{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T04:29:23Z","timestamp":1783744163225,"version":"3.55.0"},"reference-count":38,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T00:00:00Z","timestamp":1728345600000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020581","name":"Fondazione AIRC per la ricerca sul cancro ETS","doi-asserted-by":"publisher","award":["IG 2021#25664"],"award-info":[{"award-number":["IG 2021#25664"]}],"id":[{"id":"10.13039\/100020581","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["RF\u20102019\u201012368786"],"award-info":[{"award-number":["RF\u20102019\u201012368786"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>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\u2010wild type (GBM) is a highly malignant brain tumor characterized by diffusely infiltrative growth pattern and by a prominent neo\u2010angiogenesis. 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\u2010dependent ROS increase by antioxidants prevents senescence specifically in normal cells, without affecting tumor cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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\u2010Acetyl\u2010L\u2010Cysteine (NAC) might be used to reduce senescence\u2010associated adverse effects of axitinib treatment without altering its anti\u2010tumor activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrate that the use of the antioxidant molecule N\u2010Acetyl\u2010Cysteine (NAC) in combination with axitinib stabilizes tumor microvessels in GBM tumor orthotopic xenografts, eventually resulting in vessel normalization, and protects liver vasculature from axitinib\u2010dependent toxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Overall, we found that NAC co\u2010treatment allows vessel normalization in brain tumor vessels and exerts a protective effect on liver vasculature, therefore minimizing axitinib\u2010dependent toxicity.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.70279","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T16:51:08Z","timestamp":1728406268000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["N\u2010Acetyl\u2010L\u2010Cysteine (<scp>NAC<\/scp>) Blunts Axitinib\u2010Related Adverse Effects in Preclinical Models of Glioblastoma"],"prefix":"10.1002","volume":"13","author":[{"given":"Alessia","family":"Formato","sequence":"first","affiliation":[{"name":"Institute of Biochemistry and Cell Biology, IBBC\u2010CNR  Rome Italy"},{"name":"Department of Neuroscience, Neurosurgery Section Universit\u00e0 Cattolica del Sacro Cuore  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Salbini","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Cell Biology, IBBC\u2010CNR  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Orecchini","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Cell Biology, IBBC\u2010CNR  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Pellegrini","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Cell Biology, IBBC\u2010CNR  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariachiara","family":"Buccarelli","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine Istituto Superiore di Sanit\u00e0  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia\u00a0Ricci","family":"Vitiani","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine Istituto Superiore di Sanit\u00e0  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Giannetti","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Institute of Anatomy Universit\u00e0 Cattolica del Sacro Cuore  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Pallini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Neurosurgery Section Universit\u00e0 Cattolica del Sacro Cuore  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2953-9291","authenticated-orcid":false,"given":"Quintino\u00a0Giorgio","family":"D'Alessandris","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Neurosurgery Section Universit\u00e0 Cattolica del Sacro Cuore  Rome Italy"},{"name":"Department of Neurosurgery Fondazione Policlinico Universitario A. Gemelli IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liverana","family":"Lauretti","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Neurosurgery Section Universit\u00e0 Cattolica del Sacro Cuore  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Martini","sequence":"additional","affiliation":[{"name":"Universit\u00e0 degli Studi di Messina  Messina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"De\u00a0Falco","sequence":"additional","affiliation":[{"name":"Institute of Endocrinology and Experimental Oncology (IEOS), National Research Council (CNR)  Naples Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Levi","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Cell Biology, IBBC\u2010CNR  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8755-0042","authenticated-orcid":false,"given":"Maria\u00a0Laura","family":"Falchetti","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Cell Biology, IBBC\u2010CNR  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria\u00a0Patrizia","family":"Mongiardi","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Cell Biology, IBBC\u2010CNR  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,10,8]]},"reference":[{"key":"e_1_2_10_2_1","first-page":"269","article-title":"Axitinib: A Review of Its Safety and Efficacy in the Treatment of Adults With Advanced Renal Cell Carcinoma","volume":"7","author":"Gross\u2010Goupil M.","year":"2013","journal-title":"Clinical Medicine Insights"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-0652"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S109640"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.28112"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/07357907.2017.1310221"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noab106"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1308345"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2011.0038"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm8122031"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-017-2629-z"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-016-2092-2"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-016-1836-3"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2022.08.014"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.5768"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.13769"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-019-0798-2"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep21557"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-0644"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-1364"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401872"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-03828-z"},{"key":"e_1_2_10_23_1","first-page":"14","article-title":"Characterization of Glioblastoma Cells Response to Regorafenib","volume":"24","author":"Mongiardi M. P.","year":"2022","journal-title":"Cancers (Basel)"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-015-0185-z"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.31983"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.11.8463-8471.1998"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2017.04.009"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-1717"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2018.00048"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-017-0516-3"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17204-5"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2016.02.008"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-021-02231-x"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/now304"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12231"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.euo.2021.05.007"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1617455"},{"key":"e_1_2_10_38_1","first-page":"333","article-title":"Axitinib: Newly Approved for Renal Cell Carcinoma","volume":"3","author":"Tyler T.","year":"2012","journal-title":"Journal of the Advanced Practitioner in Oncology"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-023-02869-2"}],"container-title":["Cancer Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.70279","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T16:48:33Z","timestamp":1747673313000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cam4.70279"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10]]},"references-count":38,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2024,10]]}},"alternative-id":["10.1002\/cam4.70279"],"URL":"https:\/\/doi.org\/10.1002\/cam4.70279","archive":["Portico"],"relation":{},"ISSN":["2045-7634","2045-7634"],"issn-type":[{"value":"2045-7634","type":"print"},{"value":"2045-7634","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10]]},"assertion":[{"value":"2024-02-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-20","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70279"}}