{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T01:19:33Z","timestamp":1768267173716,"version":"3.49.0"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,7,3]],"date-time":"2020-07-03T00:00:00Z","timestamp":1593734400000},"content-version":"vor","delay-in-days":184,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aid for Scientific Research","award":["19K09485"],"award-info":[{"award-number":["19K09485"]}]},{"DOI":"10.13039\/501100001691","name":"Japanese Society for the Promotion of Science","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Polyglutamylation is a reversible protein modification that commonly occurs in tumor cells. Methotrexate (MTX) in tumor cells is polyglutamylated and strongly binds to dihydrofolate reductase (DHFR) without competitive inhibition by leucovorin. Therefore, tumor cells with high polyglutamylation levels are supposed to be selectively killed, whereas normal cells with lower polyglutamylation are rescued by leucovorin. This study investigated the combined effects of MTX plus histone deacetylase inhibitors (HDACIs), which upregulate MTX polyglutamylation, in primary central nervous system lymphoma (PCNSL).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We evaluated cell viability after MTX treatment and leucovorin rescue and compared the expression of folylpolyglutamate synthetase (FPGS), \u03b3-glutamyl hydrolase (GGH), and DHFR in 2 human PCNSL-derived cell lines (HKBML and TK) and a human Burkitt lymphoma cell line (TL-1). Combination treatments were created using 4 HDACIs: panobinostat, vorinostat, sodium butyrate, and valproic acid. The expression of DHFR was examined as well as ratios of FPGS\/GGH expression. The combined effects of MTX plus HDACIs were evaluated using a cell viability assay, mass spectroscopy imaging, and subcutaneous and intracranial xenograft models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>HDACIs upregulated the ratio of FPGS\/GGH expression resulting in increased polyglutamylation of MTX, but also downregulated expression of the target molecule of MTX: DHFR. The combination of MTX and vorinostat decreased cell viability in vitro (P &amp;lt; .05) and tumor volumes in a subcutaneous model (P &amp;lt; .0001), and prolonged survival in an intracranial model (P &amp;lt; .01), relative to controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>HDACIs enhanced the therapeutic effect of MTX through increased polyglutamylation of MTX and concomitant downregulation of DHFR expression.<\/jats:p><\/jats:sec>","DOI":"10.1093\/noajnl\/vdaa084","type":"journal-article","created":{"date-parts":[[2020,7,3]],"date-time":"2020-07-03T15:35:25Z","timestamp":1593790525000},"source":"Crossref","is-referenced-by-count":8,"title":["Histone deacetylase inhibition enhances the therapeutic effects of methotrexate on primary central nervous system lymphoma"],"prefix":"10.1093","volume":"2","author":[{"given":"Kenji","family":"Fujimoto","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Kumamoto University Hospital, Kumamoto, Japan"},{"name":"Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoki","family":"Shinojima","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Kumamoto University Hospital, Kumamoto, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitsuhiro","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Division of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoyuki","family":"Nakano","sequence":"additional","affiliation":[{"name":"Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan"},{"name":"Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichi","family":"Ichimura","sequence":"additional","affiliation":[{"name":"Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akitake","family":"Mukasa","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Kumamoto University Hospital, Kumamoto, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,7,3]]},"reference":[{"issue":"6","key":"2020081306163837300_CIT0001","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1007\/s00401-016-1536-2","article-title":"Genomic characterization of primary central nervous system lymphoma","volume":"131","author":"Fukumura","year":"2016","journal-title":"Acta Neuropathol."},{"issue":"2","key":"2020081306163837300_CIT0002","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s00401-016-1664-8","article-title":"Genome-wide DNA methylation profiling identifies primary central nervous system lymphoma as a distinct entity different from systemic diffuse large B-cell lymphoma","volume":"133","author":"Nakamura","year":"2017","journal-title":"Acta Neuropathol."},{"issue":"6","key":"2020081306163837300_CIT0003","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nrneurol.2013.83","article-title":"Diagnosis and treatment of primary CNS lymphoma","volume":"9","author":"Korfel","year":"2013","journal-title":"Nat Rev Neurol."},{"issue":"2","key":"2020081306163837300_CIT0004","doi-asserted-by":"crossref","first-page":"190","DOI":"10.3171\/jns.1989.70.2.0190","article-title":"High-dose methotrexate for non-AIDS primary central nervous system lymphoma. Report of 13 cases","volume":"70","author":"Gabbai","year":"1989","journal-title":"J Neurosurg."},{"issue":"2","key":"2020081306163837300_CIT0005","doi-asserted-by":"crossref","first-page":"221","DOI":"10.3171\/jns.1999.91.2.0221","article-title":"Rapid infusion of high-dose methotrexate resulting in enhanced penetration into cerebrospinal fluid and intensified tumor response in primary central nervous system lymphomas","volume":"91","author":"Hiraga","year":"1999","journal-title":"J Neurosurg."},{"key":"2020081306163837300_CIT0006","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1146\/annurev.nutr.21.1.255","article-title":"New perspectives on folate catabolism","volume":"21","author":"Suh","year":"2001","journal-title":"Annu Rev Nutr."},{"issue":"5 Suppl. 18","key":"2020081306163837300_CIT0007","first-page":"S18","article-title":"Folate and antifolate pharmacology","volume":"24","author":"Kamen","year":"1997","journal-title":"Semin Oncol."},{"issue":"2 Suppl. 6","key":"2020081306163837300_CIT0008","first-page":"24","article-title":"Roles of folylpoly-gamma-glutamate synthetase in therapeutics with tetrahydrofolate antimetabolites: an overview","volume":"26","author":"Moran","year":"1999","journal-title":"Semin Oncol."},{"issue":"17","key":"2020081306163837300_CIT0009","doi-asserted-by":"crossref","first-page":"9720","DOI":"10.1016\/S0021-9258(17)39298-0","article-title":"Enhanced inhibition of thymidylate synthase by methotrexate polyglutamates","volume":"260","author":"Allegra","year":"1985","journal-title":"J Biol Chem."},{"issue":"5","key":"2020081306163837300_CIT0010","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1007\/s00280-014-2580-z","article-title":"Leucovorin rescue allows effective high-dose pralatrexate treatment and an increase in therapeutic index in mesothelioma xenografts","volume":"74","author":"Tedeschi","year":"2014","journal-title":"Cancer Chemother Pharmacol."},{"issue":"14","key":"2020081306163837300_CIT0011","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1056\/NEJM199610033351408","article-title":"Intrinsic and acquired resistance to methotrexate in acute leukemia","volume":"335","author":"Gorlick","year":"1996","journal-title":"N Engl J Med."},{"issue":"2","key":"2020081306163837300_CIT0012","first-page":"588","article-title":"Antifolate polyglutamylation and competitive drug displacement at dihydrofolate reductase as important elements in leucovorin rescue in L1210 cells","volume":"46","author":"Matherly","year":"1986","journal-title":"Cancer Res."},{"issue":"12 Pt 1","key":"2020081306163837300_CIT0013","first-page":"6395","article-title":"Role of methotrexate polyglutamates in methotrexate- and sequential methotrexate-5-fluorouracil-mediated cell kill","volume":"45","author":"McGuire","year":"1985","journal-title":"Cancer Res."},{"issue":"31","key":"2020081306163837300_CIT0014","doi-asserted-by":"crossref","first-page":"2593","DOI":"10.2174\/1381612033453712","article-title":"Anticancer antifolates: current status and future directions","volume":"9","author":"McGuire","year":"2003","journal-title":"Curr Pharm Des."},{"issue":"8","key":"2020081306163837300_CIT0015","first-page":"3190","article-title":"Polyglutamylation, an important element in methotrexate cytotoxicity and selectivity in tumor versus murine granulocytic progenitor cells in vitro","volume":"44","author":"Fabre","year":"1984","journal-title":"Cancer Res."},{"issue":"1","key":"2020081306163837300_CIT0016","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s40478-018-0522-4","article-title":"Clinical significance of polyglutamylation in primary central nervous system lymphoma","volume":"6","author":"Shinojima","year":"2018","journal-title":"Acta Neuropathol Commun."},{"issue":"7","key":"2020081306163837300_CIT0017","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1158\/0008-5472.CAN-12-3086","article-title":"TGF-\u03b2 mediates homing of bone marrow-derived human mesenchymal stem cells to glioma stem cells","volume":"73","author":"Shinojima","year":"2013","journal-title":"Cancer Res."},{"issue":"22","key":"2020081306163837300_CIT0018","doi-asserted-by":"crossref","first-page":"5034","DOI":"10.1200\/JCO.2005.13.524","article-title":"Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma","volume":"23","author":"Abrey","year":"2005","journal-title":"J Clin Oncol."},{"issue":"1","key":"2020081306163837300_CIT0019","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.celrep.2019.08.087","article-title":"Phosphoethanolamine accumulation protects cancer cells under glutamine starvation through downregulation of PCYT2","volume":"29","author":"Osawa","year":"2019","journal-title":"Cell Rep."},{"issue":"12","key":"2020081306163837300_CIT0020","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1200\/JCO.2008.19.0694","article-title":"Phase II trial of vorinostat in recurrent glioblastoma multiforme: a north central cancer treatment group study","volume":"27","author":"Galanis","year":"2009","journal-title":"J Clin Oncol."},{"issue":"21","key":"2020081306163837300_CIT0021","first-page":"7291","article-title":"Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA","volume":"63","author":"Kim","year":"2003","journal-title":"Cancer Res."},{"issue":"3","key":"2020081306163837300_CIT0022","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1158\/1078-0432.CCR-06-1261","article-title":"Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor: effects on gene expression and growth of glioma cells in vitro and in vivo","volume":"13","author":"Yin","year":"2007","journal-title":"Clin Cancer Res."},{"issue":"18","key":"2020081306163837300_CIT0023","first-page":"5165","article-title":"Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo","volume":"60","author":"Butler","year":"2000","journal-title":"Cancer Res."},{"issue":"2\u20133","key":"2020081306163837300_CIT0024","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/S0925-4439(02)00079-0","article-title":"Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase","volume":"1587","author":"Banerjee","year":"2002","journal-title":"Biochim Biophys Acta."},{"issue":"4","key":"2020081306163837300_CIT0025","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1634\/theoncologist.1-4-223","article-title":"Resistance mechanisms to methotrexate in tumors","volume":"1","author":"Bertino","year":"1996","journal-title":"Oncologist."},{"issue":"8","key":"2020081306163837300_CIT0026","first-page":"2149","article-title":"Impaired polyglutamylation of methotrexate as a cause of resistance in CCRF-CEM cells after short-term, high-dose treatment with this drug","volume":"48","author":"Pizzorno","year":"1988","journal-title":"Cancer Res."},{"issue":"1","key":"2020081306163837300_CIT0027","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1124\/mol.52.1.155","article-title":"Differences in folylpolyglutamate synthetase and dihydrofolate reductase expression in human B-lineage versus T-lineage leukemic lymphoblasts: mechanisms for lineage differences in methotrexate polyglutamylation and cytotoxicity","volume":"52","author":"Galpin","year":"1997","journal-title":"Mol Pharmacol."},{"issue":"3","key":"2020081306163837300_CIT0028","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/35106079","article-title":"Histone deacetylases and cancer: causes and therapies","volume":"1","author":"Marks","year":"2001","journal-title":"Nat Rev Cancer."},{"issue":"37","key":"2020081306163837300_CIT0029","doi-asserted-by":"crossref","first-page":"5541","DOI":"10.1038\/sj.onc.1210620","article-title":"Histone deacetylase inhibitors: molecular mechanisms of action","volume":"26","author":"Xu","year":"2007","journal-title":"Oncogene."},{"issue":"9","key":"2020081306163837300_CIT0030","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/nrd2133","article-title":"Anticancer activities of histone deacetylase inhibitors","volume":"5","author":"Bolden","year":"2006","journal-title":"Nat Rev Drug Discov."},{"issue":"10","key":"2020081306163837300_CIT0031","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1158\/1541-7786.MCR-07-0324","article-title":"Histone deacetylase inhibitors: overview and perspectives","volume":"5","author":"Dokmanovic","year":"2007","journal-title":"Mol Cancer Res."},{"issue":"3","key":"2020081306163837300_CIT0032","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/leu.2009.282","article-title":"Histone deacetylase inhibitors induce FPGS mRNA expression and intracellular accumulation of long-chain methotrexate polyglutamates in childhood acute lymphoblastic leukemia: implications for combination therapy","volume":"24","author":"Leclerc","year":"2010","journal-title":"Leukemia."},{"issue":"2","key":"2020081306163837300_CIT0033","first-page":"151","article-title":"Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines","volume":"2","author":"Glaser","year":"2003","journal-title":"Mol Cancer Ther."},{"issue":"4","key":"2020081306163837300_CIT0034","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1111\/j.1471-4159.2005.03098.x","article-title":"Suberoylanilide hydroxamic acid (SAHA) has potent anti-glioma properties in vitro, ex vivo and in vivo","volume":"93","author":"Ey\u00fcpoglu","year":"2005","journal-title":"J Neurochem."},{"issue":"3","key":"2020081306163837300_CIT0035","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/s11060-007-9337-z","article-title":"Continuous intracranial administration of suberoylanilide hydroxamic acid (SAHA) inhibits tumor growth in an orthotopic glioma model","volume":"83","author":"Ugur","year":"2007","journal-title":"J Neurooncol."},{"issue":"12","key":"2020081306163837300_CIT0036","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1136\/gut.2004.042713","article-title":"Effects of folylpolyglutamate synthetase modulation on chemosensitivity of colon cancer cells to 5-fluorouracil and methotrexate","volume":"53","author":"Sohn","year":"2004","journal-title":"Gut."},{"issue":"6","key":"2020081306163837300_CIT0037","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/0277-5379(87)90289-6","article-title":"Effect of dose and repeat intravenous 24 hr infusions of methotrexate on cerebrospinal fluid availability in children with hematological malignancies","volume":"23","author":"Thyss","year":"1987","journal-title":"Eur J Cancer Clin Oncol."},{"issue":"2","key":"2020081306163837300_CIT0038","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4103\/0976-0105.177703","article-title":"A simple practice guide for dose conversion between animals and human","volume":"7","author":"Nair","year":"2016","journal-title":"J Basic Clin Pharm."}],"container-title":["Neuro-Oncology Advances"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/noa\/advance-article-pdf\/doi\/10.1093\/noajnl\/vdaa084\/33460748\/vdaa084.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/noa\/article-pdf\/2\/1\/vdaa084\/33647581\/vdaa084.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/noa\/article-pdf\/2\/1\/vdaa084\/33647581\/vdaa084.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T00:11:20Z","timestamp":1616458280000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/noa\/article\/doi\/10.1093\/noajnl\/vdaa084\/5866990"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,1]]},"references-count":38,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,1,1]]}},"URL":"https:\/\/doi.org\/10.1093\/noajnl\/vdaa084","relation":{},"ISSN":["2632-2498"],"issn-type":[{"value":"2632-2498","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,1]]},"published":{"date-parts":[[2020,1,1]]},"article-number":"vdaa084"}}