A novobiocin derivative, XN4, triggers ferroptosis in gastric cancer cells via the activation of NOX4. (31st December 2022)

• Record Type: Journal Article
• Authors: Li, Rongrong; Yin, Bin; Zeng, Deyu; Liu, Zhenyang
• Is Part Of: Pharmaceutical biology. Volume 60:Number 1(2022)
• Page Start: 1449
• Page End: 1457
• Publication Date: 2022-12-31
• Subjects: Malondialdehyde -- deferoxamine mesylate -- erastin -- liproxstatin-1 -- lipid peroxidation -- mitochondrial damage; Pharmacognosy -- Periodicals; Materia medica, Vegetable -- Periodicals; 615.321
• DOI: 10.1080/13880209.2022.2099431
• Languages: English
• ISSNs: 1388-0209

Abstract

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 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 (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 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.