{"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":1790258133357,"version":"4.1.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T00:00:00Z","timestamp":1670198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Cisplatin is an effective chemotherapeutic agent for treating triple negative breast cancer (TNBC). Nevertheless, cisplatin-resistance might develop during the course of treatment, allegedly by metabolic reprograming, which might influence epigenetic regulation. We hypothesized that the histone deacetylase inhibitor (HDACi) valproic acid (VPA) can counter the cisplatin-induced metabolic changes leading to its resistance. We performed targeted metabolomic and real time PCR analyses on MDA-MB-231 TNBC cells treated with cisplatin, VPA or their combination. 22 (88%) out of the 25 metabolites most significantly modified by the treatments, were acylcarnitines (AC) and three (12%) were phosphatidylcholines (PCs). The most discernible effects were up-modulation of AC by cisplatin and, contrarily, their down-modulation by VPA, which was partial in the VPA-cisplatin combination. Furthermore, the VPA-cisplatin combination increased PCs, sphingomyelins (SM) and hexose levels, as compared to the other treatments. These changes predicted modulation of different metabolic pathways, notably fatty acid degradation, by VPA. Lastly, we also show that the VPA-cisplatin combination increased mRNA levels of the fatty acid oxidation (FAO) promoting enzymes acyl-CoA synthetase long chain family member 1 (ACSL1) and decreased mRNA levels of fatty acid synthase (FASN), which is the rate limiting enzyme of long-chain fatty acid synthesis. In conclusion, VPA supplementation altered lipid metabolism, especially fatty acid oxidation and lipid synthesis, in cisplatin-treated MDA-MB-231 TNBC cells. This metabolic reprogramming might reduce cisplatin resistance. This finding may lead to the discovery of new therapeutic targets, which might reduce side effects and counter drug tolerance in TNBC patients.<\/jats:p>","DOI":"10.3389\/fcell.2022.1014798","type":"journal-article","created":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T04:32:20Z","timestamp":1670214740000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Metabolomic profiling of triple negative breast cancer cells suggests that valproic acid can enhance the anticancer effect of cisplatin"],"prefix":"10.3389","volume":"10","author":[{"given":"Avital","family":"Granit","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kumudesh","family":"Mishra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinorah","family":"Barasch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamar","family":"Peretz-Yablonsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Eyal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Or","family":"Kakhlon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1007\/s00726-009-0396-7","article-title":"Polyamines: Fundamental characters in chemistry and biology","volume":"38","author":"Agostinelli","year":"2010","journal-title":"Amino Acids"},{"key":"B2","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1016\/j.bcp.2009.10.011","article-title":"Inhibition of hepatic carnitine palmitoyl-transferase I (CPT IA) by valproyl-CoA as a possible mechanism of valproate-induced steatosis","volume":"79","author":"Aires","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e0125617","DOI":"10.1371\/journal.pone.0125617","article-title":"OXPHOS-mediated induction of NAD+ promotes complete oxidation of fatty acids and interdicts non-alcoholic fatty liver disease","volume":"10","author":"Akie","year":"2015","journal-title":"PLoS One"},{"key":"B4","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: A practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B Methodol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"108190","DOI":"10.1016\/j.pharmthera.2022.108190","article-title":"HDACs and the epigenetic plasticity of cancer cells: Target the complexity","volume":"238","author":"Brancolini","year":"2022","journal-title":"Pharmacol. Ther."},{"key":"B6","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1016\/j.molcel.2011.05.004","article-title":"Acetyl-CoA induces cell growth and proliferation by promoting the acetylation of histones at growth genes","volume":"42","author":"Cai","year":"2011","journal-title":"Mol. Cell"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e0135083","DOI":"10.1371\/journal.pone.0135083","article-title":"Mechanism of cisplatin-induced cytotoxicity is correlated to impaired metabolism due to mitochondrial ROS generation","volume":"10","author":"Choi","year":"2015","journal-title":"PLoS One"},{"key":"B8","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.cmet.2013.05.017","article-title":"Cellular fatty acid metabolism and cancer","volume":"18","author":"Currie","year":"2013","journal-title":"Cell Metab."},{"key":"B9","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.eplepsyres.2011.10.028","article-title":"Effects of valproate on glutamate metabolism in rat brain slices: A (13)C NMR study","volume":"99","author":"El Hage","year":"2012","journal-title":"Epilepsy Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1429","DOI":"10.1016\/s0006-2952(96)00507-2","article-title":"Inhibition of carnitine biosynthesis by valproic acid in rats--the biochemical mechanism of inhibition","volume":"52","author":"Farkas","year":"1996","journal-title":"Biochem. Pharmacol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"6263","DOI":"10.1074\/jbc.RA119.012376","article-title":"Inhibition of the polyamine synthesis enzyme ornithine decarboxylase sensitizes triple-negative breast cancer cells to cytotoxic chemotherapy","volume":"295","author":"Geck","year":"2020","journal-title":"J. Biol. Chem."},{"key":"B12","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1002\/epi4.12269","article-title":"Lacosamide at therapeutic concentrations induces histone hyperacetylation in vitro","volume":"3","author":"Granit","year":"2018","journal-title":"Epilepsia Open"},{"key":"B13","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1007\/s002280050504","article-title":"Increased urinary excretion of carnitine in patients treated with cisplatin","volume":"54","author":"Heuberger","year":"1998","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"5977","DOI":"10.1158\/0008-5472.CAN-05-4673","article-title":"Fatty acid synthase and cancer: New application of an old pathway","volume":"66","author":"Kuhajda","year":"2006","journal-title":"Cancer Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"4789","DOI":"10.1158\/1078-0432.CCR-10-1239","article-title":"Cisplatin-induced downregulation of OCTN2 affects carnitine wasting","volume":"16","author":"Lancaster","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"E2477","DOI":"10.3390\/cancers12092477","article-title":"ATP production relies on fatty acid oxidation rather than glycolysis in pancreatic ductal adenocarcinoma","volume":"12","author":"Lee","year":"2020","journal-title":"Cancers"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2169","DOI":"10.1016\/s0021-9258(18)69886-2","article-title":"The natural occurrence of coenzyme Q and related compounds","volume":"234","author":"Lester","year":"1959","journal-title":"J. Biol. Chem."},{"key":"B18","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1080\/15563650902752376","article-title":"Carnitine in the treatment of valproic acid-induced toxicity","volume":"47","author":"Lheureux","year":"2009","journal-title":"Clin. Toxicol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1016\/j.bbalip.2009.09.024","article-title":"Acyl-CoA synthesis, lipid metabolism and lipotoxicity","volume":"1801","author":"Li","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"B20","doi-asserted-by":"publisher","first-page":"5109","DOI":"10.1111\/jcmm.15148","article-title":"Sirt3 modulates fatty acid oxidation and attenuates cisplatin-induced AKI in mice","volume":"24","author":"Li","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2182","DOI":"10.1158\/1055-9965.EPI-13-0584","article-title":"Review of mass spectrometry-based metabolomics in cancer research","volume":"22","author":"Liesenfeld","year":"2013","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"B22","doi-asserted-by":"publisher","first-page":"e81162","DOI":"10.1371\/journal.pone.0081162","article-title":"Cisplatin induces a mitochondrial-ROS response that contributes to cytotoxicity depending on mitochondrial redox status and bioenergetic functions","volume":"8","author":"Marullo","year":"2013","journal-title":"PLoS One"},{"key":"B23","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1002\/ana.410030105","article-title":"Valproic acid in epilepsy: Clinical and pharmacological effects","volume":"3","author":"Mattson","year":"1978","journal-title":"Ann. Neurol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"3146","DOI":"10.1016\/s0021-9258(18)51887-1","article-title":"Benzoate derivatives as intermediates in the biosynthesis of coenzyme Q in the rat","volume":"238","author":"Olson","year":"1963","journal-title":"J. Biol. Chem."},{"key":"B25","doi-asserted-by":"publisher","first-page":"W388","DOI":"10.1093\/nar\/gkab382","article-title":"MetaboAnalyst 5.0: Narrowing the gap between raw spectra and functional insights","volume":"49","author":"Pang","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/s0305-7372(79)80057-2","article-title":"Cisplatin (cis-diamminedichloroplatinum II)","volume":"6","author":"Prestayko","year":"1979","journal-title":"Cancer Treat. Rev."},{"key":"B27","doi-asserted-by":"publisher","first-page":"47691","DOI":"10.18632\/oncotarget.17868","article-title":"Enolase 1 stimulates glycolysis to promote chemoresistance in gastric cancer","volume":"8","author":"Qian","year":"2017","journal-title":"Oncotarget"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e2226","DOI":"10.1038\/cddis.2016.132","article-title":"Fatty acid oxidation and carnitine palmitoyltransferase I: Emerging therapeutic targets in cancer","volume":"7","author":"Qu","year":"2016","journal-title":"Cell Death Dis."},{"key":"B29","doi-asserted-by":"publisher","first-page":"742859","DOI":"10.3389\/fmolb.2021.742859","article-title":"(1)H -nmr metabolomics study of the effect of cisplatin and casiopeina IIgly on MDA-MB-231 breast tumor cells","volume":"8","author":"Resendiz-Acevedo","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1007\/BF03261931","article-title":"Carnitine and acylcarnitines: Pharmacokinetic, pharmacological and clinical aspects","volume":"51","author":"Reuter","year":"2012","journal-title":"Clin. Pharmacokinet."},{"key":"B31","doi-asserted-by":"publisher","first-page":"11785","DOI":"10.1038\/s41598-020-68725-5","article-title":"Valproate inhibits mitochondrial bioenergetics and increases glycolysis in Saccharomyces cerevisiae","volume":"10","author":"Salsaa","year":"2020","journal-title":"Sci. Rep."},{"key":"B32","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.ebiom.2017.01.026","article-title":"Environmental enteric dysfunction is associated with carnitine deficiency and altered fatty acid oxidation","volume":"17","author":"Semba","year":"2017","journal-title":"EBioMedicine"},{"key":"B33","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21387","article-title":"Cancer statistics, 2017","volume":"71","author":"Siegel","year":"2021","journal-title":"Ca. Cancer J. Clin."},{"key":"B34","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1007\/s10545-008-0841-x","article-title":"Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: A review","volume":"31","author":"Silva","year":"2008","journal-title":"J. Inherit. Metab. Dis."},{"key":"B35","doi-asserted-by":"publisher","first-page":"684545","DOI":"10.3389\/fphar.2021.684545","article-title":"The role of the carnitine\/organic cation transporter novel 2 in the clinical outcome of patients with locally advanced esophageal carcinoma treated with oxaliplatin","volume":"12","author":"Sun","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1007\/s13238-021-00846-7","article-title":"Metabolic reprogramming and epigenetic modifications on the path to cancer","volume":"13","author":"Sun","year":"2021","journal-title":"Protein Cell"},{"key":"B37","doi-asserted-by":"publisher","first-page":"303","DOI":"10.2147\/JEP.S267383","article-title":"Advances in our understanding of the molecular mechanisms of action of cisplatin in cancer therapy","volume":"13","author":"Tchounwou","year":"2021","journal-title":"J. Exp. Pharmacol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"691795","DOI":"10.3389\/fmolb.2021.691795","article-title":"The role of tumour metabolism in cisplatin resistance","volume":"8","author":"Wang","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"3409","DOI":"10.3390\/cancers13143409","article-title":"Valproic acid and breast cancer: State of the art in 2021","volume":"13","author":"Wawruszak","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B40","doi-asserted-by":"publisher","first-page":"e0143013","DOI":"10.1371\/journal.pone.0143013","article-title":"Assessment of interactions between cisplatin and two histone deacetylase inhibitors in MCF7, T47D and MDA-MB-231 human breast cancer cell lines - an isobolographic analysis","volume":"10","author":"Wawruszak","year":"2015","journal-title":"PLoS One"},{"key":"B41","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1186\/s13058-020-01296-5","article-title":"Triple-negative breast cancer molecular subtyping and treatment progress","volume":"22","author":"Yin","year":"2020","journal-title":"Breast Cancer Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1080\/00498254.2019.1618510","article-title":"Metabolomics reveals the effect of valproic acid on MCF-7 and MDA-MB-231 cells","volume":"50","author":"Zhou","year":"2020","journal-title":"Xenobiotica."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.1014798\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T04:32:24Z","timestamp":1670214744000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.1014798\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,5]]},"references-count":42,"alternative-id":["10.3389\/fcell.2022.1014798"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2022.1014798","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,5]]},"article-number":"1014798"}}