{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T01:09:01Z","timestamp":1789520941027,"version":"build-2803163510"},"reference-count":84,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,10,19]],"date-time":"2019-10-19T00:00:00Z","timestamp":1571443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"iNOVA4Health, FCT and European Union\u2019s Horizon 2020","award":["PTDC\/MEC-ONC\/29327\/2017 and grant agreement No 810856"],"award-info":[{"award-number":["PTDC\/MEC-ONC\/29327\/2017 and grant agreement No 810856"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Ovarian cancer is the main cause of death from gynecological cancer, with its poor prognosis mainly related to late diagnosis and chemoresistance (acquired or intrinsic) to conventional alkylating and reactive oxygen species (ROS)-generating drugs. We and others reported that the availability of cysteine and glutathione (GSH) impacts the mechanisms of resistance to carboplatin in ovarian cancer. Different players in cysteine metabolism can be crucial in chemoresistance, such as the cystine\/glutamate antiporter system Xc (xCT) and the H2S-synthesizing enzyme cystathionine \u03b2-synthase (CBS) in the pathway of cysteine catabolism. We hypothesized that, by disrupting cysteine metabolic flux, chemoresistance would be reverted. Since the xCT transporter is also able to take up selenium, we used selenium-containing chrysin (SeChry) as a plausible competitive inhibitor of xCT. For that, we tested the effects of SeChry on three different ovarian cancer cell lines (ES2, OVCAR3, and OVCAR8) and in two non-malignant cell lines (HaCaT and HK2). Results showed that, in addition to being highly cytotoxic, SeChry does not affect the uptake of cysteine, although it increases GSH depletion, indicating that SeChry might induce oxidative stress. However, enzymatic assays revealed an inhibitory effect of SeChry toward CBS, thus preventing production of the antioxidant H2S. Notably, our data showed that SeChry and folate-targeted polyurea dendrimer generation four (SeChry@PUREG4-FA) nanoparticles increased the specificity for SeChry delivery to ovarian cancer cells, reducing significantly the toxicity against non-malignant cells. Collectively, our data support SeChry@PUREG4-FA nanoparticles as a targeted strategy to improve ovarian cancer treatment, where GSH depletion and CBS inhibition underlie SeChry cytotoxicity.<\/jats:p>","DOI":"10.3390\/nu11102523","type":"journal-article","created":{"date-parts":[[2019,10,21]],"date-time":"2019-10-21T03:40:29Z","timestamp":1571629229000},"page":"2523","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Targeting Glutathione and Cystathionine \u03b2-Synthase in Ovarian Cancer Treatment by Selenium\u2013Chrysin Polyurea Dendrimer Nanoformulation"],"prefix":"10.3390","volume":"11","author":[{"given":"In\u00eas","family":"Santos","sequence":"first","affiliation":[{"name":"CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisboa, Portugal"},{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3822-2835","authenticated-orcid":false,"given":"Cristiano","family":"Ramos","sequence":"additional","affiliation":[{"name":"CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisboa, Portugal"},{"name":"Instituto Portugu\u00eas de Oncologia de Lisboa Francisco Gentil (IPOLFG), Rua Prof Lima Basto, 1099-023 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy","family":"Mendes","sequence":"additional","affiliation":[{"name":"CEDOC, Chronic Diseases Research Centre, NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas, Universidade NOVA de Lisboa, Campo dos M\u00e1rtires da P\u00e1tria, 130, 1169-056 Lisboa, 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Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.bpobgyn.2016.08.006","article-title":"Epidemiology of epithelial ovarian cancer","volume":"41","author":"Webb","year":"2017","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2936","DOI":"10.1021\/pr070041v","article-title":"Epithelial ovarian cancer: Disease etiology, treatment, detection, and investigational gene, metabolite, and protein biomarkers","volume":"6","author":"Williams","year":"2007","journal-title":"J. Proteome Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"341723","DOI":"10.1155\/2015\/341723","article-title":"Hereditary ovarian cancer: Not only BRCA 1 and 2 genes","volume":"2015","author":"Toss","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4008","DOI":"10.18632\/oncotarget.14021","article-title":"Chemoresistance and targeted therapies in ovarian and endometrial cancers","volume":"8","author":"Brasseur","year":"2017","journal-title":"Oncotarget"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.critrevonc.2016.03.014","article-title":"Cispaltin versus carboplatin: Comparative review of therapeutic management in solid malignancies","volume":"102","author":"Ho","year":"2016","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ctrv.2006.09.006","article-title":"Molecular mechanisms of resistance and toxicity associated with platinating agents","volume":"33","author":"Rabik","year":"2007","journal-title":"Cancer Treat. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Marullo, R., Werner, E., Degtyareva, N., Moore, B., Altavilla, G., Ramalingam, S.S., and Doetsch, P.W. (2013). Cisplatin induces a mitochondrial-ROS response that contributes to cytotoxicity depending on mitochondrial redox status and bioenergetic functions. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0081162"},{"key":"ref_10","first-page":"7131","article-title":"Oxidative stress induced by carboplatin promotes apoptosis and inhibits migration of HN\u20113 cells","volume":"16","author":"He","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e2253","DOI":"10.1038\/cddis.2016.105","article-title":"ROS homeostasis and metabolism: A dangerous liason in cancer cells","volume":"7","author":"Panieri","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/ars.2017.7058","article-title":"A review of hydrogen sulfide synthesis, metabolism and measurement: Is modulation of hydrogen sulfide a novel therapeutic for cancer?","volume":"31","author":"Cao","year":"2019","journal-title":"Antioxid. Redox Signal."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1002\/cncr.2820710224","article-title":"Mechanisms of drug resistance in ovarian cancer","volume":"71","author":"Johnson","year":"1993","journal-title":"Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/S1028-4559(09)60143-1","article-title":"Mechanisms involved in chemoresistance in ovarian cancer","volume":"44","author":"Ling","year":"2005","journal-title":"Taiwan J. Obstet. Gynecol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/S1353-8020(02)00018-4","article-title":"Glutathione depletion and oxidative stress","volume":"8","author":"Mytilineou","year":"2002","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.mam.2008.08.009","article-title":"Structure, function, and post-translational regulation of the catalytic and modifier subunits of glutamate cysteine ligase","volume":"30","author":"Franklin","year":"2009","journal-title":"Mol. Asp. Med."},{"key":"ref_17","first-page":"28","article-title":"Glutathione\u2014A master antioxidant and an immune system modulator","volume":"1","author":"Dhivya","year":"2012","journal-title":"J. Biol. Inf. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Nunes, S.C., and Serpa, J. (2018). Glutathione in ovarian cancer: A double-edged sword. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19071882"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3070","DOI":"10.1073\/pnas.89.7.3070","article-title":"High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis","volume":"89","author":"Godwin","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","first-page":"1","article-title":"Total thiols: Biomedical importance and their alteration in various disorders","volume":"8","author":"Prakash","year":"2009","journal-title":"Online J. Health Allied Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1369\/jhc.5A6840.2006","article-title":"Distribution of the cystine\/glutamate antiporter system xc-in the brain, kidney, and duodenum","volume":"54","author":"Burdo","year":"2006","journal-title":"J. Histochem. Cytochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s13048-015-0140-8","article-title":"A metabolomic approach to identifying platinum resistance in ovarian cancer","volume":"8","author":"Poisson","year":"2015","journal-title":"J. Ovarian Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1089\/ars.2011.4391","article-title":"The cystine\/glutamate antiporter system xc\u2212 in health and disease: From molecular mechanisms to novel therapeutic opportunities","volume":"18","author":"Lewerenz","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4813","DOI":"10.1007\/s13277-015-4290-5","article-title":"HNF1\u03b2 drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC)","volume":"37","author":"Nunes","year":"2016","journal-title":"Tumor Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8513","DOI":"10.1038\/s41598-018-27753-y","article-title":"Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity","volume":"8","author":"Nunes","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4145","DOI":"10.1096\/fj.201701095R","article-title":"Cystathionine b-synthase regulates mitochondrial morphogenesis in ovarian cancer","volume":"32","author":"Chakraborty","year":"2018","journal-title":"FASEB J."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Bhattacharyya, S., Saha, S., Giri, K., Lanza, I.R., Nair, K.S., Jennings, N.B., Rodriguez-Aguayo, C., Lopez-Berestein, G., Basal, E., and Weaver, A.L. (2013). Cystathionine beta-synthase (CBS) contributes to advanced ovarian cancer progression and drug resistance. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079167"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.freeradbiomed.2015.05.024","article-title":"Role of cystathionine \u03b2-synthase in human breast Cancer","volume":"86","author":"Sen","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.redox.2015.03.003","article-title":"Expression of xCT and activity of system xc(\u2212) are regulated by NRF2 in human breast cancer cells in response to oxidative stress","volume":"5","author":"Habib","year":"2015","journal-title":"Redox Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"15074","DOI":"10.1038\/ncomms15074","article-title":"The glutamate\/cystine xCT antiporter antagonizes glutamine metabolism and reduces nutrient flexibility","volume":"8","author":"Shin","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"74132","DOI":"10.18632\/oncotarget.12356","article-title":"Mitochondrial dysfunction enhances cisplatin resistance in human gastric cancer cells via the ROS-activated GCN2-eIF2\u03b1-ATF4-xCT pathway","volume":"7","author":"Wang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1016\/S0021-9258(17)43371-0","article-title":"Induction of cystine and glutamate transport activity in human fibroblasts by diethylmaleate and other electrophilic agents","volume":"259","author":"Bannai","year":"1984","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1089\/scd.2017.0123","article-title":"SLC7A11 overexpression in glioblastoma is associated with increased cancer stem cell-like properties","volume":"26","author":"Polewski","year":"2017","journal-title":"Stem. Cells Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7446","DOI":"10.1158\/0008-5472.CAN-04-4267","article-title":"Cystine-glutamate transporter SLC7A11 in cancer chemosensitivity and chemoresistance","volume":"65","author":"Huang","year":"2005","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/s10555-007-9050-6","article-title":"Pharmacogenetics\/genomics of membrane transporters in cancer chemotherapy","volume":"26","author":"Huang","year":"2007","journal-title":"Cancer Metastasis Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.3892\/or.2015.3712","article-title":"Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-\u03b3-lyase function","volume":"33","author":"Chen","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Nagane, M., Kanai, E., Shibata, Y., Shimizu, T., and Yoshioka, C. (2018). Sulfasalazine, an inhibitor of the cystine-glutamate antiporter, reduces DNA damage repair and enhances radiosensitivity in murine B16F10 melanoma. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0195151"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e1054549","DOI":"10.1080\/23723556.2015.1054549","article-title":"The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents","volume":"2","author":"Yu","year":"2015","journal-title":"Mol. Cell. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.2147\/DDDT.S107679","article-title":"Sulfasalazine inhibits inflammation and fibrogenesis in pancreas via NF-\u03baB signaling pathway in rats with oxidative stress-induced pancreatic injury","volume":"10","author":"Yan","year":"2016","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"85","DOI":"10.2131\/jts.42.85","article-title":"Selenium uptake through cystine transporter mediated by glutathione conjugation","volume":"42","author":"Tobe","year":"2017","journal-title":"J. Toxicol. Sci."},{"key":"ref_41","first-page":"272","article-title":"Imbalance in protein thiol redox regulation and cancer-preventive efficacy of selenium","volume":"2","author":"Gopalakrishna","year":"2016","journal-title":"React. Oxyg. Species"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.freeradbiomed.2018.05.001","article-title":"Organic selenium compounds as potential chemotherapeutic agents for improved cancer treatment","volume":"127","author":"Gandin","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Watts, S.D., Torres-Salazar, D., Divito, C.B., and Amara, S.G. (2014). Cysteine transport through excitatory amino acid transporter 3 (EAAT3). PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0109245"},{"key":"ref_44","first-page":"4249","article-title":"Prevention of carboplatin-induced resistance in human ovarian tumor xenografts by selenite","volume":"33","author":"Caffrey","year":"2013","journal-title":"Anticancer Res."},{"key":"ref_45","first-page":"299","article-title":"Bimodal actions of selenium essential for antioxidant and toxic pro-oxidant activities: The selenium paradox (Review)","volume":"5","author":"Lee","year":"2012","journal-title":"Mol. Med. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s13167-010-0033-2","article-title":"Selenium in the prevention of human cancers","volume":"1","author":"Fernandes","year":"2010","journal-title":"EPMA J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"11400","DOI":"10.1073\/pnas.0902204106","article-title":"Extracellular thiol-assisted selenium uptake dependent on the xc- cystine transporter explains the cancer-specific cytotoxicity of selenite","volume":"106","author":"Olm","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4250","DOI":"10.1021\/acs.jmedchem.5b00230","article-title":"Selenium-containing chrysin and quercetin derivatives: Attractive scaffolds for cancer therapy","volume":"58","author":"Martins","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.ejmech.2014.07.013","article-title":"Flavones: An important scaffold for medicinal chemistry","volume":"84","author":"Singh","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.fitote.2015.03.019","article-title":"Suppression of inflammatory response by chrysin, a flavone isolated from Potentilla evestita Th. Wolf. In silico predictive study on its mechanistic effect","volume":"103","author":"Rauf","year":"2015","journal-title":"Fitoterapia"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Gon\u00e7alves-Dias, C., Morello, J., Semedo, V., Correia, M.J., Coelho, N.R., Monteiro, E.C., Antunes, A.M.M., and Pereira, S.A. (2019). The mercapturomic profile of health and non-communicable diseases. High Throughput, 8.","DOI":"10.3390\/ht8020010"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.ejps.2017.05.010","article-title":"Unmasking efavirenz neurotoxicity: Time matters to the underlying mechanisms","volume":"105","author":"Grilo","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5162","DOI":"10.1002\/anie.201200362","article-title":"Biocompatible polyurea dendrimers with pH-dependent fluorescence","volume":"51","author":"Restani","year":"2012","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_54","unstructured":"Yoon, K., Harris, J.M., Bentley, M.D., Fang, Z., and Viegas, T. (2012). Multifunctional Forms of Polyoxazoline Copolymers and Drug Compositions Comprising the Same. (8,501,899), U.S. Patent."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1002\/mabi.201500131","article-title":"POxylated polyurea dendrimers: Smart core-shell vectors with IC50 lowering capacity","volume":"15","author":"Restani","year":"2015","journal-title":"Macromol. Biosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1038\/s41598-018-36994-w","article-title":"Screening pyridine derivatives against human hydrogen sulfide-synthesizing enzymes by orthogonal methods","volume":"9","author":"Zuhra","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Nunes, S.C., Lopes-Coelho, F., Gouveia-Fernandes Sofia Ramos, C., Pereira, S.A., and Serpa, J. (2018). Cysteine boosters the evolutionary adaptation to CoCl2 mimicked hypoxia conditions, favouring carboplatin resistance in ovarian cancer. BMC Evol. Biol., 18.","DOI":"10.1186\/s12862-018-1214-1"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"7941","DOI":"10.1007\/s12035-018-0961-8","article-title":"Alterations in system expression in the retina of type 1 diabetic rats and the role of Nrf2","volume":"55","author":"Calaza","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/s41419-018-0340-4","article-title":"Glucose metabolism and NRF2 coordinate the antioxidant response in melanoma resistant to MAPK inhibitors","volume":"9","author":"Khamari","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"14240","DOI":"10.1074\/jbc.M117.798405","article-title":"The glutamate\/cystine antiporter SLC7A11\/xCT enhances cancer cell dependency on glucose by exporting glutamate","volume":"292","author":"Koppula","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1152\/physrev.00017.2011","article-title":"Phisiologycal implications of hydrogen sulfide: A whiff exploration that blossomed","volume":"92","author":"Wang","year":"2012","journal-title":"Physiol. Rev."},{"key":"ref_62","first-page":"6290931","article-title":"Hydrogen sulfide biochemistry and interplay with other gaseous","volume":"2018","author":"Vicente","year":"2018","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1089\/ars.2013.5339","article-title":"Enzymology of H2S biogenesis, decay and signaling","volume":"20","author":"Kabil","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Rizzo, A., Napoli, A., Roggiani, F., Tomassetti, A., and Id, D.M. (2018). One-carbon metabolism: Biological players in epithelial ovarian cancer. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19072092"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s11523-018-0577-y","article-title":"Preparation of folic acid-targeted temperature-sensitive magnetoliposomes and their antitumor effects in vitro and in vivo","volume":"13","author":"Wang","year":"2018","journal-title":"Target. Oncol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"7265","DOI":"10.1038\/sj.onc.1206933","article-title":"Cisplatin: Mode of cytotoxic action and molecular basis of resistance","volume":"22","author":"Siddik","year":"2003","journal-title":"Oncogene"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.critrevonc.2007.02.001","article-title":"Mechanisms of resistance to cisplatin and carboplatin","volume":"63","author":"Stewart","year":"2007","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/01.ASN.0000042803.28024.92","article-title":"Metabolism of cisplatin to a nephrotoxin in proximal tubule cells","volume":"14","author":"Townsend","year":"2003","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"38681","DOI":"10.18632\/oncotarget.9583","article-title":"EAAT3 promotes amino acid transport and proliferation of porcine intestinal epithelial cells","volume":"7","author":"Ye","year":"2016","journal-title":"Oncotarget"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1046\/j.1471-4159.2003.01630.x","article-title":"The glutamate transporters EAAT2 and EAAT3 mediate cysteine uptake in cortical neuron cultures","volume":"84","author":"Chen","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_71","first-page":"402","article-title":"Antisense lncRNA As-SLC7A11 suppresses epithelial ovarian cancer progression mainly by targeting SLC7A11","volume":"72","author":"Yuan","year":"2017","journal-title":"Pharmazie"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"31891","DOI":"10.1074\/jbc.274.45.31891","article-title":"Na(+)-dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) of the blood-brain barrier. A mechanism for glutamate removal","volume":"274","author":"Dejoseph","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1958174","DOI":"10.1155\/2016\/1958174","article-title":"The Nrf2\/HO-1 axis in cancer cell growth and chemoresistance","volume":"2016","author":"Furfaro","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"972913","DOI":"10.1155\/2013\/972913","article-title":"Role of glutathione in cancer progression and chemoresisstance","volume":"2013","author":"Traverso","year":"2013","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1056\/NEJM198008283030913","article-title":"Endometrial cancer","volume":"303","author":"Cohen","year":"1980","journal-title":"N. Engl. J. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1089\/ars.2012.4944","article-title":"The gasotransmitter hydrogen sulfide induces Nrf2-target genes by inactivating the Keap1 ubiquitin ligase substrate adaptor through formation of a disulfide bond between Cys-226 and Cys-613","volume":"19","author":"Hourihan","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"37367","DOI":"10.18632\/oncotarget.5424","article-title":"Role of cystathionine beta synthase in lipid metabolism in ovarian cancer","volume":"6","author":"Chakraborty","year":"2015","journal-title":"Oncotarget"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.jtemb.2018.02.024","article-title":"Strategies for the development of selenium-based anticancer drugs","volume":"50","author":"Collery","year":"2018","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1089\/ars.2014.5933","article-title":"The therapeutic potential of cystathionine-b-synthetase\/hydrogen sulfide inhibition in cancer","volume":"22","author":"Hellmich","year":"2015","journal-title":"Antioxid. Redox Signal."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.jconrel.2014.03.057","article-title":"EPR: Evidence and fallacy","volume":"190","author":"Nichols","year":"2014","journal-title":"J. Control. Release"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/nrd2614","article-title":"Nanoparticle therapeutics: An emerging treatment modality for cancer","volume":"7","author":"Davis","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1517\/17425247.2012.665365","article-title":"Recent trends in cancer drug resistance reversal strategies using nanoparticles","volume":"9","author":"Palakurthi","year":"2012","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.addr.2012.09.033","article-title":"Nanoparticle and targeted systems for cancer therapy","volume":"64","author":"Blanchette","year":"2012","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.freeradbiomed.2017.01.028","article-title":"Comparison of the redox chemistry of sulfur- and selenium-containing analogs of uracil","volume":"104","author":"Payne","year":"2017","journal-title":"Free Radic. Biol. Med."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/11\/10\/2523\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:27:45Z","timestamp":1760189265000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/11\/10\/2523"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,19]]},"references-count":84,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["nu11102523"],"URL":"https:\/\/doi.org\/10.3390\/nu11102523","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,19]]}}}