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Camptothecin Sensitizes Hepatocellular Carcinoma Cells to Sorafenib- Induced Ferroptosis Via Suppression of Nrf2

Sorafenib is a potent inducer of ferroptosis used to manage hepatocellular carcinoma (HCC). The ferroptosis induced by sorafenib activates the p62–Keap1–Nrf2 pathway. Abnormal activation of Nrf2 reduces sorafenib’s efficiency and ferroptosis action and induces sorafenib’s resistance. Consequently, o...

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Autores principales: Elkateb, Ahmed S., Nofal, Shahira, Ali, Sahar A., Atya, Hanaa B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10359394/
https://www.ncbi.nlm.nih.gov/pubmed/37171695
http://dx.doi.org/10.1007/s10753-023-01823-4
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author Elkateb, Ahmed S.
Nofal, Shahira
Ali, Sahar A.
Atya, Hanaa B.
author_facet Elkateb, Ahmed S.
Nofal, Shahira
Ali, Sahar A.
Atya, Hanaa B.
author_sort Elkateb, Ahmed S.
collection PubMed
description Sorafenib is a potent inducer of ferroptosis used to manage hepatocellular carcinoma (HCC). The ferroptosis induced by sorafenib activates the p62–Keap1–Nrf2 pathway. Abnormal activation of Nrf2 reduces sorafenib’s efficiency and ferroptosis action and induces sorafenib’s resistance. Consequently, our study tried to study the effect of a novel combination of sorafenib and Camptothecin (CPT, Nrf2 inhibitor) to improve sorafenib’s ferroptosis action and reduce sorafenib resistance in the treatment of HCC. We evaluated the efficacy of sorafenib and/or CPT using HepG2 and Huh7 cell lines. MTT assay evaluated the anti-proliferation effects. The combination index (CI) and dose reduction index (DRI) were calculated using Isobologram analysis. Malondialdehyde (MDA), total antioxidant capacity (TAC), iron concentration, glutathione peroxidase (GPX4), and glutathione reductase (GR) activity assays were used to determine the ferroptosis action of drugs. Western blot was used to investigate the expression of the implicated proteins. Bioinformatics tools were used to determine the correlation between these proteins. Finally, the HPLC technique is used to measure cellular drug uptake. Our results revealed a strong synergism between sorafenib and CPT. The synergetic combination significantly increases lipid peroxidation and iron concentration, decreases TAC, GPX4 and GR activity, and reduces the expression of both Nrf2 and SLC7A11. The downregulation of Nrf2 expression has a vital role in the reduction of resistance mediators to sorafenib against HCC cells like (p62, MT1G, and ABCG2) and improves the cellular uptake of sorafenib. The current study provided evidence that Nrf2 inhibition by CPT improves sorafenib’s sensitivity and reduces sorafenib’s resistance via the augmentation of sorafenib’s ferroptosis action.
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spelling pubmed-103593942023-07-22 Camptothecin Sensitizes Hepatocellular Carcinoma Cells to Sorafenib- Induced Ferroptosis Via Suppression of Nrf2 Elkateb, Ahmed S. Nofal, Shahira Ali, Sahar A. Atya, Hanaa B. Inflammation Research Sorafenib is a potent inducer of ferroptosis used to manage hepatocellular carcinoma (HCC). The ferroptosis induced by sorafenib activates the p62–Keap1–Nrf2 pathway. Abnormal activation of Nrf2 reduces sorafenib’s efficiency and ferroptosis action and induces sorafenib’s resistance. Consequently, our study tried to study the effect of a novel combination of sorafenib and Camptothecin (CPT, Nrf2 inhibitor) to improve sorafenib’s ferroptosis action and reduce sorafenib resistance in the treatment of HCC. We evaluated the efficacy of sorafenib and/or CPT using HepG2 and Huh7 cell lines. MTT assay evaluated the anti-proliferation effects. The combination index (CI) and dose reduction index (DRI) were calculated using Isobologram analysis. Malondialdehyde (MDA), total antioxidant capacity (TAC), iron concentration, glutathione peroxidase (GPX4), and glutathione reductase (GR) activity assays were used to determine the ferroptosis action of drugs. Western blot was used to investigate the expression of the implicated proteins. Bioinformatics tools were used to determine the correlation between these proteins. Finally, the HPLC technique is used to measure cellular drug uptake. Our results revealed a strong synergism between sorafenib and CPT. The synergetic combination significantly increases lipid peroxidation and iron concentration, decreases TAC, GPX4 and GR activity, and reduces the expression of both Nrf2 and SLC7A11. The downregulation of Nrf2 expression has a vital role in the reduction of resistance mediators to sorafenib against HCC cells like (p62, MT1G, and ABCG2) and improves the cellular uptake of sorafenib. The current study provided evidence that Nrf2 inhibition by CPT improves sorafenib’s sensitivity and reduces sorafenib’s resistance via the augmentation of sorafenib’s ferroptosis action. Springer US 2023-05-12 2023 /pmc/articles/PMC10359394/ /pubmed/37171695 http://dx.doi.org/10.1007/s10753-023-01823-4 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research
Elkateb, Ahmed S.
Nofal, Shahira
Ali, Sahar A.
Atya, Hanaa B.
Camptothecin Sensitizes Hepatocellular Carcinoma Cells to Sorafenib- Induced Ferroptosis Via Suppression of Nrf2
title Camptothecin Sensitizes Hepatocellular Carcinoma Cells to Sorafenib- Induced Ferroptosis Via Suppression of Nrf2
title_full Camptothecin Sensitizes Hepatocellular Carcinoma Cells to Sorafenib- Induced Ferroptosis Via Suppression of Nrf2
title_fullStr Camptothecin Sensitizes Hepatocellular Carcinoma Cells to Sorafenib- Induced Ferroptosis Via Suppression of Nrf2
title_full_unstemmed Camptothecin Sensitizes Hepatocellular Carcinoma Cells to Sorafenib- Induced Ferroptosis Via Suppression of Nrf2
title_short Camptothecin Sensitizes Hepatocellular Carcinoma Cells to Sorafenib- Induced Ferroptosis Via Suppression of Nrf2
title_sort camptothecin sensitizes hepatocellular carcinoma cells to sorafenib- induced ferroptosis via suppression of nrf2
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10359394/
https://www.ncbi.nlm.nih.gov/pubmed/37171695
http://dx.doi.org/10.1007/s10753-023-01823-4
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