{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T21:04:52Z","timestamp":1791493492079,"version":"4.3.4"},"reference-count":63,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T00:00:00Z","timestamp":1653264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007076","name":"MYNERVA","doi-asserted-by":"publisher","award":["#21267"],"award-info":[{"award-number":["#21267"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007076","name":"MYNERVA","doi-asserted-by":"publisher","award":["2017WXR7ZT_004"],"award-info":[{"award-number":["2017WXR7ZT_004"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007076","name":"MYNERVA","doi-asserted-by":"publisher","award":["NET-2018-12365935"],"award-info":[{"award-number":["NET-2018-12365935"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]},{"name":"PRIN","award":["#21267"],"award-info":[{"award-number":["#21267"]}]},{"name":"PRIN","award":["2017WXR7ZT_004"],"award-info":[{"award-number":["2017WXR7ZT_004"]}]},{"name":"PRIN","award":["NET-2018-12365935"],"award-info":[{"award-number":["NET-2018-12365935"]}]},{"name":"Ministero della Salute","award":["#21267"],"award-info":[{"award-number":["#21267"]}]},{"name":"Ministero della Salute","award":["2017WXR7ZT_004"],"award-info":[{"award-number":["2017WXR7ZT_004"]}]},{"name":"Ministero della Salute","award":["NET-2018-12365935"],"award-info":[{"award-number":["NET-2018-12365935"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>In the present study, we characterized the metabolic background of different Acute Myeloid Leukemias\u2019 (AMLs) cells and described a heterogeneous and highly flexible energetic metabolism. Using the Seahorse XF Agilent, we compared the metabolism of normal hematopoietic progenitors with that of primary AML blasts and five different AML cell lines. We assessed the efficacy and mechanism of action of the association of high doses of ascorbate, a powerful oxidant, with the metabolic inhibitor buformin, which inhibits mitochondrial complex I and completely shuts down mitochondrial contributions in ATP production. Primary blasts from seventeen AML patients, assayed for annexin V and live\/dead exclusion by flow cytometry, showed an increase in the apoptotic effect using the drug combination, as compared with ascorbate alone. We show that ascorbate inhibits glycolysis through interfering with HK1\/2 and GLUT1 functions in hematopoietic cells. Ascorbate combined with buformin decreases mitochondrial respiration and ATP production and downregulates glycolysis, enhancing the apoptotic effect of ascorbate in primary blasts from AMLs and sparing normal CD34+ bone marrow progenitors. In conclusion, our data have therapeutic implications especially in fragile patients since both agents have an excellent safety profile, and the data also support the clinical evaluation of ascorbate\u2013buformin in association with different mechanism drugs for the treatment of refractory\/relapsing AML patients with no other therapeutic options.<\/jats:p>","DOI":"10.3390\/cancers14102565","type":"journal-article","created":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T22:57:22Z","timestamp":1653346642000},"page":"2565","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Ascorbate Plus Buformin in AML: A Metabolic Targeted Treatment"],"prefix":"10.3390","volume":"14","author":[{"given":"Cristina","family":"Banella","sequence":"first","affiliation":[{"name":"Neurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy"},{"name":"Department of Health Sciences, Meyer Children\u2019s University Hospital, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6763-2876","authenticated-orcid":false,"given":"Gianfranco","family":"Catalano","sequence":"additional","affiliation":[{"name":"Neurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy"},{"name":"Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5411-1502","authenticated-orcid":false,"given":"Serena","family":"Travaglini","sequence":"additional","affiliation":[{"name":"Neurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy"},{"name":"Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvira","family":"Pelosi","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Ottone","sequence":"additional","affiliation":[{"name":"Neurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy"},{"name":"Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Zaza","sequence":"additional","affiliation":[{"name":"Neurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy"},{"name":"Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisella","family":"Guerrera","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Flow Cytometry Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4552-9226","authenticated-orcid":false,"given":"Daniela Francesca","family":"Angelini","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Flow Cytometry Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2226-6518","authenticated-orcid":false,"given":"Pasquale","family":"Niscola","sequence":"additional","affiliation":[{"name":"Hematology Unit, Saint\u2019 Eugenio Hospital, University of Rome Tor Vergata, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariadomenica","family":"Divona","sequence":"additional","affiliation":[{"name":"Policlinico Tor Vergata, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6488-4891","authenticated-orcid":false,"given":"Luca","family":"Battistini","sequence":"additional","affiliation":[{"name":"Neuroimmunology and Flow Cytometry Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Screnci","sequence":"additional","affiliation":[{"name":"Banca Regionale Sangue Cordone Ombelicale UOC Immunoematologia e Medicina Trasfusionale, Policlinico Umberto I, 00161 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Ammatuna","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7900-8942","authenticated-orcid":false,"given":"Ugo","family":"Testa","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Nervi","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences and Biotechnologies, University of Roma La Sapienza, 04100 Latina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6164-4761","authenticated-orcid":false,"given":"Maria Teresa","family":"Voso","sequence":"additional","affiliation":[{"name":"Neurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy"},{"name":"Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelida Ines","family":"Noguera","sequence":"additional","affiliation":[{"name":"Neurooncoemtology Units, Santa Lucia Foundation, I.R.C.C.S., 00143 Rome, Italy"},{"name":"Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.cell.2012.06.023","article-title":"The Origin and Evolution of Mutations in Acute Myeloid Leukemia","volume":"150","author":"Welch","year":"2012","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/nature13038","article-title":"Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia","volume":"506","author":"Shlush","year":"2014","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1016\/S0140-6736(06)69780-8","article-title":"Acute myeloid leukaemia","volume":"368","author":"Estey","year":"2006","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1056\/NEJMra1406184","article-title":"Acute Myeloid Leukemia","volume":"373","author":"Weisdorf","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kreitz, J., Sch\u00f6nfeld, C., Seibert, M., Stolp, V., Alshamleh, I., Oellerich, T., Steffen, B., Schwalbe, H., Schn\u00fctgen, F., and Kurrle, N. (2019). Metabolic Plasticity of Acute Myeloid Leukemia. Cells, 8.","DOI":"10.3390\/cells8080805"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1101\/gad.326470.119","article-title":"Metabolic dependencies and vulnerabilities in leukemia","volume":"33","author":"Rashkovan","year":"2019","journal-title":"Genes Dev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"775167","DOI":"10.3389\/fonc.2021.775167","article-title":"Editorial: Metabolic Rewiring in Leukemias","volume":"11","author":"Noguera","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.ccell.2018.08.016","article-title":"Subversion of Systemic Glucose Metabolism as a Mechanism to Support the Growth of Leukemia Cells","volume":"34","author":"Ye","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/j.ccr.2011.10.015","article-title":"Inhibition of Mitochondrial Translation as a Therapeutic Strategy for Human Acute Myeloid Leukemia","volume":"20","author":"Sriskanthadevan","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.stem.2012.12.013","article-title":"BCL-2 Inhibition Targets Oxidative Phosphorylation and Selectively Eradicates Quiescent Human Leukemia Stem Cells","volume":"12","author":"Lagadinou","year":"2013","journal-title":"Cell Stem Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/j.ccell.2018.10.005","article-title":"Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells","volume":"34","author":"Jones","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1182\/blood.2019898114","article-title":"Cysteine depletion targets leukemia stem cells through inhibition of electron transport complex II","volume":"134","author":"Jones","year":"2019","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1158\/2159-8290.CD-16-0441","article-title":"Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism","volume":"7","author":"Farge","year":"2017","journal-title":"Cancer Discov."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s13046-015-0221-y","article-title":"Metabolic reprogramming: The emerging concept and associated therapeutic strategies","volume":"34","author":"Yoshida","year":"2015","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/s13139-013-0231-7","article-title":"Intratumoral Metabolic Heterogeneity for Prediction of Disease Progression After Concurrent Chemoradiotherapy in Patients with Inoperable Stage III Non-Small-Cell Lung Cancer","volume":"48","author":"Kang","year":"2014","journal-title":"Nucl. Med. Mol. Imaging"},{"key":"ref_16","first-page":"1","article-title":"Emerging roles of Myc in stem cell biology and novel tumor therapies","volume":"37","author":"Yoshida","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/s42255-019-0032-0","article-title":"Metabolic signatures of cancer cells and stem cells","volume":"1","author":"Intlekofer","year":"2019","journal-title":"Nat. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.stem.2012.10.005","article-title":"Metabolic Regulation in Pluripotent Stem Cells during Reprogramming and Self-Renewal","volume":"11","author":"Zhang","year":"2012","journal-title":"Cell Stem Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1182\/bloodadvances.2020002981","article-title":"The metabolic reprogramming in acute myeloid leukemia patients depends on their genotype and is a prognostic marker","volume":"5","author":"Presti","year":"2021","journal-title":"Blood Adv."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/j.cell.2017.07.032","article-title":"Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression","volume":"170","author":"Cimmino","year":"2017","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"709543","DOI":"10.3389\/fonc.2021.709543","article-title":"Ascorbate Inhibits Proliferation and Promotes Myeloid Differentiation in TP53-Mutant Leukemia","volume":"11","author":"Magon","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_22","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_23","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/bs.afnr.2017.11.006","article-title":"Dietary Vitamin C in Human Health","volume":"83","author":"Granger","year":"2018","journal-title":"Adv. Food Nutr. Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lasfar, A. (2018). High Doses of Vitamin C and Leukemia: In Vitro Update. Myeloid Leukemia, IntechOpen.","DOI":"10.5772\/intechopen.68969"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"32550","DOI":"10.18632\/oncotarget.15925","article-title":"High-dose ascorbate and arsenic trioxide selectively kill acute myeloid leukemia and acute promyelocytic leukemia blasts in vitro","volume":"8","author":"Noguera","year":"2017","journal-title":"Oncotarget"},{"key":"ref_26","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_27","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1007\/s00277-015-2464-2","article-title":"Cytotoxic effects of high concentrations of sodium ascorbate on human myeloid cell lines","volume":"94","author":"Mastrangelo","year":"2015","journal-title":"Ann. Hematol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1023\/A:1007168032289","article-title":"Dehydroascorbic acid irreversibly inhibits hexokinase activity","volume":"209","author":"Fiorani","year":"2000","journal-title":"Mol. Cell. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1089\/ars.2017.7255","article-title":"Redox Regulation of Hexokinases","volume":"30","author":"Heneberg","year":"2019","journal-title":"Antioxid. Redox Signal."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10269","DOI":"10.1158\/0008-5472.CAN-06-1500","article-title":"Metformin Is an AMP Kinase\u2013Dependent Growth Inhibitor for Breast Cancer Cells","volume":"66","author":"Zakikhani","year":"2006","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1007\/s12672-014-0188-8","article-title":"Metformin-Induced Killing of Triple-Negative Breast Cancer Cells Is Mediated by Reduction in Fatty Acid Synthase via miRNA-193b","volume":"5","author":"Cochrane","year":"2014","journal-title":"Horm. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Queiroz, E.A.I.F., Puukila, S., Eichler, R., Sampaio, S.C., Forsyth, H.L., Lees, S.J., Barbosa, A.M., Dekker, R.F.H., Fortes, Z.B., and Khaper, N. (2014). Metformin Induces Apoptosis and Cell Cycle Arrest Mediated by Oxidative Stress, AMPK and FOXO3a in MCF-7 Breast Cancer Cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098207"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"E534","DOI":"10.1002\/ijc.29193","article-title":"The biguanides metformin and phenformin inhibit angiogenesis, local and metastatic growth of breast cancer by targeting both neoplastic and microenvironment cells","volume":"136","author":"Orecchioni","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1158\/1940-6207.CAPR-10-0055","article-title":"Metformin Prevents Tobacco Carcinogen\u2013Induced Lung Tumorigenesis","volume":"3","author":"Memmott","year":"2010","journal-title":"Cancer Prev. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2590","DOI":"10.3892\/mmr.2016.4830","article-title":"Metformin inhibits growth of human non-small cell lung cancer cells via liver kinase B-1-independent activation of adenosine monophosphate-activated protein kinase","volume":"13","author":"Guo","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e199","DOI":"10.1038\/cddis.2011.86","article-title":"Metformin inhibits melanoma development through autophagy and apoptosis mechanisms","volume":"2","author":"Tomic","year":"2011","journal-title":"Cell Death Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.ejphar.2011.07.004","article-title":"In vitro and in vivo anti-melanoma action of metformin","volume":"668","author":"Janjetovic","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"50542","DOI":"10.18632\/oncotarget.10671","article-title":"Metformin requires 4E-BPs to induce apoptosis and repress translation of Mcl-1 in hepatocellular carcinoma cells","volume":"8","author":"Bhat","year":"2017","journal-title":"Oncotarget"},{"key":"ref_39","first-page":"2705","article-title":"Buformin exhibits anti-proliferative and anti-invasive effects in endometrial cancer cells","volume":"8","author":"Kilgore","year":"2016","journal-title":"Am. J. Transl. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4034","DOI":"10.1038\/onc.2009.255","article-title":"A restricted signature of miRNAs distinguishes APL blasts from normal promyelocytes","volume":"28","author":"Careccia","year":"2009","journal-title":"Oncogene"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.hemonc.2020.02.005","article-title":"Absence of FGFR3\u2013TACC3 rearrangement in hematological malignancies with numerical chromosomal alteration","volume":"14","author":"Banella","year":"2021","journal-title":"Hematol. Oncol. Stem Cell Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/leu.2017.231","article-title":"Retinoic acid and arsenic trioxide sensitize acute promyelocytic leukemia cells to ER stress","volume":"32","author":"Masciarelli","year":"2018","journal-title":"Leukemia"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"66386","DOI":"10.18632\/oncotarget.11964","article-title":"PML\/RARa inhibits PTEN expression in hematopoietic cells by competing with PU.1 transcriptional activity","volume":"7","author":"Noguera","year":"2016","journal-title":"Oncotarget"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"E263","DOI":"10.1002\/ajh.25911","article-title":"Genetic lesions disrupting calreticulin 3\u2032-untranslated region in JAK2 mutation-negative polycythemia vera","volume":"95","author":"Quattrocchi","year":"2020","journal-title":"Am. J. Hematol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Banella, C., Catalano, G., Travaglini, S., Divona, M., Masciarelli, S., Guerrera, G., Fazi, F., Lo-Coco, F., Voso, M.T., and Noguera, N.I. (2019). PML\/RARa Interferes with NRF2 Transcriptional Activity Increasing the Sensitivity to Ascorbate of Acute Promyelocytic Leukemia Cells. Cancers, 12.","DOI":"10.3390\/cancers12010095"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1002\/ajh.24287","article-title":"18 FDG-PET\/CT: 21st century approach to leukemic tumors in 124 cases","volume":"91","author":"Cunningham","year":"2016","journal-title":"Am. J. Hematol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1182\/blood-2014-08-594408","article-title":"AML cells have low spare reserve capacity in their respiratory chain that renders them susceptible to oxidative metabolic stress","volume":"125","author":"Sriskanthadevan","year":"2015","journal-title":"Blood"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1161\/CIRCRESAHA.115.307599","article-title":"Disruption of Glut1 in Hematopoietic Stem Cells Prevents Myelopoiesis and Enhanced Glucose Flux in Atheromatous Plaques of ApoE(-\/-) Mice","volume":"118","author":"Sarrazy","year":"2016","journal-title":"Circ. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1056\/NEJMoa1301689","article-title":"Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia","volume":"368","author":"Ley","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1038\/nature10738","article-title":"Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing","volume":"481","author":"Ding","year":"2012","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1038\/nrc3706","article-title":"Leukaemia: A pre-leukaemic reservoir","volume":"14","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1056\/NEJMoa1716863","article-title":"Molecular Minimal Residual Disease in Acute Myeloid Leukemia","volume":"378","author":"Grob","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/nature22993","article-title":"Tracing the origins of relapse in acute myeloid leukaemia to stem cells","volume":"547","author":"Shlush","year":"2017","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.stem.2016.06.001","article-title":"Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche","volume":"19","author":"Ye","year":"2016","journal-title":"Cell Stem Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.1172\/JCI40671","article-title":"Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1\/AMPK pathway via a decrease in hepatic energy state","volume":"120","author":"Foretz","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1038\/leu.2013.107","article-title":"Mitochondrial energetic and AKT status mediate metabolic effects and apoptosis of metformin in human leukemic cells","volume":"27","author":"Scotland","year":"2013","journal-title":"Leukemia"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/s41568-019-0135-7","article-title":"Targeting cancer vulnerabilities with high-dose vitamin C","volume":"19","author":"Ngo","year":"2019","journal-title":"Nat. Rev. Cancer"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1146\/annurev-nutr-071714-034228","article-title":"Regulation of the Epigenome by Vitamin C","volume":"35","author":"Young","year":"2015","journal-title":"Annu. Rev. Nutr."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/nature12362","article-title":"Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells","volume":"500","author":"Blaschke","year":"2013","journal-title":"Nature"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/nature23876","article-title":"Ascorbate regulates haematopoietic stem cell function and leukaemogenesis","volume":"549","author":"Agathocleous","year":"2017","journal-title":"Nature"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.ccr.2010.11.015","article-title":"Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation","volume":"18","author":"Figueroa","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1016\/j.celrep.2014.11.004","article-title":"DNA Hydroxymethylation Profiling Reveals that WT1 Mutations Result in Loss of TET2 Function in Acute Myeloid Leukemia","volume":"9","author":"Rampal","year":"2014","journal-title":"Cell Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.leukres.2017.12.009","article-title":"The synergy of Vitamin C with decitabine activates TET2 in leukemic cells and significantly improves overall survival in elderly patients with acute myeloid leukemia","volume":"66","author":"Zhao","year":"2018","journal-title":"Leuk. Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/10\/2565\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:17:09Z","timestamp":1760138229000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/14\/10\/2565"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,23]]},"references-count":63,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["cancers14102565"],"URL":"https:\/\/doi.org\/10.3390\/cancers14102565","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,23]]}}}