N‐Acetyl‐L‐Cysteine (NAC) Blunts Axitinib‐Related Adverse Effects in Preclinical Models of Glioblastoma
ABSTRACT Objective Axitinib is a tyrosine kinase inhibitor characterized by a strong affinity for Vascular Endothelial Growth Factor Receptors (VEGFRs). It was approved in 2012 by Food and Drug Administration and European Medicines Agency as a second line treatment for advanced renal cell carcinoma...
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| Format: | Article |
| Language: | English |
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Wiley
2024-10-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.70279 |
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| author | Alessia Formato Maria Salbini Elisa Orecchini Manuela Pellegrini Mariachiara Buccarelli Lucia Ricci Vitiani Stefano Giannetti Roberto Pallini Quintino Giorgio D'Alessandris Liverana Lauretti Maurizio Martini Valentina De Falco Andrea Levi Maria Laura Falchetti Maria Patrizia Mongiardi |
| author_facet | Alessia Formato Maria Salbini Elisa Orecchini Manuela Pellegrini Mariachiara Buccarelli Lucia Ricci Vitiani Stefano Giannetti Roberto Pallini Quintino Giorgio D'Alessandris Liverana Lauretti Maurizio Martini Valentina De Falco Andrea Levi Maria Laura Falchetti Maria Patrizia Mongiardi |
| author_sort | Alessia Formato |
| collection | DOAJ |
| description | ABSTRACT Objective Axitinib is a tyrosine kinase inhibitor characterized by a strong affinity for Vascular Endothelial Growth Factor Receptors (VEGFRs). It was approved in 2012 by Food and Drug Administration and European Medicines Agency as a second line treatment for advanced renal cell carcinoma and is currently under evaluation in clinical trial for the treatment of other cancers. Glioblastoma IDH‐wild type (GBM) is a highly malignant brain tumor characterized by diffusely infiltrative growth pattern and by a prominent neo‐angiogenesis. In GBM, axitinib has demonstrated a limited effectiveness as a monotherapy, while it was recently shown to significantly improve its efficacy in combination treatments. In preclinical models, axitinib has been reported to trigger cellular senescence both in tumor as well as in normal cells, through a mechanism involving intracellular reactive oxygen species (ROS) accumulation and activation of Ataxia Telangiectasia Mutated kinase (ATM). Limiting axitinib‐dependent ROS increase by antioxidants prevents senescence specifically in normal cells, without affecting tumor cells. Methods We used brain tumor xenografts obtained by engrafting Glioma Stem Cells (GSCs) into the brain of immunocompromised mice, to investigate the hypothesis that the antioxidant molecule N‐Acetyl‐L‐Cysteine (NAC) might be used to reduce senescence‐associated adverse effects of axitinib treatment without altering its anti‐tumor activity. Results We demonstrate that the use of the antioxidant molecule N‐Acetyl‐Cysteine (NAC) in combination with axitinib stabilizes tumor microvessels in GBM tumor orthotopic xenografts, eventually resulting in vessel normalization, and protects liver vasculature from axitinib‐dependent toxicity. Conclusion Overall, we found that NAC co‐treatment allows vessel normalization in brain tumor vessels and exerts a protective effect on liver vasculature, therefore minimizing axitinib‐dependent toxicity. |
| format | Article |
| id | doaj-art-7cc7cde955aa431da8a4db85e35cb3d3 |
| institution | OA Journals |
| issn | 2045-7634 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj-art-7cc7cde955aa431da8a4db85e35cb3d32025-08-20T02:32:11ZengWileyCancer Medicine2045-76342024-10-011319n/an/a10.1002/cam4.70279N‐Acetyl‐L‐Cysteine (NAC) Blunts Axitinib‐Related Adverse Effects in Preclinical Models of GlioblastomaAlessia Formato0Maria Salbini1Elisa Orecchini2Manuela Pellegrini3Mariachiara Buccarelli4Lucia Ricci Vitiani5Stefano Giannetti6Roberto Pallini7Quintino Giorgio D'Alessandris8Liverana Lauretti9Maurizio Martini10Valentina De Falco11Andrea Levi12Maria Laura Falchetti13Maria Patrizia Mongiardi14Institute of Biochemistry and Cell Biology, IBBC‐CNR Rome ItalyInstitute of Biochemistry and Cell Biology, IBBC‐CNR Rome ItalyInstitute of Biochemistry and Cell Biology, IBBC‐CNR Rome ItalyInstitute of Biochemistry and Cell Biology, IBBC‐CNR Rome ItalyDepartment of Oncology and Molecular Medicine Istituto Superiore di Sanità Rome ItalyDepartment of Oncology and Molecular Medicine Istituto Superiore di Sanità Rome ItalyDepartment of Neuroscience, Institute of Anatomy Università Cattolica del Sacro Cuore Rome ItalyDepartment of Neuroscience, Neurosurgery Section Università Cattolica del Sacro Cuore Rome ItalyDepartment of Neuroscience, Neurosurgery Section Università Cattolica del Sacro Cuore Rome ItalyDepartment of Neuroscience, Neurosurgery Section Università Cattolica del Sacro Cuore Rome ItalyUniversità degli Studi di Messina Messina ItalyInstitute of Endocrinology and Experimental Oncology (IEOS), National Research Council (CNR) Naples ItalyInstitute of Biochemistry and Cell Biology, IBBC‐CNR Rome ItalyInstitute of Biochemistry and Cell Biology, IBBC‐CNR Rome ItalyInstitute of Biochemistry and Cell Biology, IBBC‐CNR Rome ItalyABSTRACT Objective Axitinib is a tyrosine kinase inhibitor characterized by a strong affinity for Vascular Endothelial Growth Factor Receptors (VEGFRs). It was approved in 2012 by Food and Drug Administration and European Medicines Agency as a second line treatment for advanced renal cell carcinoma and is currently under evaluation in clinical trial for the treatment of other cancers. Glioblastoma IDH‐wild type (GBM) is a highly malignant brain tumor characterized by diffusely infiltrative growth pattern and by a prominent neo‐angiogenesis. In GBM, axitinib has demonstrated a limited effectiveness as a monotherapy, while it was recently shown to significantly improve its efficacy in combination treatments. In preclinical models, axitinib has been reported to trigger cellular senescence both in tumor as well as in normal cells, through a mechanism involving intracellular reactive oxygen species (ROS) accumulation and activation of Ataxia Telangiectasia Mutated kinase (ATM). Limiting axitinib‐dependent ROS increase by antioxidants prevents senescence specifically in normal cells, without affecting tumor cells. Methods We used brain tumor xenografts obtained by engrafting Glioma Stem Cells (GSCs) into the brain of immunocompromised mice, to investigate the hypothesis that the antioxidant molecule N‐Acetyl‐L‐Cysteine (NAC) might be used to reduce senescence‐associated adverse effects of axitinib treatment without altering its anti‐tumor activity. Results We demonstrate that the use of the antioxidant molecule N‐Acetyl‐Cysteine (NAC) in combination with axitinib stabilizes tumor microvessels in GBM tumor orthotopic xenografts, eventually resulting in vessel normalization, and protects liver vasculature from axitinib‐dependent toxicity. Conclusion Overall, we found that NAC co‐treatment allows vessel normalization in brain tumor vessels and exerts a protective effect on liver vasculature, therefore minimizing axitinib‐dependent toxicity.https://doi.org/10.1002/cam4.70279axitinibbrain tumor xenograftendotheliumglioblastoma IDH‐wild typeglioma stem cellsN‐acetyl‐L‐cysteine |
| spellingShingle | Alessia Formato Maria Salbini Elisa Orecchini Manuela Pellegrini Mariachiara Buccarelli Lucia Ricci Vitiani Stefano Giannetti Roberto Pallini Quintino Giorgio D'Alessandris Liverana Lauretti Maurizio Martini Valentina De Falco Andrea Levi Maria Laura Falchetti Maria Patrizia Mongiardi N‐Acetyl‐L‐Cysteine (NAC) Blunts Axitinib‐Related Adverse Effects in Preclinical Models of Glioblastoma Cancer Medicine axitinib brain tumor xenograft endothelium glioblastoma IDH‐wild type glioma stem cells N‐acetyl‐L‐cysteine |
| title | N‐Acetyl‐L‐Cysteine (NAC) Blunts Axitinib‐Related Adverse Effects in Preclinical Models of Glioblastoma |
| title_full | N‐Acetyl‐L‐Cysteine (NAC) Blunts Axitinib‐Related Adverse Effects in Preclinical Models of Glioblastoma |
| title_fullStr | N‐Acetyl‐L‐Cysteine (NAC) Blunts Axitinib‐Related Adverse Effects in Preclinical Models of Glioblastoma |
| title_full_unstemmed | N‐Acetyl‐L‐Cysteine (NAC) Blunts Axitinib‐Related Adverse Effects in Preclinical Models of Glioblastoma |
| title_short | N‐Acetyl‐L‐Cysteine (NAC) Blunts Axitinib‐Related Adverse Effects in Preclinical Models of Glioblastoma |
| title_sort | n acetyl l cysteine nac blunts axitinib related adverse effects in preclinical models of glioblastoma |
| topic | axitinib brain tumor xenograft endothelium glioblastoma IDH‐wild type glioma stem cells N‐acetyl‐L‐cysteine |
| url | https://doi.org/10.1002/cam4.70279 |
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