Effect and mechanism of novel HDAC inhibitor ZDLT-1 in colorectal cancer by regulating apoptosis and inflammation.

Autor: Geng H; Teaching Hospital of Shenyang Pharmaceutical University, General Hospital of Northern Theater Command, 100016 Shenyang City, Liaoning Province, PR China; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang City, Liaoning Province, PR China. Electronic address: x876892517@163.com., Zheng F; Teaching Hospital of Shenyang Pharmaceutical University, General Hospital of Northern Theater Command, 100016 Shenyang City, Liaoning Province, PR China; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang City, Liaoning Province, PR China. Electronic address: zhengfangyuanzxq@163.com., Sun W; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang City, Liaoning Province, PR China. Electronic address: s17824267658@163.com., Huang S; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang City, Liaoning Province, PR China; Pharmacy Department, Tianjin Hospital, Tianjin, PR China. Electronic address: hsq199696@163.com., Wang Z; Teaching Hospital of Shenyang Pharmaceutical University, General Hospital of Northern Theater Command, 100016 Shenyang City, Liaoning Province, PR China; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang City, Liaoning Province, PR China. Electronic address: 15091190776@163.com., Yang K; Teaching Hospital of Shenyang Pharmaceutical University, General Hospital of Northern Theater Command, 100016 Shenyang City, Liaoning Province, PR China; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang City, Liaoning Province, PR China. Electronic address: syphuyks100@163.com., Wang C; Teaching Hospital of Shenyang Pharmaceutical University, General Hospital of Northern Theater Command, 100016 Shenyang City, Liaoning Province, PR China; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang City, Liaoning Province, PR China. Electronic address: W1877816073@outlook.com., Tian C; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang City, Liaoning Province, PR China. Electronic address: syphu_tiancaizhi@163.com., Xu C; Teaching Hospital of Shenyang Pharmaceutical University, General Hospital of Northern Theater Command, 100016 Shenyang City, Liaoning Province, PR China; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang City, Liaoning Province, PR China. Electronic address: Charlottexu1996@163.com., Zhai G; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang City, Liaoning Province, PR China. Electronic address: z1098319369@163.com., Zhao M; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang City, Liaoning Province, PR China. Electronic address: zmy_dl@126.com., Hou S; Luoxin Pharmaceuticals Group Stock Co., Ltd., Linyi, PR China. Electronic address: shanbohou@luoxin.cn., Song A; Luoxin Pharmaceuticals Group Stock Co., Ltd., Linyi, PR China. Electronic address: aigangsong@luoxin.cn., Zhang Y; Teaching Hospital of Shenyang Pharmaceutical University, General Hospital of Northern Theater Command, 100016 Shenyang City, Liaoning Province, PR China; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang City, Liaoning Province, PR China. Electronic address: zhangyingshi@syphu.edu.cn., Zhao Q; Teaching Hospital of Shenyang Pharmaceutical University, General Hospital of Northern Theater Command, 100016 Shenyang City, Liaoning Province, PR China; Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang City, Liaoning Province, PR China. Electronic address: zhaoqingchun1967@163.com.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2024 Dec 25; Vol. 143 (Pt 1), pp. 113333. Date of Electronic Publication: 2024 Oct 09.
DOI: 10.1016/j.intimp.2024.113333
Abstrakt: Background: Histone deacetylase (HDAC) is a potential target for Colorectal Cancer (CRC) molecular target therapy, dehydroharmine derivative ZDLT-1 was designed to inhibit CRC cell proliferation by inhibiting HDAC target. This study aimed to explore the effect of ZDLT-1 could induce apoptosis in CRC in vitro and in vivo, and determine the mechanism of ZDLT-1.
Methods: First, MTT assay, colony formation, wound healing, Transwell assay, Hoechst33342 staining and Annexin V-FITC/PI double staining assay were used to investigate the in vitro effect of ZDLT-1. Second, the toxicity and the anti-tumor effect of ZDLT-1 by subcutaneous tumorigenesis assay were used to determine the in vivo effect of ZDLT-1. In terms of mechanism, we evaluated the effect of ZDLT-1 on HDAC downstream proteins such as HIF-1α, NF-κB, Cleaved-Caspase-3/9, GSDMD and acetylated histone by immunofluorescence and Western blot assessments.
Results: This study confirmed that ZDLT-1 had anti-tumor activity by inhibiting cell proliferation in vitro and solid tumor growth in vivo. Furthermore, ZDLT-1 can inhibit CRC cell invasion, migration and apoptosis in vitro. Moreover, ZDLT-1 can promote the expression of apoptosis proteins in HIF-1α/Caspase-3/Caspase-9 pathway and inhibit the expression of tumor-related immune proteins mainly in NF-κB/GSDMD/GSDME pathway.
Conclusion: ZDLT-1 as HDAC inhibitor could suppresses CRC cell growth in vivo and in vitro by triggering HIF-1α/Caspase-3/Caspase-9 pathway in promoting apoptosis, and triggering NF-κB/GSDMD/GSDME pathway in inhibiting tumor inflammation. Our results propose dehydroharmine derivative ZDLT-1 as a promising therapeutic small molecular agent for CRC.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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