EX527, a sirtuins 1 inhibitor, sensitizes T-cell leukemia to death receptor-mediated apoptosis by downregulating cellular FLICE inhibitory protein.

Autor: Guo R; Department of Clinical Laboratory, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.; Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.; Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, Xinxiang Medical University, Xinxiang, China., Wei Y; Henan Red Cross Blood Center, Xinxiang, China., Du Y; Department of Clinical Laboratory, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.; Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.; Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, Xinxiang Medical University, Xinxiang, China., Liu L; Departments of Laboratory Medicine, Zhoukou Central Hospital, Zhoukou, China., Zhang H; Department of Microbiology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China., Ren R; Department of Clinical Laboratory, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.; Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.; Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, Xinxiang Medical University, Xinxiang, China., Sun R; Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.; Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, Xinxiang Medical University, Xinxiang, China., Zhang T; Department of Microbiology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China., Xiong X; School of Forensic Medicine, Xinxiang Medical University, Xinxiang, China., Zhao L; Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.; Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, Xinxiang Medical University, Xinxiang, China., Wang H; Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.; Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, Xinxiang Medical University, Xinxiang, China., Guo X; Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, Xinxiang Medical University, Xinxiang, China.; Department of Microbiology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China., Zhu X; Department of Clinical Laboratory, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.; Henan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.; Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, Xinxiang Medical University, Xinxiang, China.
Jazyk: angličtina
Zdroj: Cancer biology & therapy [Cancer Biol Ther] 2024 Dec 31; Vol. 25 (1), pp. 2402588. Date of Electronic Publication: 2024 Sep 17.
DOI: 10.1080/15384047.2024.2402588
Abstrakt: Death receptor-mediated extrinsic apoptosis system had been developed as a promising therapeutic strategy in clinical oncology, such as TRAIL therapy. However, multiple studies have demonstrated that TRAIL resistance is the biggest problem for disappointing clinical trials despite preclinical success. Targeting cellular FLICE inhibitory protein (cFLIP) is one strategy of combinatorial therapies to overcome resistance to DR-mediated apoptosis due to its negative regulator of extrinsic apoptosis. E × 527 (Selisistat) is a specific inhibitor of SIRT1 activity with safe and well tolerance in clinical trials. Here, we show that E × 527 could strengthen significantly activation of rhFasL-mediated apoptotic signaling pathway and increased apoptotic rate of T leukemia cells with high expression of cFLIP. Mechanically, Inhibition of SIRT1 by E × 527 increased polyubiquitination level of cFLIP via increasing acetylation of Ku70, which could promote proteosomal degradation of cFLIP protein. It implied that combinatorial therapies of E × 527 plus TRAIL may have a potential as a novel clinical application for TRAIL-resistant hematologic malignancies.
Databáze: MEDLINE