Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Typ-2-Diabetes und Adipositas Klimawandel und Gesundheit Neues aus dem Markt Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Fachpsychotherapie Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende Patientenratgeber
Erweiterte Suche
Anmelden
nach oben
Journal of Neuro-Oncology

15.02.2025 | Research

N-acetylcysteine remodels the tumor microenvironment of primary and recurrent mouse glioblastoma

verfasst von: Xiwei Zhu, Fanen Yuan, Qian Sun, Chen Yang, Hongxiang Jiang, Xi Xiang, Xinyi Zhang, Zhiqiang Sun, Yuxin Wei, Qianxue Chen, Linzhi Cai

Erschienen in: Journal of Neuro-Oncology

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Glioblastoma (GBM) exhibits a high ROS character, giving rise to an immunosuppressive microenvironment and tumor vascular abnormality. This study investigated the potential effect of N-acetylcysteine (NAC), an antioxidant, on primary and recurrent mouse brain tumors.

Methods

We measured reactive oxygen species (ROS)/ glutathione (GSH) levels in human GBM. Additionally, we conducted NAC trials on primary mouse brain tumor models (GL261-Luc, CT2A-Luc) and a recurrent mouse GBM model (GL261-iCasp9-Luc). After brain tumor inoculation, mice received a daily 100 mg/kg NAC treatment, and the tumor volume was monitored via IVIS imaging. The efficacy of NAC was evaluated through survival time, tumor volume, ROS/GSH levels, M1/M2 macrophages, immune cells infiltration, and tumor vascularization.

Results

Human GBM suffered from significant oxidative stress. With NAC treatment, mouse brain tumors exhibited a lower ROS level, more M1-like tumor-associated macrophages/microglia (TAMs), more CD8 + T cell infiltration, and a normalized vascular character. NAC inhibited tumor growth and suppressed recurrence in mouse brain tumor models.

Conclusion

NAC is a promising adjunctive drug to remodel the brain tumors microenvironment.
Literatur
1.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996PubMedCrossRef
2.
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10(5):459–466PubMedCrossRef
3.
Brandes AA, Tosoni A, Franceschi E, Sotti G, Frezza G, Amistà P, Morandi L, Spagnolli F, Ermani M (2009) Recurrence pattern after temozolomide concomitant with and adjuvant to radiotherapy in newly diagnosed patients with glioblastoma: correlation With MGMT promoter methylation status. J Clin Oncol 27(8):1275–1279PubMedCrossRef
4.
Aldape K, Brindle KM, Chesler L, Chopra R, Gajjar A, Gilbert MR, Gottardo N, Gutmann DH, Hargrave D, Holland EC et al (2019) Challenges to curing primary brain tumours. Nat Rev Clin Oncol 16(8):509–520PubMedPubMedCentralCrossRef
5.
Cheung EC, Vousden KH (2022) The role of ROS in tumour development and progression. Nat Rev Cancer 22(5):280–297PubMedCrossRef
6.
West XZ, Malinin NL, Merkulova AA, Tischenko M, Kerr BA, Borden EC, Podrez EA, Salomon RG, Byzova TV (2010) Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature 467(7318):972–976PubMedPubMedCentralCrossRef
7.
Kuo CL, Ponneri Babuharisankar A, Lin YC, Lien HW, Lo YK, Chou HY, Tangeda V, Cheng LC, Cheng AN, Lee AY (2022) Mitochondrial oxidative stress in the tumor microenvironment and cancer immunoescape: foe or friend? J Biomed Sci 29(1):74PubMedPubMedCentralCrossRef
8.
Ye Z, Ai X, Yang K, Yang Z, Fei F, Liao X, Qiu Z, Gimple RC, Yuan H, Huang H et al (2023) Targeting microglial metabolic rewiring synergizes with immune-checkpoint blockade therapy for glioblastoma. Cancer Discov 13(4):974–1001PubMedPubMedCentralCrossRef
9.
Khan F, Pang L, Dunterman M, Lesniak MS, Heimberger AB, Chen P (2023) Macrophages and microglia in glioblastoma: heterogeneity, plasticity, and therapy. J Clin Invest 133(1):10CrossRef
10.
Friebel E, Kapolou K, Unger S, Núñez NG, Utz S, Rushing EJ, Regli L, Weller M, Greter M, Tugues S et al (2020) Single-cell mapping of human brain cancer reveals tumor-specific instruction of tissue-invading leukocytes. Cell 181(7):1626-1642.e1620PubMedCrossRef
11.
Cui X, Morales RT, Qian W, Wang H, Gagner JP, Dolgalev I, Placantonakis D, Zagzag D, Cimmino L, Snuderl M et al (2018) Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis. Biomaterials 161:164–178PubMedPubMedCentralCrossRef
12.
Xing J, Cai H, Lin Z, Zhao L, Xu H, Song Y, Wang Z, Liu C, Hu G, Zheng J et al (2023) Examining the function of macrophage oxidative stress response and immune system in glioblastoma multiforme through analysis of single-cell transcriptomics. Front Immunol 14:1288137PubMedCrossRef
13.
Zhang Y, Choksi S, Chen K, Pobezinskaya Y, Linnoila I, Liu ZG (2013) ROS play a critical role in the differentiation of alternatively activated macrophages and the occurrence of tumor-associated macrophages. Cell Res 23(7):898–914PubMedPubMedCentralCrossRef
14.
Rao R, Han R, Ogurek S, Xue C, Wu LM, Zhang L, Zhang L, Hu J, Phoenix TN, Waggoner SN et al (2022) Glioblastoma genetic drivers dictate the function of tumor-associated macrophages/microglia and responses to CSF1R inhibition. Neuro Oncol 24(4):584–597PubMedCrossRef
15.
Rushworth GF, Megson IL (2014) Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther 141(2):150–159PubMedCrossRef
16.
Kudo H, Mio T, Kokunai T, Tamaki N, Sumino K, Matsumoto S (1990) Quantitative analysis of glutathione in human brain tumors. J Neurosurg 72(4):610–615PubMedCrossRef
17.
Deng J, Liu AD, Hou GQ, Zhang X, Ren K, Chen XZ, Li SSC, Wu YS, Cao X (2019) N-acetylcysteine decreases malignant characteristics of glioblastoma cells by inhibiting Notch2 signaling. J Exp Clin Cancer Res 38(1):2PubMedPubMedCentralCrossRef
18.
Yin J, Ge X, Ding F, He L, Song K, Shi Z, Ge Z, Zhang J, Ji J, Wang X et al (2024) Reactivating PTEN to impair glioma stem cells by inhibiting cytosolic iron-sulfur assembly. Sci Transl Med 16(739):eadg5553PubMedCrossRef
19.
Trachootham D, Alexandre J, Huang P (2009) Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8(7):579–591PubMedCrossRef
20.
Noch EK, Palma L, Yim I, Bullen N, Barnett D, Walsh A, Bhinder B, Benedetti E, Krumsiek J, Gurvitch J et al (2024) Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production. Proc Natl Acad Sci USA 121(8):e2317343121PubMedPubMedCentralCrossRef
21.
Zhang L, Cao Y, Guo X, Wang X, Han X, Kanwore K, Hong X, Zhou H, Gao D (2023) Hypoxia-induced ROS aggravate tumor progression through HIF-1α-SERPINE1 signaling in glioblastoma. J Zhejiang Univ Sci B 24(1):32–49PubMedCrossRef
22.
23.
Klemm F, Maas RR, Bowman RL, Kornete M, Soukup K, Nassiri S, Brouland JP, Iacobuzio-Donahue CA, Brennan C, Tabar V et al (2020) Interrogation of the microenvironmental landscape in brain tumors reveals disease-specific alterations of immune cells. Cell 181(7):1643-1660.e1617PubMedPubMedCentralCrossRef
24.
Müller S, Kohanbash G, Liu SJ, Alvarado B, Carrera D, Bhaduri A, Watchmaker PB, Yagnik G, Di Lullo E, Malatesta M et al (2017) Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment. Genome Biol 18(1):234PubMedPubMedCentralCrossRef
25.
Majidpoor J, Mortezaee K (2021) Angiogenesis as a hallmark of solid tumors - clinical perspectives. Cell Oncol (Dordr) 44(4):715–737PubMedCrossRef
26.
McDonald DM, Baluk P (2002) Significance of blood vessel leakiness in cancer. Cancer Res 62(18):5381–5385PubMed
27.
Glorieux C, Liu S, Trachootham D, Huang P (2024) Targeting ROS in cancer: rationale and strategies. Nat Rev Drug Discov 23(8):583–606PubMedCrossRef
28.
Vicente-Gutierrez C, Bonora N, Bobo-Jimenez V, Jimenez-Blasco D, Lopez-Fabuel I, Fernandez E, Josephine C, Bonvento G, Enriquez JA, Almeida A et al (2019) Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour. Nat Metab 1(2):201–211PubMedCrossRef
29.
Dringen R (2000) Metabolism and functions of glutathione in brain. Prog Neurobiol 62(6):649–671PubMedCrossRef
30.
Forman HJ, Davies KJ, Ursini F (2014) How do nutritional antioxidants really work: nucleophilic tone and para-hormesis versus free radical scavenging in vivo. Free Radic Biol Med 66:24–35PubMedCrossRef
31.
Forman HJ, Zhang H (2021) Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat Rev Drug Discov 20(9):689–709PubMedPubMedCentralCrossRef
32.
Sayin VI, Ibrahim MX, Larsson E, Nilsson JA, Lindahl P, Bergo MO (2014) Antioxidants accelerate lung cancer progression in mice. Sci Transl Med 6(221):215CrossRef
33.
Le Gal K, Ibrahim MX, Wiel C, Sayin VI, Akula MK, Karlsson C, Dalin MG, Akyürek LM, Lindahl P, Nilsson J et al (2015) Antioxidants can increase melanoma metastasis in mice. Sci Transl Med 7(308):308
34.
Piskounova E, Agathocleous M, Murphy MM, Hu Z, Huddlestun SE, Zhao Z, Leitch AM, Johnson TM, DeBerardinis RJ, Morrison SJ (2015) Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527(7577):186–191PubMedPubMedCentralCrossRef
35.
Wiel C, Le Gal K, Ibrahim MX, Jahangir CA, Kashif M, Yao H, Ziegler DV, Xu X, Ghosh T, Mondal T et al (2019) BACH1 stabilization by antioxidants stimulates lung cancer metastasis. Cell 178(2):330-345.e322PubMedCrossRef
36.
Griess B, Mir S, Datta K, Teoh-Fitzgerald M (2020) Scavenging reactive oxygen species selectively inhibits M2 macrophage polarization and their pro-tumorigenic function in part, via Stat3 suppression. Free Radic Biol Med 147:48–60PubMedCrossRef
37.
Zou W, Chen L (2008) Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 8(6):467–477PubMedCrossRef
38.
Tu S, Lin X, Qiu J, Zhou J, Wang H, Hu S, Yao Y, Wang Y, Deng Y, Zhou Y et al (2021) Crosstalk between tumor-associated microglia/macrophages and CD8-positive T cells plays a key role in glioblastoma. Front Immunol 12:650105PubMedPubMedCentralCrossRef
39.
Chung EY, Liu J, Homma Y, Zhang Y, Brendolan A, Saggese M, Han J, Silverstein R, Selleri L, Ma X (2007) Interleukin-10 expression in macrophages during phagocytosis of apoptotic cells is mediated by homeodomain proteins Pbx1 and Prep-1. Immunity 27(6):952–964PubMedPubMedCentralCrossRef
40.
Reardon DA, Turner S, Peters KB, Desjardins A, Gururangan S, Sampson JH, McLendon RE, Herndon JE 2nd, Jones LW, Kirkpatrick JP et al (2011) A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma. J Natl Compr Canc Netw 9(4):414–427PubMedPubMedCentralCrossRef
41.
Jetten N, Verbruggen S, Gijbels MJ, Post MJ, De Winther MP, Donners MM (2014) Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo. Angiogenesis 17(1):109–118PubMedCrossRef
42.
Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8(8):618–631PubMedCrossRef
43.
Huang Y, Kim BYS, Chan CK, Hahn SM, Weissman IL, Jiang W (2018) Improving immune-vascular crosstalk for cancer immunotherapy. Nat Rev Immunol 18(3):195–203PubMedPubMedCentralCrossRef
Metadaten
Titel
N-acetylcysteine remodels the tumor microenvironment of primary and recurrent mouse glioblastoma
verfasst von
Xiwei Zhu
Fanen Yuan
Qian Sun
Chen Yang
Hongxiang Jiang
Xi Xiang
Xinyi Zhang
Zhiqiang Sun
Yuxin Wei
Qianxue Chen
Linzhi Cai
Publikationsdatum
15.02.2025
Verlag
Springer US
Erschienen in
Journal of Neuro-Oncology
Print ISSN: 0167-594X
Elektronische ISSN: 1573-7373
DOI
https://doi.org/10.1007/s11060-025-04971-9

Kompaktes Leitlinien-Wissen Neurologie (Link öffnet in neuem Fenster)

Mit medbee Pocketcards schnell und sicher entscheiden.
Leitlinien-Wissen kostenlos und immer griffbereit auf ihrem Desktop, Handy oder Tablet.

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Podcast

Vom Wert der Ernährung bei neurodegenerativen Erkrankungen

Am Beispiel Parkinson zeigt sich, dass Ernährung nicht nur präventiv förderlich ist, sondern auch die Wirkung von Medikamenten und den Krankheitsverlauf beeinflusst. Prof. Dr. Andrés Ceballos-Baumann, München, fasst die aktuelle Studienlage zusammen, nennt die bestehenden Probleme und veranschaulicht seine Vorgehensweise.

Passen Psychopharmaka und Pille zusammen?

Wie relevant Wechselwirkungen zwischen hormonellen Kontrazeptiva und Psychopharmaka sein können, schilderte Dr. med. Dominik Dabbert beim diesjährigen FOKO. Worauf es in der Praxis ankommt und wie gefährliche Wechselwirkungen vermieden werden können, lesen Sie hier. 

ePA: Entlastung oder Mehrarbeit?

Die elektronische Patientenakte (ePA) soll das Gesundheitswesen revolutionieren. Mit über 2000 Krankenhäusern und mehr als 100.000 ärztlichen Praxen ist sie eines der größten Digitalisierungsprojekte Europas. Während die Politik die ePA als „Gamechanger“ feiert, zeigt sich in der Praxis ein anderes Bild.

Einjährige Valaciclovir-Therapie schützt nicht vor Zoster-Rezidiv

Die Zoster Eye Disease Study (ZEDS) liefert gleich zwei ernüchternde Erkenntnisse: Eine einjährige Therapie mit niedrig dosiertem Valaciclovir kann weder einen Herpes zoster ophthalmicus (HZO) noch eine Post-Zoster-Neuralgie (PZN) verhindern.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen
Bildnachweise