A novobiocin derivative, XN4, triggers ferroptosis in gastric cancer cells via the activation of NOX4.
Pharm Biol
; 60(1): 1449-1457, 2022 Dec.
Article
em En
| MEDLINE
| ID: mdl-35938505
ABSTRACT
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 ANDMETHODS:
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 (IC50 values of XN4 on SGC-7901 and BGC-823 cells 1.592 ± 0.14 µmol/L and 2.022 ± 0.19 µmol/L) and Fe2+ 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 Fe2+ 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 ANDCONCLUSIONS:
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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Gástricas
/
Ferroptose
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article