antioxidant therapy induced elevated ROS levels to activate the Unc-51-like kinase 1 (ULK1) pathway to promote protective autophagy and ULK1-dependent mitophagy. Thus, the combined inhibition of NUAK1 and ULK1 showed a strong synergistic effect in different tumor types. Herein, the potential antitumor activities of a dual NUAK1/ULK1 inhibitor MRT68921 were evaluated in both tumor cell lines and animal models. MRT68921 significantly kills tumor cells by breaking the balance of oxidative stress signals. These results highlight the potential of MRT68921 as an effective agent for tumor therapy.
利用氧化应激最近被认为是肿瘤治疗的一种潜在策略。NUAK 家族 SNF1 样激酶 1（NUAK1）是抗氧化防御系统的关键组成部分，是肿瘤生存所必需的。因此，NUAK1 被认为是癌症治疗的一个有吸引力的靶点。然而，抗氧化治疗诱导 ROS 水平升高，激活 UNC-51 样激酶 1（ULK1）途径，促进保护性自噬和 ULK1 依赖性线粒体自噬。因此，NUAK1 和 ULK1 的联合抑制在不同的肿瘤类型中表现出很强的协同作用。在此，评估了双重 NUAK1/ULK1 抑制剂 MRT68921 在肿瘤细胞系和动物模型中的潜在抗肿瘤活性。MRT68921 通过打破氧化应激信号的平衡显著杀死肿瘤细胞。这些结果突出了 MRT68921 作为一种有效的肿瘤治疗药物的潜力。
