A novobiocin derivative, XN4, triggers ferroptosis in gastric cancer cells via the activation of NOX4.

Szczegóły
Abstrakt

Tytuł:: A novobiocin derivative, XN4, triggers ferroptosis in gastric cancer cells via the activation of NOX4.
Autorzy:: Li R; Department of Medical Oncology-Gastroenterology and Urology, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
Yin B; Department of Gastric Pancreatic Surgery, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
Zeng D; Department of Medical Oncology-Gastroenterology and Urology, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
Liu Z; Department of Medical Oncology-Gastroenterology and Urology, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
Źródło:: Pharmaceutical biology [Pharm Biol] 2022 Dec; Vol. 60 (1), pp. 1449-1457.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Publication: [London] : Taylor & Francis
Original Publication: Lisse, the Netherlands : Swets & Zeitlinger, c1998-
MeSH Terms:: Ferroptosis*
Stomach Neoplasms*/drug therapy
Apoptosis ; Cell Death ; Humans ; Lipid Peroxidation ; NADPH Oxidase 4/metabolism ; NADPH Oxidase 4/pharmacology ; Novobiocin/pharmacology ; Reactive Oxygen Species/metabolism
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Contributed Indexing:: Keywords: Malondialdehyde; deferoxamine mesylate; erastin; lipid peroxidation; liproxstatin-1; mitochondrial damage
Substance Nomenclature:: 0 (Reactive Oxygen Species)
17EC19951N (Novobiocin)
EC 1.6.3.- (NADPH Oxidase 4)
EC 1.6.3.- (NOX4 protein, human)
Entry Date(s):: Date Created: 20220808 Date Completed: 20220809 Latest Revision: 20220811
Update Code:: 20240104
PubMed Central ID:: PMC9361764
DOI:: 10.1080/13880209.2022.2099431
PMID:: 35938505
: Czasopismo naukowe

Pełny tekst

Context: A novobiocin derivative, XN4, has been shown to promote cell apoptosis in chronic myeloid leukaemia.
Objective: This study explores the mechanism by which XN4 promotes ferroptosis of gastric cancer (GC) cells.
Materials and Methods: Human GC SGC-7901 and BGC-823 cells were treated with different XN4 concentrations (0, 0.1, 0.5, 1.0, 5.0, and 10.0 μmol/L) to evaluate effects of XN4. Additionally, cells were pre-treated for 24 h with si-NOX4, for 1 h with the iron chelator deferoxamine mesylate (DFO) or for 1 h with the lipid peroxidation inhibitor liproxstatin-1 before being treated with XN4 to analyse the mechanism of XN4.
Results: XN4 increased cell death (IC 50 values of XN4 on SGC-7901 and BGC-823 cells: 1.592 ± 0.14 μmol/L and 2.022 ± 0.19 μmol/L) and Fe 2+ levels in SGC-7901 and BGC-823 cells. These effects of 2.0 μmol/L XN4 were abolished by 100 μmol/L DFO treatment. XN4 enhanced transferrin and transferrin receptor expression to induce Fe 2+ accumulation. XN4 decreased mitochondrial membrane potentials in GC cells, similar to erastin. Additionally, XN4 increased MDA, hydrogen peroxide, and ROS levels, but diminished total glutathione levels. Liproxstatin-1 (200 nmol/L) nullified the effects of XN4 (2.0 μmol/L) on MDA levels and cell death. Moreover, GPX4 levels decreased, but NOX4 and ferroptosis-related protein PTGS2 levels increased in GC cells following XN4 treatment, which was nullified by NOX4 knockdown.
Discussion and Conclusions: The pro-ferroptotic role of XN4 in GC might enable it to become a promising drug for GC treatment in the future despite the need for extensive research.

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