{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:47Z","timestamp":1787027867188,"version":"build-2736575974"},"reference-count":60,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,7]],"date-time":"2023-01-07T00:00:00Z","timestamp":1673049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Pascoe pharmazeutische Praeparate GmbH","award":["D.31.15100"],"award-info":[{"award-number":["D.31.15100"]}]},{"name":"Pascoe pharmazeutische Praeparate GmbH","award":["D.32.22506"],"award-info":[{"award-number":["D.32.22506"]}]},{"name":"Pascoe pharmazeutische Praeparate GmbH","award":["D.30.21947"],"award-info":[{"award-number":["D.30.21947"]}]},{"name":"Else-Uebelmesser-Stiftung","award":["D.31.15100"],"award-info":[{"award-number":["D.31.15100"]}]},{"name":"Else-Uebelmesser-Stiftung","award":["D.32.22506"],"award-info":[{"award-number":["D.32.22506"]}]},{"name":"Else-Uebelmesser-Stiftung","award":["D.30.21947"],"award-info":[{"award-number":["D.30.21947"]}]},{"name":"Open Access Publishing Fund of the University of Tuebingen","award":["D.31.15100"],"award-info":[{"award-number":["D.31.15100"]}]},{"name":"Open Access Publishing Fund of the University of Tuebingen","award":["D.32.22506"],"award-info":[{"award-number":["D.32.22506"]}]},{"name":"Open Access Publishing Fund of the University of Tuebingen","award":["D.30.21947"],"award-info":[{"award-number":["D.30.21947"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Ascorbate acts as a prooxidant when administered parenterally at high supraphysiological doses, which results in the generation of hydrogen peroxide in dependence on oxygen. Most cancer cells are susceptible to the emerging reactive oxygen species (ROS). Accordingly, we evaluated high-dose ascorbate for the treatment of the B16F10 melanoma model. To investigate the effects of ascorbate on the B16F10 cell line in vitro, viability, cellular impedance, and ROS production were analyzed. In vivo, C57BL\/6NCrl mice were subcutaneously injected into the right flank with B16F10 cells and tumor-bearing mice were treated intraperitoneally with ascorbate (3 g\/kg bodyweight), immunotherapy (anti-programmed cell death protein 1 (PD1) antibody J43; 2 mg\/kg bodyweight), or both treatments combined. The efficacy and toxicity were analyzed by measuring the respective tumor sizes and mouse weights accompanied by histological analysis of the protein levels of proliferating cell nuclear antigen (Pcna), glucose transporter 1 (Glut-1), and CD3. Treatment of B16F10 melanoma-carrying mice with high-dose ascorbate yielded plasma levels in the pharmacologically effective range, and ascorbate showed efficacy as a monotherapy and when combined with PD1 inhibition. Our data suggest the applicability of ascorbate as an additional therapeutic agent that can be safely combined with immunotherapy and has the potential to potentiate anti-PD1-based immune checkpoint blockades.<\/jats:p>","DOI":"10.3390\/cells12020254","type":"journal-article","created":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T03:25:58Z","timestamp":1673234758000},"page":"254","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["High-Dose Ascorbate in Combination with Anti-PD1 Checkpoint Inhibition as Treatment Option for Malignant Melanoma"],"prefix":"10.3390","volume":"12","author":[{"given":"Markus","family":"Burkard","sequence":"first","affiliation":[{"name":"Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, Garbenstra\u00dfe 30, 70599 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2542-7022","authenticated-orcid":false,"given":"Heike","family":"Niessner","sequence":"additional","affiliation":[{"name":"Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, Garbenstra\u00dfe 30, 70599 Stuttgart, Germany"},{"name":"Division of Dermatooncology, Department of Dermatology, University of Tuebingen, Liebermeisterstra\u00dfe 25, 72076 Tuebingen, Germany"},{"name":"Cluster of Excellence iFIT (EXC 2180) \u201cImage-Guided and Functionally Instructed Tumor Therapies\u201d, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Leischner","sequence":"additional","affiliation":[{"name":"Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, Garbenstra\u00dfe 30, 70599 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alban","family":"Piotrowsky","sequence":"additional","affiliation":[{"name":"Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, Garbenstra\u00dfe 30, 70599 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Renner","sequence":"additional","affiliation":[{"name":"Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, Garbenstra\u00dfe 30, 70599 Stuttgart, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Marongiu","sequence":"additional","affiliation":[{"name":"Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, Garbenstra\u00dfe 30, 70599 Stuttgart, Germany"},{"name":"Department of Internal Medicine VIII, University Hospital Tuebingen, Otfried-Mueller-Stra\u00dfe 10, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich M.","family":"Lauer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine VIII, University Hospital Tuebingen, Otfried-Mueller-Stra\u00dfe 10, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Busch","sequence":"additional","affiliation":[{"name":"Dermatologie zum Delfin, Stadthausstra\u00dfe 12, 8400 Winterthur, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3922-3327","authenticated-orcid":false,"given":"Tobias","family":"Sinnberg","sequence":"additional","affiliation":[{"name":"Division of Dermatooncology, Department of Dermatology, University of Tuebingen, Liebermeisterstra\u00dfe 25, 72076 Tuebingen, Germany"},{"name":"Cluster of Excellence iFIT (EXC 2180) \u201cImage-Guided and Functionally Instructed Tumor Therapies\u201d, 72076 Tuebingen, Germany"},{"name":"Department of Dermatology, Venereology and Allergology, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sascha","family":"Venturelli","sequence":"additional","affiliation":[{"name":"Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, Garbenstra\u00dfe 30, 70599 Stuttgart, Germany"},{"name":"Department of Vegetative and Clinical Physiology, Institute of Physiology, University of Tuebingen, Wilhelmstra\u00dfe 56, 72074 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.bbamcr.2016.01.025","article-title":"Roads to melanoma: Key pathways and emerging players in melanoma progression and oncogenic signaling","volume":"1863","author":"Paluncic","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5826\/dpc.0702a01","article-title":"Epidemiological trends in skin cancer","volume":"7","author":"Apalla","year":"2017","journal-title":"Dermatol. Pract. Concept."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3041","DOI":"10.1073\/pnas.0711741105","article-title":"Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity","volume":"105","author":"Tsai","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1080\/1744666X.2022.2044796","article-title":"BRAF inhibitors and their immunological effects in malignant melanoma","volume":"18","author":"Adams","year":"2022","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1056\/NEJMoa1103782","article-title":"Improved survival with vemurafenib in melanoma with BRAF V600E mutation","volume":"364","author":"Chapman","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1056\/NEJMoa1302369","article-title":"Nivolumab plus ipilimumab in advanced melanoma","volume":"369","author":"Wolchok","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1056\/NEJMoa1910836","article-title":"Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma","volume":"381","author":"Larkin","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/S0140-6736(14)60958-2","article-title":"Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-comparison cohort of a phase 1 trial","volume":"384","author":"Robert","year":"2014","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e000333","DOI":"10.1136\/jitc-2019-000333","article-title":"Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: A DeCOG* study in 380 patients","volume":"8","author":"Amaral","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1158\/1078-0432.CCR-08-1825","article-title":"Anti-programmed death-1 synergizes with granulocyte macrophage colony-stimulating factor--secreting tumor cell immunotherapy providing therapeutic benefit to mice with established tumors","volume":"15","author":"Li","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5209","DOI":"10.1158\/0008-5472.CAN-12-1187","article-title":"PD-1 blockade enhances T-cell migration to tumors by elevating IFN-\u03b3 inducible chemokines","volume":"72","author":"Peng","year":"2012","journal-title":"Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/nrd4591","article-title":"Combination cancer immunotherapy and new immunomodulatory targets","volume":"14","author":"Mahoney","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1007\/s13555-021-00525-9","article-title":"Looking into a Better Future: Novel Therapies for Metastatic Melanoma","volume":"11","author":"Villani","year":"2021","journal-title":"Dermatol. Ther. (Heidelb)"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1200\/JCO.19.01464","article-title":"Long-Term Outcomes and Responses to Retreatment in Patients With Melanoma Treated With PD-1 Blockade","volume":"38","author":"Palmer","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1001\/jamaoncol.2019.2187","article-title":"Five-Year Survival and Correlates Among Patients With Advanced Melanoma, Renal Cell Carcinoma, or Non-Small Cell Lung Cancer Treated With Nivolumab","volume":"5","author":"Topalian","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Amaral, T., Seeber, O., Mersi, E., Sanchez, S., Thomas, I., Meiwes, A., Forschner, A., Leiter, U., Eigentler, T., and Keim, U. (2020). Primary Resistance to PD-1-Based Immunotherapy-A Study in 319 Patients with Stage IV Melanoma. Cancers, 12.","DOI":"10.3390\/cancers12041027"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e125057","DOI":"10.1172\/jci.insight.125057","article-title":"Targeting tumor-resident mast cells for effective anti-melanoma immune responses","volume":"4","author":"Kaesler","year":"2019","journal-title":"JCI Insight"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Hilke, F.J., Sinnberg, T., Gschwind, A., Niessner, H., Demidov, G., Amaral, T., Ossowski, S., Bonzheim, I., R\u00f6cken, M., and Riess, O. (2020). Distinct Mutation Patterns Reveal Melanoma Subtypes and Influence Immunotherapy Response in Advanced Melanoma Patients. Cancers, 12.","DOI":"10.3390\/cancers12092359"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3685","DOI":"10.1073\/pnas.73.10.3685","article-title":"Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer","volume":"73","author":"Cameron","year":"1976","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4538","DOI":"10.1073\/pnas.75.9.4538","article-title":"Supplemental ascorbate in the supportive treatment of cancer: Reevaluation of prolongation of survival times in terminal human cancer","volume":"75","author":"Cameron","year":"1978","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Nauman, G., Gray, J.C., Parkinson, R., Levine, M., and Paller, C.J. (2018). Systematic Review of Intravenous Ascorbate in Cancer Clinical Trials. Antioxidants, 7.","DOI":"10.3390\/antiox7070089"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.ccell.2017.02.018","article-title":"O2\u00b7\u2212 and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate","volume":"31","author":"Schoenfeld","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"8749","DOI":"10.1073\/pnas.0702854104","article-title":"Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo","volume":"104","author":"Chen","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"11105","DOI":"10.1073\/pnas.0804226105","article-title":"Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice","volume":"105","author":"Chen","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1056\/NEJM197909273011303","article-title":"Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial","volume":"301","author":"Creagan","year":"1979","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1056\/NEJM198501173120301","article-title":"High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison","volume":"312","author":"Moertel","year":"1985","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"533","DOI":"10.7326\/0003-4819-140-7-200404060-00010","article-title":"Vitamin C pharmacokinetics: Implications for oral and intravenous use","volume":"140","author":"Padayatty","year":"2004","journal-title":"Ann. Intern. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1093\/annonc\/mdn377","article-title":"Phase I clinical trial of i.v. ascorbic acid in advanced malignancy","volume":"19","author":"Hoffer","year":"2008","journal-title":"Ann. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s00280-013-2179-9","article-title":"Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer","volume":"72","author":"Stephenson","year":"2013","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41698-017-0044-8","article-title":"Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2","volume":"2","author":"Lv","year":"2018","journal-title":"NPJ Precis. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"222ra18","DOI":"10.1126\/scitranslmed.3007154","article-title":"High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy","volume":"6","author":"Ma","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1126\/science.aaa5004","article-title":"Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH","volume":"350","author":"Yun","year":"2015","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1042\/BST20180169","article-title":"Vitamin C and immune cell function in inflammation and cancer","volume":"46","author":"Ang","year":"2018","journal-title":"Biochem. Soc. Trans."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.imbio.2014.03.006","article-title":"Vitamin C treatment of mouse bone marrow-derived dendritic cells enhanced CD8(+) memory T cell production capacity of these cells in vivo","volume":"219","author":"Jeong","year":"2014","journal-title":"Immunobiology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1073\/pnas.1908158117","article-title":"High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model","volume":"117","author":"Luchtel","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"eaay8707","DOI":"10.1126\/scitranslmed.aay8707","article-title":"High-dose vitamin C enhances cancer immunotherapy","volume":"12","author":"Germano","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Niessner, H., Burkard, M., Leischner, C., Renner, O., Pl\u00f6ger, S., Meraz-Torres, F., B\u00f6cker, M., Hirn, C., Lauer, U.M., and Venturelli, S. (2022). Therapeutic Efficacy of Pharmacological Ascorbate on Braf Inhibitor Resistant Melanoma Cells In Vitro and In Vivo. Cells, 11.","DOI":"10.3390\/cells11071229"},{"key":"ref_38","first-page":"e2","article-title":"Decreased Plasma Ascorbate Levels in Stage IV Melanoma Patients","volume":"01","author":"Schleich","year":"2015","journal-title":"Metab. Nutr. Oncol."},{"key":"ref_39","first-page":"3019","article-title":"Measurement of DCF fluorescence as a measure of reactive oxygen species in murine islets of Langerhans","volume":"6","author":"Wang","year":"2014","journal-title":"Anal. Methods Adv. Methods Appl."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"(2013). World Medical Association Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA, 310, 2191\u20132194.","DOI":"10.1001\/jama.2013.281053"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1111\/jcmm.12207","article-title":"The ROS-induced cytotoxicity of ascorbate is attenuated by hypoxia and HIF-1alpha in the NCI60 cancer cell lines","volume":"18","author":"Sinnberg","year":"2014","journal-title":"J. Cell. Mol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"13604","DOI":"10.1073\/pnas.0506390102","article-title":"Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues","volume":"102","author":"Chen","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1016\/j.biopha.2018.11.078","article-title":"Pharmacologic ascorbate as a pro-drug for hydrogen peroxide release to kill mycobacteria","volume":"109","author":"Pei","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Venturelli, S., Leischner, C., Helling, T., Burkard, M., and Marongiu, L. (2021). Vitamins as Possible Cancer Biomarkers: Significance and Limitations. Nutrients, 13.","DOI":"10.3390\/nu13113914"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1080\/10717544.2017.1370619","article-title":"Ascorbyl palmitate-incorporated paclitaxel-loaded composite nanoparticles for synergistic anti-tumoral therapy","volume":"24","author":"Zhou","year":"2017","journal-title":"Drug Deliv."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7154","DOI":"10.1039\/D0BM01738H","article-title":"Mesoporous silica integrated with Fe3O4 and palmitoyl ascorbate as a new nano-Fenton reactor for amplified tumor oxidation therapy","volume":"8","author":"Sun","year":"2020","journal-title":"Biomater. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1097\/01.cmr.0000232297.99160.9e","article-title":"Sodium ascorbate inhibits growth via the induction of cell cycle arrest and apoptosis in human malignant melanoma A375.S2 cells","volume":"16","author":"Lin","year":"2006","journal-title":"Melanoma Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1002\/jcp.20286","article-title":"Sodium ascorbate (vitamin C) induces apoptosis in melanoma cells via the down-regulation of transferrin receptor dependent iron uptake","volume":"204","author":"Kang","year":"2005","journal-title":"J. Cell. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1007\/s00262-003-0407-6","article-title":"L-ascorbic acid (vitamin C) induces the apoptosis of B16 murine melanoma cells via a caspase-8-independent pathway","volume":"52","author":"Kang","year":"2003","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1002\/jcb.21336","article-title":"The molecular mechanisms of vitamin C on cell cycle regulation in B16F10 murine melanoma","volume":"102","author":"Hahm","year":"2007","journal-title":"J. Cell. Biochem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"6590","DOI":"10.1158\/1078-0432.CCR-19-0594","article-title":"First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma","volume":"25","author":"Allen","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"35","DOI":"10.3892\/ijo.2021.5215","article-title":"Parenteral high-dose ascorbate\u2014A possible approach for the treatment of glioblastoma (Review)","volume":"58","author":"Renner","year":"2021","journal-title":"Int. J. Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.freeradbiomed.2011.05.031","article-title":"Anti-cancer effect of pharmacologic ascorbate and its interaction with supplementary parenteral glutathione in preclinical cancer models","volume":"51","author":"Chen","year":"2011","journal-title":"Free Radic. Biol. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"8109","DOI":"10.7150\/thno.35378","article-title":"Hepatomas are exquisitely sensitive to pharmacologic ascorbate (P-AscH-)","volume":"9","author":"Zhang","year":"2019","journal-title":"Theranostics"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1248\/bpb.b18-00967","article-title":"Ameliorative Effect of High-Dose Vitamin C Administration on Dextran Sulfate Sodium-Induced Colitis Mouse Model","volume":"42","author":"Kondo","year":"2019","journal-title":"Biol. Pharm. Bull."},{"key":"ref_56","first-page":"3880","article-title":"Vitamin C induces human melanoma A375 cell apoptosis via Bax- and Bcl-2-mediated mitochondrial pathways","volume":"18","author":"Chen","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"995","DOI":"10.7150\/ijbs.67329","article-title":"Ascorbic acid induced TET2 enzyme activation enhances cancer immunotherapy efficacy in renal cell carcinoma","volume":"18","author":"Peng","year":"2022","journal-title":"Int. J. Biol. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.freeradbiomed.2015.06.032","article-title":"Antitumor effect of pharmacologic ascorbate in the B16 murine melanoma model","volume":"87","author":"Serrano","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"112553","DOI":"10.1016\/j.biopha.2021.112553","article-title":"The potential role of vitamin C in empowering cancer immunotherapy","volume":"146","author":"Bedhiafi","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.immuni.2013.07.012","article-title":"Oncology meets immunology: The cancer-immunity cycle","volume":"39","author":"Chen","year":"2013","journal-title":"Immunity"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/2\/254\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:02:59Z","timestamp":1760119379000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/2\/254"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,7]]},"references-count":60,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["cells12020254"],"URL":"https:\/\/doi.org\/10.3390\/cells12020254","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,7]]}}}