A novobiocin derivative, XN4, triggers ferroptosis in gastric cancer cells via the activation of NOX4
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...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | Pharmaceutical Biology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/13880209.2022.2099431 |
| _version_ | 1811314318862450688 |
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| author | Rongrong Li Bin Yin Deyu Zeng Zhenyang Liu |
| author_facet | Rongrong Li Bin Yin Deyu Zeng Zhenyang Liu |
| author_sort | Rongrong Li |
| collection | DOAJ |
| description | 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 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 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. |
| first_indexed | 2024-04-13T11:09:39Z |
| format | Article |
| id | doaj.art-34b503753e59444db8249396901fc291 |
| institution | Directory Open Access Journal |
| issn | 1388-0209 1744-5116 |
| language | English |
| last_indexed | 2024-04-13T11:09:39Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Pharmaceutical Biology |
| spelling | doaj.art-34b503753e59444db8249396901fc2912022-12-22T02:49:09ZengTaylor & Francis GroupPharmaceutical Biology1388-02091744-51162022-12-016011449145710.1080/13880209.2022.2099431A novobiocin derivative, XN4, triggers ferroptosis in gastric cancer cells via the activation of NOX4Rongrong Li0Bin Yin1Deyu Zeng2Zhenyang Liu3Department of Medical Oncology-Gastroenterology and Urology, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, ChinaDepartment of Gastric Pancreatic Surgery, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, ChinaDepartment of Medical Oncology-Gastroenterology and Urology, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, ChinaDepartment of Medical Oncology-Gastroenterology and Urology, Hunan Cancer Hospital, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, ChinaContext 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 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 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.https://www.tandfonline.com/doi/10.1080/13880209.2022.2099431Malondialdehydedeferoxamine mesylateerastinliproxstatin-1lipid peroxidationmitochondrial damage |
| spellingShingle | Rongrong Li Bin Yin Deyu Zeng Zhenyang Liu A novobiocin derivative, XN4, triggers ferroptosis in gastric cancer cells via the activation of NOX4 Pharmaceutical Biology Malondialdehyde deferoxamine mesylate erastin liproxstatin-1 lipid peroxidation mitochondrial damage |
| title | A novobiocin derivative, XN4, triggers ferroptosis in gastric cancer cells via the activation of NOX4 |
| title_full | A novobiocin derivative, XN4, triggers ferroptosis in gastric cancer cells via the activation of NOX4 |
| title_fullStr | A novobiocin derivative, XN4, triggers ferroptosis in gastric cancer cells via the activation of NOX4 |
| title_full_unstemmed | A novobiocin derivative, XN4, triggers ferroptosis in gastric cancer cells via the activation of NOX4 |
| title_short | A novobiocin derivative, XN4, triggers ferroptosis in gastric cancer cells via the activation of NOX4 |
| title_sort | novobiocin derivative xn4 triggers ferroptosis in gastric cancer cells via the activation of nox4 |
| topic | Malondialdehyde deferoxamine mesylate erastin liproxstatin-1 lipid peroxidation mitochondrial damage |
| url | https://www.tandfonline.com/doi/10.1080/13880209.2022.2099431 |
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