{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:55:33Z","timestamp":1790258133318,"version":"4.1.0"},"reference-count":50,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T00:00:00Z","timestamp":1646006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>To target breast cancer (BC), epigenetic modulation could be a promising therapy strategy due to its role in the genesis, growth, and metastases of BC. Valproic acid (VPA) is a well-known histone deacetylase inhibitor (HDACi), which due to its epigenetic focus needs to be studied in depth to understand the effects it might elicit in BC cells. The aim of this work is to contribute to exploring the complete pharmacological mechanism of VPA in killing cancer cells using MCF-7. LC-MS\/MS metabolomics studies were applied to MCF-7 treated with VPA. The results show that VPA promote cell death by altering metabolic pathways principally pentose phosphate pathway (PPP) and 2\u2032deoxy-\u03b1-D-ribose-1-phosphate degradation related with metabolites that decrease cell proliferation and cell growth, interfere with energy sources and enhance reactive oxygen species (ROS) levels. We even suggest that mechanisms such as ferropoptosis could be involved due to deregulation of L-cysteine. These results suggest that VPA has different pharmacological mechanisms in killing cancer cells including apoptotic and nonapoptotic mechanisms, and due to the broad impact that HDACis have in cells, metabolomic approaches are a great source of information to generate new insights for this type of molecule.<\/jats:p>","DOI":"10.3390\/ijms23052645","type":"journal-article","created":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T20:11:14Z","timestamp":1646079074000},"page":"2645","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Untargeted LC-MS\/MS Metabolomics Study on the MCF-7 Cell Line in the Presence of Valproic Acid"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5661-834X","authenticated-orcid":false,"given":"Alan Rub\u00e9n","family":"Estrada-P\u00e9rez","sequence":"first","affiliation":[{"name":"Laboratorio de Dise\u00f1o y Desarrollo de Nuevos F\u00e1rmacos e Innovaci\u00f3n Biotecnol\u00f3gica (Laboratory for the Design and Development of New Drugs and Biotechnological Innovation), SEPI, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y D\u00edaz Mir\u00f3n, Ciudad de Mexico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0012-580X","authenticated-orcid":false,"given":"Martha Cecilia","family":"Rosales-Hern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Laboratorio de Biof\u00edsica y Biocat\u00e1lisis, SEPI, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y D\u00edaz Mir\u00f3n, Ciudad de Mexico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1930-5288","authenticated-orcid":false,"given":"Juan Benjam\u00edn","family":"Garc\u00eda-V\u00e1zquez","sequence":"additional","affiliation":[{"name":"Laboratorio de Dise\u00f1o y Desarrollo de Nuevos F\u00e1rmacos e Innovaci\u00f3n Biotecnol\u00f3gica (Laboratory for the Design and Development of New Drugs and Biotechnological Innovation), SEPI, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y D\u00edaz Mir\u00f3n, Ciudad de Mexico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Bakalara","sequence":"additional","affiliation":[{"name":"CNRS, ENSTBB-Bordeaux INP, Univerist\u00e9 de Bordeaux, 146 rue L\u00e9oSaignat, 33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1727-9912","authenticated-orcid":false,"given":"Benedicte","family":"Fromager","sequence":"additional","affiliation":[{"name":"Ecole Nationale Sup\u00e9rieure de Chimie de Montpellier, 34296 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4973-5265","authenticated-orcid":false,"given":"Jos\u00e9","family":"Correa-Basurto","sequence":"additional","affiliation":[{"name":"Laboratorio de Dise\u00f1o y Desarrollo de Nuevos F\u00e1rmacos e Innovaci\u00f3n Biotecnol\u00f3gica (Laboratory for the Design and Development of New Drugs and Biotechnological Innovation), SEPI, Escuela Superior de Medicina, Instituto Polit\u00e9cnico Nacional, Plan de San Luis y D\u00edaz Mir\u00f3n, Ciudad de Mexico 11340, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s40659-017-0140-9","article-title":"Awareness and current knowledge of breast cancer","volume":"50","author":"Akram","year":"2017","journal-title":"Biol. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.amsu.2019.11.021","article-title":"Molecular classification of breast cancer: A retrospective cohort study","volume":"49","year":"2020","journal-title":"Ann. Med. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1158\/1055-9965.EPI-19-0546","article-title":"Alcohol consumption, cigarette smoking, and risk of breast cancer for BRCA1 and BRCA2 mutation carriers: Results from the BRCA1 and BRCA2 cohort consortium","volume":"29","author":"Li","year":"2020","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3279","DOI":"10.3390\/cancers3033279","article-title":"Assessment of the evolution of cancer treatment therapies","volume":"3","author":"Arruebo","year":"2011","journal-title":"Cancers"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1051\/bmdcn\/2017070423","article-title":"A review on the effects of current chemotherapy drugs and natural agents in treating non-small cell lung cancer","volume":"7","author":"Huang","year":"2017","journal-title":"Biomedicine"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s12943-017-0596-9","article-title":"Epigenetics in cancer stem cells","volume":"16","author":"Toh","year":"2017","journal-title":"Mol. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"37","DOI":"10.3727\/000000001783992687","article-title":"Role of histone acetylation in the assembly and modulation of chromatin structures","volume":"9","author":"Annunziato","year":"2000","journal-title":"Gene Expr."},{"key":"ref_8","first-page":"371832","article-title":"Physical and functional HAT\/HDAC interplay regulates protein acetylation balance","volume":"2011","author":"Simone","year":"2010","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1369\/0022155413506582","article-title":"Histone Deacetylases: A Saga of Perturbed Acetylation Homeostasis in Cancer","volume":"62","author":"Parbin","year":"2014","journal-title":"J. Histochem. Cytochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"732","DOI":"10.2174\/1568026615666150825140822","article-title":"Role of Histone Acetylation in Cell Cycle Regulation","volume":"16","author":"Koprinarova","year":"2016","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/s41580-018-0081-3","article-title":"Functions and mechanisms of non-histone protein acetylation","volume":"20","author":"Narita","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Eckschlager, T., Plch, J., Stiborova, M., and Hrabeta, J. (2017). Histone deacetylase inhibitors as anticancer drugs. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071414"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1172\/JCI69738","article-title":"New and emerging HDAC inhibitors for cancer treatment","volume":"124","author":"West","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1101\/cshperspect.a018713","article-title":"Erasers of histone acetylation: The histone deacetylase enzymes","volume":"6","author":"Seto","year":"2014","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_15","first-page":"1677","article-title":"Histone deacetylases 1, 6 and 8 are critical for invasion in breast cancer","volume":"25","author":"Park","year":"2011","journal-title":"Oncol. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2759","DOI":"10.2174\/1568026615666141208105614","article-title":"An Overview of Naturally Occurring Histone Deacetylase Inhibitors","volume":"14","author":"Kim","year":"2015","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.3892\/ijo.2015.3213","article-title":"Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation","volume":"47","author":"Mawatari","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1016\/j.celrep.2015.10.013","article-title":"Histone Deacetylases Positively Regulate Transcription through the Elongation Machinery","volume":"13","author":"Greer","year":"2015","journal-title":"Cell Rep."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Chiang, Y.S., Huang, Y.F., Midha, M.K., Chen, T.H., Shiau, H.C., and Chiu, K.P. (2018). Single cell transcriptome analysis of MCF-7 reveals consistently and inconsistently expressed gene groups each associated with distinct cellular localization and functions. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0199471"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ejps.2008.06.003","article-title":"Inhibit multidrug resistance and induce apoptosis by using glycocholic acid and epirubicin","volume":"35","author":"Lo","year":"2008","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/S0039-128X(97)00050-0","article-title":"Effect of bile acids and estradiol on thymidine incorporation into DNA in MCF-7 and MCF-10A breast cell lines","volume":"62","author":"Raju","year":"1997","journal-title":"Steroids"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"S87","DOI":"10.5604\/01.3001.0010.5501","article-title":"Bile acids and cancer: Direct and environmental-dependent effects","volume":"16","author":"Wang","year":"2017","journal-title":"Ann. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.yexcr.2018.11.023","article-title":"Bile acid-induced apoptosis and bile acid synthesis are reduced by over-expression of Augmenter of Liver Regeneration (ALR) in a STAT3-dependent mechanism","volume":"374","author":"Ibrahim","year":"2019","journal-title":"Exp. Cell Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1002\/hep.21819","article-title":"Insights in the regulation of cholesterol 7\u03b1-hydroxylase gene reveal a target for modulating bile acid synthesis","volume":"46","author":"Mitro","year":"2007","journal-title":"Hepatology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1111\/j.1365-2613.2008.00582.x","article-title":"Elevated activity of the oxidative and non-oxidative pentose phosphate pathway in (pre)neoplastic lesions in rat liver","volume":"89","author":"Frederiks","year":"2008","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.tibs.2014.06.005","article-title":"The pentose phosphate pathway and cancer","volume":"39","author":"Patra","year":"2014","journal-title":"Trends Biochem. Sci."},{"key":"ref_27","first-page":"4213","article-title":"Crucial role of the pentose phosphate pathway in malignant tumors (review)","volume":"17","author":"Jin","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"19926","DOI":"10.1038\/srep19926","article-title":"Quantitative Analysis of Global Proteome and Lysine Acetylome Reveal the Differential Impacts of VPA and SAHA on HL60 Cells","volume":"6","author":"Zhu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zhou, X., Li, Z., Wang, X., Jiang, G., Shan, C., and Liu, S. (2019). Metabolomics reveals the effect of valproic acid on MCF-7 and MDA-MB-231 cells. Xenobiotica, 252\u2013260.","DOI":"10.1080\/00498254.2019.1618510"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"723","DOI":"10.3389\/fonc.2020.00723","article-title":"Cysteine Depletion, a Key Action to Challenge Cancer Cells to Ferroptotic Cell Death","volume":"10","author":"Daher","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"947","DOI":"10.3389\/fonc.2020.00947","article-title":"Cysteine as a Carbon Source, a Hot Spot in Cancer Cells Survival","volume":"10","author":"Serpa","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1089\/ars.2010.3356","article-title":"High-Mobility Group Box 1, Oxidative Stress, and Disease","volume":"14","author":"Tang","year":"2011","journal-title":"Antioxidants Redox Signal."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"33368","DOI":"10.18632\/oncotarget.26077","article-title":"N-(2\u2019-Hydroxyphenyl)-2-propylpentanamide (OH-VPA), a histone deacetylase inhibitor, induces the release of nuclear HMGB1 and modifies ROS levels in HeLa cells","volume":"9","year":"2018","journal-title":"Oncotarget"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"348","DOI":"10.3389\/fonc.2019.00348","article-title":"Inflammation and metabolism in cancer cell\u2014Mitochondria key player","volume":"9","author":"Neagu","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Keeley, T.S., Yang, S., and Lau, E. (2019). The diverse contributions of fucose linkages in cancer. Cancers, 11.","DOI":"10.3390\/cancers11091241"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1096\/fj.05-5399com","article-title":"17-Beta-Estradiol induces transformation and tumorigenesis in human breast epithelial cells","volume":"20","author":"Russo","year":"2006","journal-title":"FASEB J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"31861","DOI":"10.1074\/jbc.M300190200","article-title":"Saturated fatty acid-induced apoptosis in MDA-MB-231 breast cancer cells. A role for cardiolipin","volume":"278","author":"Hardy","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2604","DOI":"10.2741\/2869","article-title":"Estrogen, phospholipase A and breast cancer","volume":"13","author":"Thomas","year":"2008","journal-title":"Front. Biosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.3892\/ijo.2013.1903","article-title":"Estrogen receptor \u03b2 inhibits estradiol-induced proliferation and migration of MCF-7 cells through regulation of mitofusin 2","volume":"42","author":"Ma","year":"2013","journal-title":"Int. J. Oncol."},{"key":"ref_41","first-page":"987","article-title":"Stearate inhibition of breast cancer cell proliferation: A mechanism involving epidermal growth factor receptor and G-proteins","volume":"148","author":"Wickramasinghe","year":"1996","journal-title":"Am. J. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1080\/01635580902825597","article-title":"Stearate Preferentially Induces Apoptosis in Human Breast Cancer Cells","volume":"61","author":"Evans","year":"2009","journal-title":"Nutr. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.cbi.2017.12.003","article-title":"Valproic acid, a histone deacetylase inhibitor, induces apoptosis in breast cancer stem cells","volume":"280","author":"Aztopal","year":"2018","journal-title":"Chem. Biol. Interact."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"622","DOI":"10.3389\/fonc.2018.00622","article-title":"NAD metabolism in cancer therapeutics","volume":"8","author":"Yaku","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/s41392-020-00354-w","article-title":"NAD+ metabolism, stemness, the immune response, and cancer","volume":"6","author":"Navas","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_46","first-page":"1","article-title":"Valproate inhibits mitochondrial bioenergetics and increases glycolysis in Saccharomyces cerevisiae","volume":"10","author":"Salsaa","year":"2020","journal-title":"Sci. Reports 2020 101"},{"key":"ref_47","first-page":"3147","article-title":"The story of MCF-7 breast cancer cell line: 40 Years of experience in research","volume":"35","author":"Raica","year":"2015","journal-title":"Anticancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.canlet.2007.10.006","article-title":"Valproic acid is a selective antiproliferative agent in estrogen-sensitive breast cancer cells","volume":"259","author":"Fortunati","year":"2008","journal-title":"Cancer Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5035","DOI":"10.1021\/ac300698c","article-title":"XCMS Online: A web-based platform to process untargeted metabolomic data","volume":"84","author":"Tautenhahn","year":"2013","journal-title":"Anal. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3156","DOI":"10.1021\/acs.analchem.7b04424","article-title":"METLIN: A Technology Platform for Identifying Knowns and Unknowns","volume":"90","author":"Guijas","year":"2018","journal-title":"Anal. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/5\/2645\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:29:10Z","timestamp":1760135350000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/5\/2645"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,28]]},"references-count":50,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["ijms23052645"],"URL":"https:\/\/doi.org\/10.3390\/ijms23052645","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,28]]}}}