{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T15:57:55Z","timestamp":1783699075459,"version":"3.55.0"},"reference-count":61,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,4,5]],"date-time":"2022-04-05T00:00:00Z","timestamp":1649116800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Else \u00dcbelmesser Stiftung","award":["grant no. D.30.21947; reference: GzV 1.14"],"award-info":[{"award-number":["grant no. D.30.21947; reference: GzV 1.14"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>High-dose ascorbate paradoxically acts as a pro-oxidant causing the formation of hydrogen peroxide in an oxygen dependent manner. Tumor cells (in particular melanoma cells) show an increased vulnerability to ascorbate induced reactive oxygen species (ROS). Therefore, high-dose ascorbate is a promising pharmacological approach to treating refractory melanomas, e.g., with secondary resistance to targeted BRAF inhibitor therapy. BRAF mutated melanoma cells were treated with ascorbate alone or in combination with the BRAF inhibitor vemurafenib. Viability, cell cycle, ROS production, and the protein levels of phospho-ERK1\/2, GLUT-1 and HIF-1\u03b1 were analyzed. To investigate the treatment in vivo, C57BL\/6NCrl mice were subcutaneously injected with D4M.3A (BrafV600E) melanoma cells and treated with intraperitoneal injections of ascorbate with or without vemurafenib. BRAF mutated melanoma cell lines either sensitive or resistant to vemurafenib were susceptible to the induction of cell death by pharmacological ascorbate. Treatment of BrafV600E melanoma bearing mice with ascorbate resulted in plasma levels in the pharmacologically active range and significantly improved the therapeutic effect of vemurafenib. We conclude that intravenous high-dose ascorbate will be beneficial for melanoma patients by interfering with the tumor\u2019s energy metabolism and can be safely combined with standard melanoma therapies such as BRAF inhibitors without pharmacological interference.<\/jats:p>","DOI":"10.3390\/cells11071229","type":"journal-article","created":{"date-parts":[[2022,4,5]],"date-time":"2022-04-05T11:26:07Z","timestamp":1649157967000},"page":"1229","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Therapeutic Efficacy of Pharmacological Ascorbate on Braf Inhibitor Resistant Melanoma Cells In Vitro and In Vivo"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2542-7022","authenticated-orcid":false,"given":"Heike","family":"Niessner","sequence":"first","affiliation":[{"name":"Department of Nutritional Biochemistry, Institute of Nutritional Sciences, University of Hohenheim, Garbenstra\u00dfe 30, 70599 Stuttgart, Germany"},{"name":"Department of Dermatology, Division of Dermatooncology, University of Tuebingen, Liebermeisterstr 25, 72076 Tuebingen, Germany"},{"name":"Cluster of Excellence iFIT (EXC 2180) \u201cImage Guided and Functionally Instructed Tumor Therapies\u201d, Eberhard Karls University of Tuebingen, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Burkard","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":"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":"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":"Sarah","family":"Pl\u00f6ger","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Division of Dermatooncology, University of Tuebingen, Liebermeisterstr 25, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Meraz-Torres","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Division of Dermatooncology, University of Tuebingen, Liebermeisterstr 25, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matti","family":"B\u00f6cker","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Division of Dermatooncology, University of Tuebingen, Liebermeisterstr 25, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constanze","family":"Hirn","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Division of Dermatooncology, University of Tuebingen, Liebermeisterstr 25, 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-Strasse 10, 72076 Tuebingen, 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"}]},{"given":"Christian","family":"Busch","sequence":"additional","affiliation":[{"name":"Dermatologie zum Delfin, Stadthausstrasse 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":"Department of Dermatology, Division of Dermatooncology, University of Tuebingen, Liebermeisterstr 25, 72076 Tuebingen, Germany"},{"name":"Cluster of Excellence iFIT (EXC 2180) \u201cImage Guided and Functionally Instructed Tumor Therapies\u201d, Eberhard Karls University of Tuebingen, 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"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,5]]},"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":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.critrevonc.2018.11.002","article-title":"Advanced stage melanoma therapies: Detailing the present and exploring the future","volume":"133","author":"Luther","year":"2019","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5070\/D3267049551","article-title":"Current and emerging treatment options for metastatic melanoma: A focused review","volume":"26","author":"Nguyen","year":"2020","journal-title":"Dermatol. Online J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0248-4900(01)01125-X","article-title":"The Raf\/MEK\/ERK pathway: New concepts of activation","volume":"93","author":"Peyssonnaux","year":"2001","journal-title":"Biol. Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1210\/rp.56.1.127","article-title":"Ras activation of the Raf kinase: Tyrosine kinase recruitment of the MAP kinase cascade","volume":"56","author":"Avruch","year":"2001","journal-title":"Recent Prog. Horm. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1056\/NEJMoa1210093","article-title":"Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations","volume":"367","author":"Flaherty","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1038\/nature00766","article-title":"Mutations of the BRAF gene in human cancer","volume":"417","author":"Davies","year":"2002","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/S0092-8674(04)00215-6","article-title":"Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF","volume":"116","author":"Wan","year":"2004","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6203","DOI":"10.1158\/1078-0432.CCR-17-0098","article-title":"BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma","volume":"23","author":"Niessner","year":"2017","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4994","DOI":"10.1158\/1078-0432.CCR-14-0776","article-title":"FDA approval summary: Vemurafenib for treatment of unresectable or metastatic melanoma with the BRAFV600E mutation","volume":"20","author":"Kim","year":"2014","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_14","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_15","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1056\/NEJMoa1112302","article-title":"Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib","volume":"366","author":"Sosman","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1016\/S1470-2045(18)30106-2","article-title":"Adjuvant vemurafenib in resected, BRAF V600 mutation-positive melanoma (BRIM8): A randomised, double-blind, placebo-controlled, multicentre, phase 3 trial","volume":"19","author":"Maio","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_17","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."},{"key":"ref_18","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_19","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1007\/s13668-020-00322-4","article-title":"Role of Vitamins in Skin Health: A Systematic Review","volume":"9","author":"Dattola","year":"2020","journal-title":"Curr. Nutr. Rep."},{"key":"ref_20","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_21","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.freeradbiomed.2009.02.016","article-title":"Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects","volume":"47","author":"Verrax","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"ref_22","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_23","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.ccell.2017.02.018","article-title":"O2-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_24","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_25","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_26","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_27","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/284629a0","article-title":"Vitamin C preferential toxicity for malignant melanoma cells","volume":"284","author":"Bram","year":"1980","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/0952-3278(88)90073-7","article-title":"Enhanced prostaglandin synthesis as a mechanism for inhibition of melanoma cell growth by ascorbic acid","volume":"34","author":"Gardiner","year":"1988","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"ref_29","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_30","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1111\/pcmr.12220","article-title":"Multiple murine BRaf(V600E) melanoma cell lines with sensitivity to PLX4032","volume":"27","author":"Jenkins","year":"2014","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.ebiom.2016.04.037","article-title":"A Nexus Consisting of Beta-Catenin and Stat3 Attenuates BRAF Inhibitor Efficacy and Mediates Acquired Resistance to Vemurafenib","volume":"8","author":"Sinnberg","year":"2016","journal-title":"EBioMedicine"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"31532","DOI":"10.1074\/jbc.M109.059246","article-title":"Proximity-based protein thiol oxidation by H2O2-scavenging peroxidases","volume":"284","author":"Gutscher","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1080\/07315724.2013.791167","article-title":"A convenient method for measuring blood ascorbate concentrations in patients receiving high-dose intravenous ascorbate","volume":"32","author":"Ma","year":"2013","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1002\/mc.22654","article-title":"Vitamin C at high concentrations induces cytotoxicity in malignant melanoma but promotes tumor growth at low concentrations","volume":"56","author":"Yang","year":"2017","journal-title":"Mol. Carcinog."},{"key":"ref_35","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_36","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_37","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_38","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_39","doi-asserted-by":"crossref","first-page":"4697","DOI":"10.1038\/onc.2014.71","article-title":"SOX2 regulates self-renewal and tumorigenicity of human melanoma-initiating cells","volume":"33","author":"Santini","year":"2014","journal-title":"Oncogene"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4898","DOI":"10.1038\/onc.2011.656","article-title":"Acquired cancer stem cell phenotypes through Oct4-mediated dedifferentiation","volume":"31","author":"Kumar","year":"2012","journal-title":"Oncogene"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5468","DOI":"10.1038\/s41388-020-1373-6","article-title":"Melanoma stem cell maintenance and chemo-resistance are mediated by CD133 signal to PI3K-dependent pathways","volume":"39","author":"Jamal","year":"2020","journal-title":"Oncogene"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/s41598-017-19057-4","article-title":"Targeting melanoma stem cells with the Vitamin E derivative \u03b4-tocotrienol","volume":"8","author":"Marzagalli","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.ccr.2009.03.018","article-title":"Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells","volume":"15","author":"Li","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5802","DOI":"10.4049\/jimmunol.1302140","article-title":"Cutting edge: Hypoxia-induced Nanog favors the intratumoral infiltration of regulatory T cells and macrophages via direct regulation of TGF-\u03b21","volume":"191","author":"Hasmim","year":"2013","journal-title":"J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1182\/blood.2019004158","article-title":"TET family dioxygenases and the TET activator vitamin C in immune responses and cancer","volume":"136","author":"Yue","year":"2020","journal-title":"Blood"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1016\/j.cell.2012.07.033","article-title":"Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma","volume":"150","author":"Lian","year":"2012","journal-title":"Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s13148-015-0087-z","article-title":"Epigenetic reprogramming of melanoma cells by vitamin C treatment","volume":"7","author":"Gustafson","year":"2015","journal-title":"Clin. Epigenet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1038\/nature09627","article-title":"COT drives resistance to RAF inhibition through MAP kinase pathway reactivation","volume":"468","author":"Johannessen","year":"2010","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1038\/nature09626","article-title":"Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation","volume":"468","author":"Nazarian","year":"2010","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.ejca.2016.12.012","article-title":"MAPK pathway in melanoma part II-secondary and adaptive resistance mechanisms to BRAF inhibition","volume":"73","author":"Amaral","year":"2017","journal-title":"Eur. J. Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.ejca.2016.12.010","article-title":"The mitogen-activated protein kinase pathway in melanoma part I\u2014Activation and primary resistance mechanisms to BRAF inhibition","volume":"73","author":"Amaral","year":"2017","journal-title":"Eur. J. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4461","DOI":"10.7150\/thno.35219","article-title":"Vitamin C kills thyroid cancer cells through ROS-dependent inhibition of MAPK\/ERK and PI3K\/AKT pathways via distinct mechanisms","volume":"9","author":"Su","year":"2019","journal-title":"Theranostics"},{"key":"ref_53","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_54","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1158\/2159-8290.CD-13-0440","article-title":"Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis","volume":"4","author":"Parmenter","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"11727","DOI":"10.1074\/jbc.M117.786442","article-title":"Disruption of mitochondrial electron transport chain function potentiates the pro-apoptotic effects of MAPK inhibition","volume":"292","author":"Trotta","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.ccr.2013.02.003","article-title":"Oncogenic BRAF regulates oxidative metabolism via PGC1\u03b1 and MITF","volume":"23","author":"Haq","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.18632\/oncotarget.1420","article-title":"Mitochondrial oxidative stress is the Achille\u2019s heel of melanoma cells resistant to Braf-mutant inhibitor","volume":"4","author":"Guerreschi","year":"2013","journal-title":"Oncotarget"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/j.cell.2018.04.012","article-title":"An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential","volume":"173","author":"Wang","year":"2018","journal-title":"Cell"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/s12943-017-0667-y","article-title":"ROS production induced by BRAF inhibitor treatment rewires metabolic processes affecting cell growth of melanoma cells","volume":"16","author":"Cesi","year":"2017","journal-title":"Mol. Cancer"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e2594","DOI":"10.1038\/cddis.2017.6","article-title":"Critical role of reactive oxygen species (ROS) for synergistic enhancement of apoptosis by vemurafenib and the potassium channel inhibitor TRAM-34 in melanoma cells","volume":"8","author":"Bauer","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1097\/CMR.0b013e3282f2a7ae","article-title":"Phase II trial of arsenic trioxide and ascorbic acid with temozolomide in patients with metastatic melanoma with or without central nervous system metastases","volume":"18","author":"Bael","year":"2008","journal-title":"Melanoma Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/7\/1229\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:48:45Z","timestamp":1760136525000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/7\/1229"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,5]]},"references-count":61,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["cells11071229"],"URL":"https:\/\/doi.org\/10.3390\/cells11071229","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,5]]}}}