{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T14:33:33Z","timestamp":1784212413394,"version":"3.55.0"},"reference-count":49,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,31]],"date-time":"2021-12-31T00:00:00Z","timestamp":1640908800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["MO 1418 \/ 7-2"],"award-info":[{"award-number":["MO 1418 \/ 7-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["Horizon 2020 research and an innovation program FET Open under grant agreement No 861878 (project \u201cNeutroCure\u201d)."],"award-info":[{"award-number":["Horizon 2020 research and an innovation program FET Open under grant agreement No 861878 (project \u201cNeutroCure\u201d)."]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Friedrich-Alexander-University (FAU) of Erlangen-N\u00fcrnberg","award":["Emerging Field Initiative, project \u201cChemistry in Live Cells\u201d"],"award-info":[{"award-number":["Emerging Field Initiative, project \u201cChemistry in Live Cells\u201d"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Radiotherapy (RT) efficacy can be improved by using radiosensitizers, i.e., drugs enhancing the effect of ionizing radiation (IR). One of the side effects of RT includes damage of normal tissue in close proximity to the treated tumor. This problem can be solved by applying cancer specific radiosensitizers. N-Alkylaminoferrocene-based (NAAF) prodrugs produce reactive oxygen species (ROS) in cancer cells, but not in normal cells. Therefore, they can potentially act as cancer specific radiosensitizers. However, early NAAF prodrugs did not exhibit this property. Since functional mitochondria are important for RT resistance, we assumed that NAAF prodrugs affecting mitochondria in parallel with increasing intracellular ROS can potentially exhibit synergy with RT. We applied sequential Cu+-catalyzed alkyne-azide cycloadditions (CuAAC) to obtain a series of NAAF derivatives with the goal of improving anticancer efficacies over already existing compounds. One of the obtained prodrugs (2c) exhibited high anticancer activity with IC50 values in the range of 5\u20137.1 \u00b5M in human ovarian carcinoma, Burkitt\u2019s lymphoma, pancreatic carcinoma and T-cell leukemia cells retained moderate water solubility and showed cancer specificity. 2c strongly affects mitochondria of cancer cells, leading to the amplification of mitochondrial and total ROS production and thus causing cell death via necrosis and apoptosis. We observed that 2c acts as a radiosensitizer in human head and neck squamous carcinoma cells. This is the first demonstration of a synergy between the radiotherapy and NAAF-based ROS amplifiers.<\/jats:p>","DOI":"10.3390\/cancers14010208","type":"journal-article","created":{"date-parts":[[2022,1,3]],"date-time":"2022-01-03T22:51:50Z","timestamp":1641250310000},"page":"208","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Intracellular Amplifiers of Reactive Oxygen Species Affecting Mitochondria as Radiosensitizers"],"prefix":"10.3390","volume":"14","author":[{"given":"Hong-Gui","family":"Xu","sequence":"first","affiliation":[{"name":"Organic Chemistry Chair II, Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-N\u00fcrnberg (FAU), Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktor","family":"Reshetnikov","sequence":"additional","affiliation":[{"name":"Organic Chemistry Chair II, Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-N\u00fcrnberg (FAU), Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marit","family":"Wondrak","sequence":"additional","affiliation":[{"name":"OncoRay\u2014National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden and Helmholtz-Zentrum Dresden\u2014Rossendorf, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Eckhardt","sequence":"additional","affiliation":[{"name":"OncoRay\u2014National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden and Helmholtz-Zentrum Dresden\u2014Rossendorf, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3912-6594","authenticated-orcid":false,"given":"Leoni A.","family":"Kunz-Schughart","sequence":"additional","affiliation":[{"name":"OncoRay\u2014National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden and Helmholtz-Zentrum Dresden\u2014Rossendorf, 01307 Dresden, Germany"},{"name":"National Center for Tumor Diseases (NCT), Partner Site Dresden, 01307 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5705-6329","authenticated-orcid":false,"given":"Christina","family":"Janko","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON), Universit\u00e4tsklinikum Erlangen, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer","family":"Tietze","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON), Universit\u00e4tsklinikum Erlangen, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Alexiou","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Section of Experimental Oncology and Nanomedicine (SEON), Universit\u00e4tsklinikum Erlangen, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannes","family":"Borchardt","sequence":"additional","affiliation":[{"name":"Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, Leipzig University, 04107 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2778-6256","authenticated-orcid":false,"given":"Achim","family":"Aigner","sequence":"additional","affiliation":[{"name":"Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, Leipzig University, 04107 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Medicine V, Heidelberg University Hospital, 69120 Heidelberg, Germany"},{"name":"Department of Hematology, First Affiliated Hospital of Soochow University, Suzhou 215006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1579-1509","authenticated-orcid":false,"given":"Michael","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Department of Medicine V, Heidelberg University Hospital, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7893-401X","authenticated-orcid":false,"given":"Leopold","family":"Sellner","sequence":"additional","affiliation":[{"name":"Department of Medicine V, Heidelberg University Hospital, 69120 Heidelberg, Germany"},{"name":"Takeda Pharmaceuticals, Cambridge, MA 02139, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Daum","sequence":"additional","affiliation":[{"name":"Organic Chemistry Chair II, Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-N\u00fcrnberg (FAU), Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany"},{"name":"Merck, Im Laternenacker 5, 8200 Schaffhausen, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00fclya Gizem","family":"\u00d6zkan","sequence":"additional","affiliation":[{"name":"Organic Chemistry Chair II, Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-N\u00fcrnberg (FAU), Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andriy","family":"Mokhir","sequence":"additional","affiliation":[{"name":"Organic Chemistry Chair II, Department of Chemistry and Pharmacy, Friedrich-Alexander University Erlangen-N\u00fcrnberg (FAU), Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"135","DOI":"10.3322\/caac.21209","article-title":"Progress and controversies: Radiation therapy for invasive breast cancer","volume":"64","author":"Jagsi","year":"2014","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1200\/JCO.2015.66.1181","article-title":"SIRFLOX: Randomized Phase III Trial Comparing First-Line mFOLFOX6 (Plus or Minus Bevacizumab) Versus mFOLFOX6 (Plus or Minus Bevacizumab) Plus Selective Internal Radiation Therapy in Patients with Metastatic Colorectal Cancer","volume":"34","author":"Heinemann","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_3","unstructured":"Knipe, H., and Sheikh, Y. (2021, December 13). 3D Conformal Radiation Therapy. Reference Article, Radiopaedia.Org. Available online: https:\/\/radiopaedia.org\/articles\/3d-conformal-radiation-therapy?lang=us."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"615","DOI":"10.3109\/09553002.2014.892227","article-title":"Cancer stem cells and radioresistance","volume":"90","author":"Rycaj","year":"2014","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1053\/srao.2003.50002","article-title":"The mechanism of action of radiosensitization of conventional chemotherapeutic agents","volume":"13","author":"Lawrence","year":"2003","journal-title":"Sem. Rad. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.clon.2007.03.010","article-title":"Chemical radiosensitizers for use in radiotherapy","volume":"19","author":"Wardman","year":"2007","journal-title":"Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1039\/C8CS00641E","article-title":"Transition metal compounds as cancer radiosensitizers","volume":"48","author":"Gill","year":"2019","journal-title":"Chem. Soc. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s10637-019-00867-4","article-title":"Veliparib in ovarian cancer: A new synthetically lethal therapeutic approach","volume":"38","author":"Boussios","year":"2020","journal-title":"Investig. New Drugs"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.4161\/cbt.8.20.9436","article-title":"Sorafenib induces preferential apoptotic killing of a drug- and radio-resistant hep G2 cells through a mitochondria-dependent oxidative stress mechanism","volume":"8","author":"Chiou","year":"2009","journal-title":"Cancer Biol. Ther."},{"key":"ref_10","first-page":"179","article-title":"Enhancement of misonidazole radiosensitization by an inhibitor of glutathione biosynthesis, Radiother","volume":"43","author":"Hodgkiss","year":"1983","journal-title":"Oncology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s13566-012-0004-4","article-title":"Radiosensitization of cervical cancer xenografts by arsenic trioxide and the role of VEGF and Ku70","volume":"1","author":"Ren","year":"2012","journal-title":"J. Radiat. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"68170","DOI":"10.18632\/oncotarget.11906","article-title":"Diisopropylamine dichloroacetate enhances radiosensitization in esophageal squamous cell carcinoma by increasing mitochondria-derived reactive oxygen species levels","volume":"7","author":"Dong","year":"2016","journal-title":"Oncotarget"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1021\/acs.bioconjchem.6b00168","article-title":"Synthesis of PEGylated ferrocene nanoconjugates as the radiosensitizer of cancer cells","volume":"27","author":"Tian","year":"2016","journal-title":"Bioconj. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Skoupilova, H., Rak, V., Pinkas, J., Karban, J., and Hrstka, R. (2020). The cytotoxic effect of newly synthesized ferrocenes against cervical carcinoma cells alone and in combination with radiotherapy. Appl. Sci., 10.","DOI":"10.3390\/app10113728"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2732","DOI":"10.1002\/cncr.32150","article-title":"National Cancer Institute (NCI) state of the science: Targeted radiosensitizers in colorectal cancer","volume":"125","author":"George","year":"2019","journal-title":"Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0014-5793(00)01638-0","article-title":"Estimation of H2O2 gradients across biomembranes","volume":"475","author":"Antunes","year":"2000","journal-title":"FEBS Lett."},{"key":"ref_17","first-page":"794","article-title":"Production of large amounts of hydrogen peroxide by human tumor cells","volume":"51","author":"Szatrowski","year":"1991","journal-title":"Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/BJ20061131","article-title":"Oxidative stress and cancer: Have we moved forward?","volume":"401","author":"Halliwell","year":"2007","journal-title":"Biochem. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6935","DOI":"10.1021\/jm400754c","article-title":"Aminoferrocene-based prodrugs and their effects on human normal and cancer cells as well as bacterial cells","volume":"56","author":"Marzenell","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3447","DOI":"10.1016\/j.bmcl.2015.07.013","article-title":"Activity of aminoferrocene-based prodrugs against prostate cancer","volume":"25","author":"Schikora","year":"2015","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1021\/jm5019548","article-title":"Improved synthesis of N-benzylaminoferrocene-based prodrugs and evaluation of their toxicity and antileukemic activity","volume":"58","author":"Daum","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1002\/anie.201706585","article-title":"Lysosome-targeting amplifiers of reactive oxygen species as anticancer prodrugs","volume":"56","author":"Daum","year":"2017","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5678","DOI":"10.1002\/chem.201701192","article-title":"Cancer specific, intracellular, reductive activation of anticancer Pt(IV)-prodrugs","volume":"23","author":"Reshetnikov","year":"2017","journal-title":"Chem. Eur. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.jinorgbio.2017.08.038","article-title":"Tuning the structure of aminoferrocene-based anticancer prodrugs to prevent their aggregation in aqueous solution","volume":"178","author":"Daum","year":"2018","journal-title":"J. Inorg. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11943","DOI":"10.1002\/anie.201805955","article-title":"ROS-responsive N-alkylaminoferrocenes for cancer cell specific targeting of mitochondria","volume":"57","author":"Reshetnikov","year":"2018","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6679","DOI":"10.1039\/C8DT01458B","article-title":"A cancer specific oxaliplatin-releasing Pt(IV)-prodrug","volume":"47","author":"Reshetnikov","year":"2018","journal-title":"Dalton Trans."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1021\/acs.bioconjchem.9b00019","article-title":"Identification of boronic acid derivatives as an active form of N-alkylaminoferrocene-based anticancer prodrugs and their radiolabeling with 18F","volume":"30","author":"Daum","year":"2019","journal-title":"Bioconjugate Chem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Reshetnikov, V., \u00d6zkan, H.G., Daum, S., Janko, C., Alexiou, C., Sauer, C., Heinrich, M.R., and Mokhir, A. (2020). N-Alkylaminoferrocene-based prodrugs targeting mitochondria of cancer cells. Molecules, 25.","DOI":"10.3390\/molecules25112545"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"11158","DOI":"10.1002\/anie.202100054","article-title":"An endoplasmic reticulum specific pro-amplifier of reactive oxygen species in cancer cells","volume":"60","author":"Xu","year":"2021","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3850","DOI":"10.1002\/chem.201200075","article-title":"ROS-inducible DNA cross-linking agent as a new anticancer prodrug building block","volume":"18","author":"Cao","year":"2012","journal-title":"Chem. Eur. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.ejmech.2017.03.041","article-title":"Hydrogen peroxide activated quinone methide precursors with enhanced DNA cross-linking capability and cytotoxicity towards cancer cells","volume":"133","author":"Wang","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8802","DOI":"10.1039\/C5CS00486A","article-title":"Ferrocifen type anticancer drugs","volume":"44","author":"Jaouen","year":"2015","journal-title":"Chem. Soc. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8421","DOI":"10.1002\/anie.201902456","article-title":"Atypical lone pair-pi interaction with quinone methides in a series of imido-ferrociphenol anticancer drug candidates","volume":"58","author":"Wang","year":"2019","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6954","DOI":"10.1021\/jm100576z","article-title":"Synthesis and selective anticancer activity of organochalcogen based redox catalysts","volume":"53","author":"Doering","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.1021\/acs.organomet.0c00306","article-title":"Anticancer effects of an electronically coupled oligoferrocene","volume":"38","author":"Zeh","year":"2020","journal-title":"Organometallics"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"100905","DOI":"10.1016\/j.tranon.2020.100905","article-title":"Targeting cancer-cell mitochondria and metabolism to improve radiotherapy response","volume":"14","author":"McCann","year":"2021","journal-title":"Transl. Oncol."},{"key":"ref_37","first-page":"e21148","article-title":"Quantitative analysis of mitochondrial membrane potential heterogeneity in unsynchronized and synchronized cancer cells","volume":"35","author":"Rovini","year":"2020","journal-title":"FASEB J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.cell.2016.12.039","article-title":"Understanding the intersections between metabolism and cancer biology","volume":"168","author":"DeBerardinis","year":"2017","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"696","DOI":"10.18632\/oncoscience.215","article-title":"Doxycycline and therapeutic targeting of the DNA damage response in cancer cells: Old drug, new purpose","volume":"2","author":"Sotgia","year":"2015","journal-title":"Oncoscience"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1021\/acs.accounts.6b00277","article-title":"Peptide-mediated delivery of chemical probes and therapeutics to mitochondria","volume":"49","author":"Jean","year":"2016","journal-title":"Acc. Chem. Res."},{"key":"ref_41","first-page":"100023","article-title":"Mitochondria-targeted nanoparticles (mitoNANO): An emerging therapeutic shortcut for cancer","volume":"3","author":"Tabish","year":"2021","journal-title":"Biomat. Biosyst."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.actbio.2021.04.054","article-title":"Mitochondria-targeted graphene for advanced cancer therapeutics","volume":"129","author":"Tabish","year":"2021","journal-title":"Acta Biomat."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1002\/jlcr.3687","article-title":"Radiosynthesis of an 18F-fluoroglycosylated aminoferrocene for in-vivo imaging of reactive oxygen species by PET","volume":"61","author":"Toms","year":"2018","journal-title":"J. Label. Compd. Radiopharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1177\/002215540205000207","article-title":"Splicing mutations in TP53 in human squamous cell carcinoma lines influence immunohistochemical detection","volume":"50","author":"Eicheler","year":"2002","journal-title":"J. Histochem. Cytochem."},{"key":"ref_45","first-page":"1031","article-title":"Van der Waals radii of elements","volume":"37","author":"Batsanov","year":"2001","journal-title":"Inorg. Mat."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.bbabio.2017.02.009","article-title":"NO control of mitochondrial function in normal and transformed cells","volume":"1858","author":"Tengan","year":"2017","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1089\/ars.2000.2.4-673","article-title":"Nitric oxide induces a decrease in the mitochondrial membrane potential of peripheral blood lymphocytes, especially in natural killer cells","volume":"2","author":"Takabayashi","year":"2008","journal-title":"Antioxid. Redox Signal."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrc2982","article-title":"The molecular biology of head and neck cancer","volume":"11","author":"Leemans","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3152","DOI":"10.1158\/1078-0432.CCR-18-2951","article-title":"The CD98 Heavy Chain Is a Marker and Regulator of Head and Neck Squamous Cell Carcinoma Radiosensitivity","volume":"25","author":"Digomann","year":"2019","journal-title":"Clin. Cancer Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/1\/208\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:57:07Z","timestamp":1760169427000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/1\/208"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,31]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["cancers14010208"],"URL":"https:\/\/doi.org\/10.3390\/cancers14010208","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,31]]}}}