{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T15:35:01Z","timestamp":1792510501692,"version":"4.5.0"},"reference-count":46,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T00:00:00Z","timestamp":1648512000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016401","name":"Jan Kornelis de Cock Stichting","doi-asserted-by":"publisher","award":["2020-43"],"award-info":[{"award-number":["2020-43"]}],"id":[{"id":"10.13039\/100016401","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004622","name":"Dutch Cancer Society","doi-asserted-by":"publisher","award":["10913\/2017-1"],"award-info":[{"award-number":["10913\/2017-1"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Melanoma is characterized by high glucose uptake, partially mediated through elevated pyruvate dehydrogenase kinase (PDK), making PDK a potential treatment target in melanoma. We aimed to reduce glucose uptake in melanoma cell lines through PDK inhibitors dichloroacetate (DCA) and AZD7545 and through PDK knockdown, to inhibit cell growth and potentially unveil metabolic co-vulnerabilities resulting from PDK inhibition. MeWo cells were most sensitive to DCA, while SK-MEL-2 was the least sensitive, with IC50 values ranging from 13.3 to 27.0 mM. DCA strongly reduced PDH phosphorylation and increased the oxygen consumption rate:extracellular acidification rate (OCR:ECAR) ratio up to 6-fold. Knockdown of single PDK isoforms had similar effects on PDH phosphorylation and OCR:ECAR ratio as DCA but did not influence sensitivity to DCA. Growth inhibition by DCA was synergistic with the glutaminase inhibitor CB-839 (2- to 5-fold sensitization) and with diclofenac, known to inhibit monocarboxylate transporters (MCTs) (3- to 8-fold sensitization). CB-839 did not affect the OCR:ECAR response to DCA, whereas diclofenac strongly inhibited ECAR and further increased the OCR:ECAR ratio. We conclude that in melanoma cell lines, DCA reduces proliferation through reprogramming of cellular metabolism and synergizes with other metabolically targeted drugs.<\/jats:p>","DOI":"10.3390\/ijms23073745","type":"journal-article","created":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T21:44:52Z","timestamp":1648590292000},"page":"3745","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Pyruvate Dehydrogenase Kinase Inhibition by Dichloroacetate in Melanoma Cells Unveils Metabolic Vulnerabilities"],"prefix":"10.3390","volume":"23","author":[{"given":"Jiske F.","family":"Tiersma","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Evers","sequence":"additional","affiliation":[{"name":"Laboratory of Pediatrics, Section Systems Medicine of Metabolism and Signalling, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara M.","family":"Bakker","sequence":"additional","affiliation":[{"name":"Laboratory of Pediatrics, Section Systems Medicine of Metabolism and Signalling, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9142-9050","authenticated-orcid":false,"given":"Mathilde","family":"Jalving","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5831-6997","authenticated-orcid":false,"given":"Steven","family":"de Jong","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"268","DOI":"10.3389\/fonc.2019.00268","article-title":"Diverse Mechanisms of BRAF Inhibitor Resistance in Melanoma Identified in Clinical and Preclinical Studies","volume":"9","author":"Luebker","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1056\/NEJMoa1904059","article-title":"Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma","volume":"381","author":"Robert","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.molmed.2014.12.007","article-title":"Molecular Drivers of Cellular Metabolic Reprogramming in Melanoma","volume":"21","author":"Abildgaard","year":"2015","journal-title":"Trends Mol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/onc.2016.198","article-title":"Metabolic Rewiring in Melanoma","volume":"36","author":"Ratnikov","year":"2017","journal-title":"Oncogene"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1158\/2159-8290.CD-13-0642","article-title":"Acquired Resistance and Clonal Evolution in Melanoma during BRAF Inhibitor Therapy","volume":"4","author":"Shi","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_6","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_7","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.molonc.2015.08.003","article-title":"Resistance to BRAF Inhibitors Induces Glutamine Dependency in Melanoma Cells","volume":"10","author":"Baenke","year":"2016","journal-title":"Mol. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7624","DOI":"10.1038\/sj.onc.1204972","article-title":"Cell Density Mediated Pericellular Hypoxia Leads to Induction of HIF-1a via Nitric Oxide and Ras\/MAP Kinase Mediated Signaling Pathways","volume":"20","author":"Sheta","year":"2001","journal-title":"Oncogene"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cmet.2015.12.006","article-title":"The Emerging Hallmarks of Cancer Metabolism","volume":"23","author":"Pavlova","year":"2016","journal-title":"Cell Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"42626","DOI":"10.1074\/jbc.M111.282046","article-title":"Comparative Metabolic Flux Profiling of Melanoma Cell Lines: Beyond the Warburg Effect","volume":"286","author":"Scott","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.cmet.2006.02.002","article-title":"HIF-1-Mediated Expression of Pyruvate Dehydrogenase Kinase: A Metabolic Switch Required for Cellular Adaptation to Hypoxia","volume":"3","author":"Kim","year":"2006","journal-title":"Cell Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.cmet.2006.01.012","article-title":"HIF-1 Mediates Adaptation to Hypoxia by Actively Downregulating Mitochondrial Oxygen Consumption","volume":"3","author":"Papandreou","year":"2006","journal-title":"Cell Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1002\/ijc.29564","article-title":"The Pyruvate Dehydrogenase Complex in Cancer: An Old Metabolic Gatekeeper Regulated by New Pathways and Pharmacological Agents","volume":"138","author":"Saunier","year":"2016","journal-title":"Int. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1517\/14728222.2015.1045416","article-title":"Overexpression of Pyruvate Dehydrogenase Kinase Supports Dichloroacetate as a Candidate for Cutaneous Melanoma Therapy","volume":"19","author":"Caldas","year":"2015","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e1223","DOI":"10.1542\/peds.2007-2062","article-title":"Evaluation of Long-Term Treatment of Children with Congenital Lactic Acidosis with Dichloroacetate","volume":"121","author":"Stacpoole","year":"2008","journal-title":"Pediatrics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1212\/WNL.53.3.612","article-title":"Dichloroacetate Stabilizes the Mutant E1alpha Subunit in Pyruvate Dehydrogenase Deficiency","volume":"53","author":"Morten","year":"1999","journal-title":"Neurology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1007\/s10637-015-0221-y","article-title":"A Phase I Open-Labeled, Single-Arm, Dose-Escalation, Study of Dichloroacetate (DCA) in Patients with Advanced Solid Tumors","volume":"33","author":"Chu","year":"2015","journal-title":"Investig. New Drugs"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1007\/s10637-013-0047-4","article-title":"Phase 1 Trial of Dichloroacetate (DCA) in Adults with Recurrent Malignant Brain Tumors","volume":"32","author":"Dunbar","year":"2014","journal-title":"Investig. New Drugs"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"31ra34","DOI":"10.1126\/scitranslmed.3000677","article-title":"Metabolic Modulation of Glioblastoma with Dichloroacetate","volume":"2","author":"Michelakis","year":"2010","journal-title":"Sci. Transl. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s00432-014-1583-9","article-title":"Dichloroacetate Should Be Considered with Platinum-Based Chemotherapy in Hypoxic Tumors Rather than as a Single Agent in Advanced Non-Small Cell Lung Cancer","volume":"140","author":"Garon","year":"2014","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1016\/j.str.2007.07.001","article-title":"Distinct Structural Mechanisms for Inhibition of Pyruvate Dehydrogenase Kinase Isoforms by AZD7545, Dichloroacetate, and Radicicol","volume":"15","author":"Kato","year":"2007","journal-title":"Structure"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Li, J., Eu, J.Q., Kong, L.R., Wang, L., Lim, Y.C., Goh, B.C., and Wong, A.L.A. (2020). Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy. Molecules, 25.","DOI":"10.3390\/molecules25204831"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"353","DOI":"10.3389\/fimmu.2018.00353","article-title":"Targeting Tumor Metabolism: A New Challenge to Improve Immunotherapy","volume":"9","author":"Kouidhi","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Stacpoole, P.W. (2017). Therapeutic Targeting of the Pyruvate Dehydrogenase Complex\/Pyruvate Dehydrogenase Kinase (PDC\/PDK) Axis in Cancer. J. Natl. Cancer Inst., 109.","DOI":"10.1093\/jnci\/djx071"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/S0026-0495(97)90252-3","article-title":"Dichloroacetate Inhibits Glutamine Oxidation by Decreasing Pyruvate Availability for Transamination","volume":"46","author":"Murray","year":"1997","journal-title":"Metab. Clin. Exp."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.celrep.2019.08.068","article-title":"Restricting Glycolysis Preserves T Cell Effector Functions and Augments Checkpoint Therapy","volume":"29","author":"Renner","year":"2019","journal-title":"Cell Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1186\/s12967-014-0247-5","article-title":"Bioenergetic Modulation with Dichloroacetate Reduces the Growth of Melanoma Cells and Potentiates Their Response to BRAFV600E Inhibition","volume":"12","author":"Abildgaard","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Gottfried, E., Lang, S.A., Renner, K., Bosserhoff, A., Gronwald, W., Rehli, M., Einhell, S., Gedig, I., Singer, K., and Seilbeck, A. (2013). New Aspects of an Old Drug\u2014Diclofenac Targets MYC and Glucose Metabolism in Tumor Cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0066987"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2510","DOI":"10.1002\/ijc.25499","article-title":"Sodium Dichloroacetate Selectively Targets Cells with Defects in the Mitochondrial ETC","volume":"127","author":"Stockwin","year":"2010","journal-title":"Int. J. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"\u0160korja Mili\u0107, N., Dolinar, K., Mi\u0161, K., Matkovi\u010d, U., Bizjak, M., Pavlin, M., Podbregar, M., and Pirkmajer, S. (2021). Suppression of Pyruvate Dehydrogenase Kinase by Dichloroacetate in Cancer and Skeletal Muscle Cells Is Isoform Specific and Partially Independent of HIF-1\u03b1. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168610"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4432","DOI":"10.1074\/jbc.M113.533885","article-title":"Structure-Guided Development of Specific Pyruvate Dehydrogenase Kinase Inhibitors Targeting the ATP-Binding Pocket","volume":"289","author":"Tso","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"10654","DOI":"10.1038\/s41598-017-10339-5","article-title":"The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5\/MEF2 Pathway","volume":"7","author":"Khan","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3012","DOI":"10.1021\/acs.jproteome.8b00184","article-title":"Liquid Chromatography-Tandem Mass Spectrometry Method Revealed That Lung Cancer Cells Exhibited Distinct Metabolite Profiles upon the Treatment with Different Pyruvate Dehydrogenase Kinase Inhibitors","volume":"17","author":"Zhang","year":"2018","journal-title":"J. Proteome Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"59458","DOI":"10.18632\/oncotarget.10694","article-title":"Dichloroacetate and Metformin Synergistically Suppress the Growth of Ovarian Cancer Cells","volume":"7","author":"Li","year":"2016","journal-title":"Oncotarget"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1182\/blood.V126.23.3059.3059","article-title":"Phase 1 Study of CB-839, a First-in-Class, Glutaminase Inhibitor in Patients with Multiple Myeloma and Lymphoma","volume":"126","author":"Vogl","year":"2015","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.canlet.2019.12.003","article-title":"Acidosis-Induced Metabolic Reprogramming in Tumor Cells Enhances the Anti-Proliferative Activity of the PDK Inhibitor Dichloroacetate","volume":"470","author":"Schoonjans","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/BF01037953","article-title":"Plasma and Synovial Fluid Concentrations of Diclofenac Sodium and Its Major Hydroxylated Metabolites during Long-Term Treatment of Rheumatoid Arthritis","volume":"25","author":"Fowler","year":"1983","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Ayyanathan, K., Kesaraju, S., Dawson-Scully, K., and Weissbach, H. (2012). Combination of Sulindac and Dichloroacetate Kills Cancer Cells via Oxidative Damage. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0039949"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"9030","DOI":"10.1074\/jbc.M511397200","article-title":"The Plasma Membrane Lactate Transporter MCT4, but Not MCT1, Is Up-Regulated by Hypoxia through a HIF-1\u03b1-Dependent Mechanism","volume":"281","author":"Ullah","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"69219","DOI":"10.18632\/oncotarget.18215","article-title":"Pre-Clinical Pharmacology of AZD3965, a Selective Inhibitor of MCT1: DLBCL, NHL and Burkitt\u2019s Lymphoma Anti-Tumor Activity","volume":"8","author":"Curtis","year":"2017","journal-title":"Oncotarget"},{"key":"ref_41","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_42","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/j.bbabio.2017.02.005","article-title":"Drug Discovery Strategies in the Field of Tumor Energy Metabolism: Limitations by Metabolic Flexibility and Metabolic Resistance to Chemotherapy","volume":"1858","author":"Amoedo","year":"2017","journal-title":"Biochim. Biophys. Acta (BBA)-Bioenerg."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"108500","DOI":"10.1016\/j.celrep.2020.108500","article-title":"Lactate Limits T Cell Proliferation via the NAD(H) Redox State","volume":"33","author":"Quinn","year":"2020","journal-title":"Cell Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1158\/1535-7163.MCT-20-0430","article-title":"The Glutaminase Inhibitor CB-839 (Telaglenastat) Enhances the Antimelanoma Activity of T-Cell-Mediated Immunotherapies","volume":"20","author":"Varghese","year":"2020","journal-title":"Mol. Cancer Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/j.tcb.2017.06.003","article-title":"Metabolic Interactions in the Tumor Microenvironment","volume":"27","author":"Lyssiotis","year":"2017","journal-title":"Trends Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"W488","DOI":"10.1093\/nar\/gkaa216","article-title":"SynergyFinder 2.0: Visual Analytics of Multi-Drug Combination Synergies","volume":"48","author":"Ianevski","year":"2020","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/7\/3745\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:45:44Z","timestamp":1760136344000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/7\/3745"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,29]]},"references-count":46,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["ijms23073745"],"URL":"https:\/\/doi.org\/10.3390\/ijms23073745","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,29]]}}}