{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T19:18:47Z","timestamp":1789154327226,"version":"build-2803163510"},"reference-count":27,"publisher":"IMR Press","issue":"7","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmazie"],"abstract":"<jats:p>Background:Glioblastoma (GBM) frequently develops resistance to temozolomide (TMZ), limiting the effectiveness of standard therapy. Histone deacetylase (HDAC) inhibitors have emerged as potential chemosensitizers; however, the comparative performance of these inhibitors and the associated mechanistic impact remain incompletely characterized.Methods:In vitro, this study systematically evaluated the effects of the Class I-selective HDAC inhibitors Entinostat and Tucidinostat, and the pan-HDAC inhibitor Vorinostat on TMZ sensitivity in multiple GBM cell lines (U87, U251, LN229). Additionally, this study assessed cell viability, morphology, and the expression of selected markers glial fibrillary acidic protein (GFAP), microtubule-associated protein 2 (MAP2), class III \u03b2-tubulin (TUBB3), and synapsin I (SYN1). In vivo, the therapeutic efficacy of Entinostat combined with TMZ was evaluated in a U87 xenograft mouse model by measuring tumor growth, and the expression of GFAP and TUBB3 was examined in tumor tissues. Clustered Regularly Interspaced Short Palindromic Repeats associated protein 9 (CRISPR-Cas9)-mediated knockout of HDAC1\/2\/3 was used to test the dependence of these effects on canonical Class I HDACs.Results:Entinostat and Tucidinostat significantly enhanced TMZ-induced cytotoxicity across all cell lines, demonstrating greater TMZ-sensitizing activity than Vorinostat under the conditions tested. Treatment was associated with altered cell morphology and changes in marker expression, including reduced GFAP and increased MAP2 and TUBB3. In the U87 xenograft model, Entinostat combined with TMZ significantly suppressed tumor growth and was associated with decreased GFAP and increased TUBB3 expression. Importantly, both TMZ sensitization and the associated morphological and marker changes persisted in HDAC1\/2\/3-knockout cells, suggesting that the effects are not fully explained by HDAC1\/2\/3 depletion. These effects were consistent across multiple cell lines and in xenograft tumors.Conclusions:Entinostat and Tucidinostat enhance TMZ sensitivity in GBM models and are associated with specific markers and morphological changes that persist despite HDAC1\/2\/3 knockout. These findings support further evaluation of Entinostat and Tucidinostat as TMZ-sensitizing agents in GBM models and highlight associated phenotypic and molecular changes that warrant further mechanistic validation.<\/jats:p>","DOI":"10.31083\/pharmazie51570","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:42:49Z","timestamp":1785411769000},"source":"Crossref","is-referenced-by-count":1,"title":["Entinostat and Tucidinostat Potentiate Temozolomide Response in Glioblastoma Models"],"prefix":"10.31083","volume":"81","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0291-5442","authenticated-orcid":true,"given":"Ruijie","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Pharmaceutical Sciences, Fudan University, 200120 Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhui","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmaceutical Sciences, Fudan University, 200120 Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinjue","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmaceutical Sciences, Fudan University, 200120 Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmaceutical Sciences, Fudan University, 200120 Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmaceutical Sciences, Fudan University, 200120 Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingquan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmaceutical Sciences, Fudan University, 200120 Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Chen R, Smith-Cohn M, Cohen AL, Colman H. Glioma Subclassifications and Their Clinical Significance. Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics. 2017; 14: 284\u2013297.","DOI":"10.1007\/s13311-017-0519-x"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathologica. 2016; 131: 803\u2013820.","DOI":"10.1007\/s00401-016-1545-1"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-oncology. 2021; 23: 1231\u20131251.","DOI":"10.1093\/neuonc\/noab106"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Johnson DR, O'Neill BP. Glioblastoma survival in the United States before and during the temozolomide era. Journal of Neuro-oncology. 2012; 107: 359\u2013364.","DOI":"10.1007\/s11060-011-0749-4"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G, et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nature Reviews. Clinical Oncology. 2021; 18: 170\u2013186.","DOI":"10.1038\/s41571-020-00447-z"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. The New England Journal of Medicine. 2005; 352: 987\u2013996.","DOI":"10.1056\/NEJMoa043330"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Jezierza\u0144ski M, Nafalska N, Stopyra M, Furgo\u0142 T, Miciak M, Kabut J, et al. Temozolomide (TMZ) in the Treatment of Glioblastoma Multiforme-A Literature Review and Clinical Outcomes. Current Oncology (Toronto, Ont.). 2024; 31: 3994\u20134002.","DOI":"10.3390\/curroncol31070296"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Filley AC, Henriquez M, Dey M. Recurrent glioma clinical trial, CheckMate-143: the game is not over yet. Oncotarget. 2017; 8: 91779\u201391794.","DOI":"10.18632\/oncotarget.21586"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Tan AC, Ashley DM, L\u00f3pez GY, Malinzak M, Friedman HS, Khasraw M. Management of glioblastoma: State of the art and future directions. CA: a Cancer Journal for Clinicians. 2020; 70: 299\u2013312.","DOI":"10.3322\/caac.21613"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Cavalli G, Heard E. Advances in epigenetics link genetics to the environment and disease. Nature. 2019; 571: 489\u2013499.","DOI":"10.1038\/s41586-019-1411-0"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Kondo Y, Katsushima K, Ohka F, Natsume A, Shinjo K. Epigenetic dysregulation in glioma. Cancer Science. 2014; 105: 363\u2013369.","DOI":"10.1111\/cas.12379"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Wu Q, Berglund AE, Etame AB. The Impact of Epigenetic Modifications on Adaptive Resistance Evolution in Glioblastoma. International Journal of Molecular Sciences. 2021; 22: 8324.","DOI":"10.3390\/ijms22158324"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. The New England Journal of Medicine. 2005; 352: 997\u20131003.","DOI":"10.1056\/NEJMoa043331"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Oldrini B, Vaquero-Siguero N, Mu Q, Kroon P, Zhang Y, Gal\u00e1n-Ganga M, et al. MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas. Nature Communications. 2020; 11: 3883.","DOI":"10.1038\/s41467-020-17717-0"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"Tian X, Liu G, Ji L, Shen Y, Gu J, Wang L, et al. Histone-acetyl epigenome regulates TGF-\u03b2 pathway-associated chemoresistance in colorectal cancer. Translational Oncology. 2025; 51: 102166.","DOI":"10.1016\/j.tranon.2024.102166"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Debbarma M, Sarkar K, Sil SK. Dissecting the epigenetic orchestra of HDAC isoforms in breast cancer development: a review. Medical Oncology (Northwood, London, England). 2024; 42: 1.","DOI":"10.1007\/s12032-024-02553-9"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Beumer JH, Tawbi H. Role of histone deacetylases and their inhibitors in cancer biology and treatment. Current Clinical Pharmacology. 2010; 5: 196\u2013208.","DOI":"10.2174\/157488410791498770"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Garmpis N, Damaskos C, Dimitroulis D, Kouraklis G, Garmpi A, Sarantis P, et al. Clinical Significance of the Histone Deacetylase 2 (HDAC-2) Expression in Human Breast Cancer. Journal of Personalized Medicine. 2022; 12: 1672.","DOI":"10.3390\/jpm12101672"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Grinshtein N, Rioseco CC, Marcellus R, Uehling D, Aman A, Lun X, et al. Small molecule epigenetic screen identifies novel EZH2 and HDAC inhibitors that target glioblastoma brain tumor-initiating cells. Oncotarget. 2016; 7: 59360\u201359376.","DOI":"10.18632\/oncotarget.10661"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Hanisch D, Krumm A, Diehl T, Stork CM, Dejung M, Butter F, et al. Class I HDAC overexpression promotes temozolomide resistance in glioma cells by regulating RAD18 expression. Cell Death & Disease. 2022; 13: 293.","DOI":"10.1038\/s41419-022-04751-7"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Lo Cascio C, Margaryan T, Luna-Melendez E, McNamara JB, White CI, Knight W, et al. Quisinostat is a brain-penetrant radiosensitizer in glioblastoma. JCI Insight. 2023; 8: e167081.","DOI":"10.1172\/jci.insight.167081"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Sun Y, Sun Y, Yue S, Wang Y, Lu F. Histone Deacetylase Inhibitors in Cancer Therapy. Current Topics in Medicinal Chemistry. 2018; 18: 2420\u20132428.","DOI":"10.2174\/1568026619666181210152115"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"Roche J, Bertrand P. Inside HDACs with more selective HDAC inhibitors. European Journal of Medicinal Chemistry. 2016; 121: 451\u2013483.","DOI":"10.1016\/j.ejmech.2016.05.047"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nature Protocols. 2013; 8: 2281\u20132308.","DOI":"10.1038\/nprot.2013.143"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Duly AMP, Kao FCL, Teo WS, Kavallaris M. \u03b2III-Tubulin Gene Regulation in Health and Disease. Frontiers in Cell and Developmental Biology. 2022; 10: 851542.","DOI":"10.3389\/fcell.2022.851542"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Marampon F, Megiorni F, Camero S, Crescioli C, McDowell HP, Sferra R, et al. HDAC4 and HDAC6 sustain DNA double strand break repair and stem-like phenotype by promoting radioresistance in glioblastoma cells. Cancer Letters. 2017; 397: 1\u201311.","DOI":"10.1016\/j.canlet.2017.03.028"},{"key":"ref27","doi-asserted-by":"publisher","unstructured":"Zhao S, Zhao R, Wang C, Ma C, Gao Z, Li B, et al. HDAC7 drives glioblastoma to a mesenchymal-like state via LGALS3-mediated crosstalk between cancer cells and macrophages. Theranostics. 2024; 14: 7072\u20137087.","DOI":"10.7150\/thno.100939"}],"container-title":["Die Pharmazie"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/Pharmazie\/81\/7\/10.31083\/Pharmazie51570","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:42:51Z","timestamp":1785411771000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/Pharmazie\/81\/7\/10.31083\/Pharmazie51570"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,24]]},"references-count":27,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026]]}},"alternative-id":["S0031-7144(26)03375-0"],"URL":"https:\/\/doi.org\/10.31083\/pharmazie51570","relation":{},"ISSN":["0031-7144","3053-691X"],"issn-type":[{"value":"0031-7144","type":"print"},{"value":"3053-691X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,24]]},"article-number":"51570"}}