{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T07:10:17Z","timestamp":1787901017457,"version":"build-2784847793"},"reference-count":40,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,8,27]],"date-time":"2023-08-27T00:00:00Z","timestamp":1693094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Polish National Science Center","award":["2016\/22\/M\/NZ7\/00375"],"award-info":[{"award-number":["2016\/22\/M\/NZ7\/00375"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>HDAC inhibitors (HDACi) hold great potential as anticancer therapies due to their ability to regulate the acetylation of both histone and non-histone proteins, which is frequently disrupted in cancer and contributes to the development and advancement of the disease. Additionally, HDACi have been shown to enhance the cytotoxic effects of DNA-damaging agents such as radiation and cisplatin. In this study, we found that histone deacetylase inhibits valproic acid (VPA), synergized with PARP1 inhibitor (PARPi), talazoparib (BMN-673), and alkylating agent, and temozolomide (TMZ) to induce DNA damage and reduce glioblastoma multiforme. At the molecular level, VPA leads to a downregulation of FANCD2 and RAD51, and the eradication of glioblastoma cells. The results of this study indicate that combining HDACi with PARPi could potentially enhance the treatment of glioblastoma, the most aggressive type of cancer that originates in the brain.<\/jats:p>","DOI":"10.3390\/jpm13091315","type":"journal-article","created":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T01:56:57Z","timestamp":1693187817000},"page":"1315","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Class I HDAC Inhibition Leads to a Downregulation of FANCD2 and RAD51, and the Eradication of Glioblastoma Cells"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5869-7993","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Drzewiecka","sequence":"first","affiliation":[{"name":"Laboratory of Medical Genetics Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominika","family":"Ja\u015bniak","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Barszczewska-Pietraszek","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5146-5225","authenticated-orcid":false,"given":"Piotr","family":"Czarny","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Medical University of Lodz, 92-216 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Kobrzycka","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Faculty of Biology and Environmental Protection, University of \u0141odz, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Wieczorek","sequence":"additional","affiliation":[{"name":"Department of Neurobiology, Faculty of Biology and Environmental Protection, University of \u0141odz, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3544-1482","authenticated-orcid":false,"given":"Maciej","family":"Radek","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Surgery of Spine and Peripheral Nerves, Medical University of Lodz, University Hospital WAM-CSW, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6052-3557","authenticated-orcid":false,"given":"Janusz","family":"Szemraj","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Medical University of Lodz, 92-216 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Skorski","sequence":"additional","affiliation":[{"name":"Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8385-7744","authenticated-orcid":false,"given":"Tomasz","family":"\u015aliwi\u0144ski","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,27]]},"reference":[{"key":"ref_1","first-page":"2275","article-title":"PARP-1 inhibition sensitizes temozolomide-treated glioblastoma cell lines and decreases drug resistance independent of MGMT activity and PTEN proficiency","volume":"44","author":"Montaldi","year":"2020","journal-title":"Oncol. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/s41571-018-0055-6","article-title":"Synthetic Lethal Therapies for Cancer: What\u2019s next after PARP Inhibitors?","volume":"13","author":"Ashworth","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6818","DOI":"10.1158\/0008-5472.CAN-18-0633","article-title":"Targeting PARP1 in XRCC1-Deficient Sporadic Invasive Breast Cancer or Preinvasive Ductal Carcinoma In Situ Induces Synthetic Lethality and Chemoprevention","volume":"78","author":"Ali","year":"2018","journal-title":"Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2968","DOI":"10.1200\/JCO.18.02238","article-title":"Niraparib Maintenance Therapy in Patients with Recurrent Ovarian Cancer After a Partial Response to the Last Platinum-Based Chemotherapy in the ENGOT-OV16\/NOVA Trial","volume":"37","author":"Matulonis","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1200\/JCO.2014.56.2728","article-title":"Olaparib Monotherapy in Patients with Advanced Cancer and a Germline BRCA1\/2 Mutation","volume":"33","author":"Kaufman","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2154","DOI":"10.1056\/NEJMoa1611310","article-title":"Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer","volume":"375","author":"Mirza","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1056\/NEJMoa1810858","article-title":"Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer","volume":"379","author":"Moore","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1056\/NEJMoa1909707","article-title":"Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer","volume":"381","author":"Coleman","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1056\/NEJMoa1910962","article-title":"Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer","volume":"381","author":"Pothuri","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1056\/NEJMoa1911440","article-title":"Olaparib for Metastatic Castration-Resistant Prostate Cancer","volume":"382","author":"Mateo","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e309","DOI":"10.1093\/oncolo\/oyad008","article-title":"Niraparib with Abiraterone Acetate and Prednisone for Metastatic Castration-Resistant Prostate Cancer: Phase II QUEST Study Results","volume":"28","author":"Chi","year":"2023","journal-title":"Oncologist"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1016\/S1470-2045(18)30333-4","article-title":"Quality of life in patients with recurrent ovarian cancer treated with niraparib versus placebo (ENGOT-OV16\/NOVA): Results from a double-blind, phase 3, randomised controlled trial","volume":"19","author":"Oza","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1093\/annonc\/mdy257","article-title":"Quality of life with talazoparib versus physician\u2019s choice of chemotherapy in patients with advanced breast cancer and germline BRCA1\/2 mutation: Patient-reported outcomes from the EMBRACA phase III trial","volume":"29","author":"Ettl","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.ejca.2021.05.037","article-title":"Efficacy and safety of first-line veliparib and carboplatin\u2013paclitaxel in patients with HER2\u2212 advanced germline BRCA+ breast cancer: Subgroup analysis of a randomised clinical trial","volume":"154","author":"Arun","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1038\/s43018-022-00439-1","article-title":"A phase II study of talazoparib monotherapy in patients with wild-type BRCA1 and BRCA2 with a mutation in other homologous recombination genes","volume":"3","author":"Gruber","year":"2022","journal-title":"Nat. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/S1470-2045(21)00073-5","article-title":"Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1\/2 mutation (SOLO2\/ENGOT-Ov21): A final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial","volume":"22","author":"Poveda","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1016\/S1470-2045(18)30365-6","article-title":"Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: A randomised, double-blind, placebo-controlled, phase 2 trial","volume":"19","author":"Clarke","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"a026831","DOI":"10.1101\/cshperspect.a026831","article-title":"HDACs and HDAC Inhibitors in Cancer Development and Therapy","volume":"6","author":"Li","year":"2016","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"vdz025","DOI":"10.1093\/noajnl\/vdz025","article-title":"Effects of valproic acid on histone deacetylase inhibition in vitro and in glioblastoma patient samples","volume":"1","author":"Berendsen","year":"2019","journal-title":"Neuro-Oncol. Adv."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/nrd4579","article-title":"Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders","volume":"14","author":"Falkenberg","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3067","DOI":"10.1158\/0008-5472.CAN-15-2680","article-title":"Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance","volume":"76","author":"Krumm","year":"2016","journal-title":"Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s13046-020-01643-6","article-title":"The application of histone deacetylases inhibitors in glioblastoma","volume":"39","author":"Chen","year":"2020","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_23","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_24","doi-asserted-by":"crossref","first-page":"616886","DOI":"10.3389\/fnmol.2021.616886","article-title":"The Effects of Selective Inhibition of Histone Deacetylase 1 and 3 in Huntington\u2019s Disease Mice","volume":"14","author":"Hecklau","year":"2021","journal-title":"Front. Mol. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"BSR20210462","DOI":"10.1042\/BSR20210462","article-title":"Histone deacetylase 10, a potential epigenetic target for therapy","volume":"41","author":"Cheng","year":"2021","journal-title":"Biosci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Drzewiecka, M., Gajos-Michniewicz, A., Hoser, G., Ja\u015bniak, D., Barszczewska-Pietraszek, G., Sitarek, P., Czarny, P., Piekarski, J., Radek, M., and Czy\u017c, M. (2023). Histone Deacetylases (HDAC) Inhibitor\u2014Valproic Acid Sensitizes Human Melanoma Cells to Dacarbazine and PARP Inhibitor. Genes, 14.","DOI":"10.3390\/genes14061295"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Liu, W., Polaczek, P., Roubal, I., Meng, Y., Choe, W., Caron, M.-C., Sedgeman, C.A., Xi, Y., Liu, C., and Wu, Q. (2021). FANCD2 and RAD51 Recombinase Directly Inhibit DNA2 Nuclease at Stalled Replication Forks and FANCD2 Acts as a Novel RAD51 Mediator in Strand Exchange to Promote Genome Stability. Biochemistry.","DOI":"10.1101\/2021.07.08.450798"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"10758","DOI":"10.1093\/nar\/gkw876","article-title":"FANCI-FANCD2 stabilizes the RAD51-DNA complex by binding RAD51 and protects the 5\u2032-DNA end","volume":"44","author":"Sato","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Thomas, M., Dubacq, C., Rabut, E., Lopez, B.S., and Guirouilh-Barbat, J. (2023). Noncanonical Roles of RAD51. Cells, 12.","DOI":"10.3390\/cells12081169"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"75551","DOI":"10.18632\/oncotarget.12270","article-title":"PARP1 inhibitor olaparib (Lynparza) exerts synthetic lethal effect against ligase 4-deficient melanomas","volume":"7","author":"Toma","year":"2016","journal-title":"Oncotarget"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"101312","DOI":"10.1016\/j.tranon.2021.101312","article-title":"HDAC inhibitors: Targets for tumor therapy, immune modulation and lung diseases","volume":"16","author":"Shanmugam","year":"2022","journal-title":"Transl. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2243","DOI":"10.1158\/1535-7163.MCT-09-0201","article-title":"Enhanced radiosensitization of human glioma cells by combining inhibition of poly(ADP-ribose) polymerase with inhibition of heat shock protein 90","volume":"8","author":"Dungey","year":"2009","journal-title":"Mol. Cancer Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/1756-8722-5-24","article-title":"Novel therapeutic agents for cutaneous T-Cell lymphoma","volume":"5","author":"Jain","year":"2012","journal-title":"J. Hematol. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.bbrc.2008.01.056","article-title":"Class II histone deacetylases play pivotal roles in heat shock protein 90-mediated proteasomal degradation of vascular endothelial growth factor receptors","volume":"368","author":"Park","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5637","DOI":"10.18632\/oncotarget.2154","article-title":"Histone Deacetylase Inhibitor Treatment Induces \u2018BRCAness\u2019 and Synergistic Lethality with PARP Inhibitor and Cisplatin against Human Triple Negative Breast Cancer Cells","volume":"5","author":"Ha","year":"2014","journal-title":"Oncotarget"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1002\/emmm.200900041","article-title":"Synthetic Lethal Targeting of PTEN Mutant Cells with PARP Inhibitors","volume":"1","author":"Martin","year":"2009","journal-title":"EMBO Mol Med"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s13058-015-0534-y","article-title":"Histone Deacetylase Inhibitor, Suberoylanilide Hydroxamic Acid (SAHA), Enhances Anti-Tumor Effects of the Poly (ADP-Ribose) Polymerase (PARP) Inhibitor Olaparib in Triple-Negative Breast Cancer Cells","volume":"17","author":"Min","year":"2015","journal-title":"Breast Cancer Res"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"36867","DOI":"10.18632\/oncotarget.26409","article-title":"Eradication of LIG4-deficient glioblastoma cells by the combination of PARP inhibitor and alkylating agent","volume":"9","author":"Toma","year":"2018","journal-title":"Oncotarget"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Romeo, M.A., Montani, M.S.G., Benedetti, R., Arena, A., D\u2019orazi, G., and Cirone, M. (2022). VPA and TSA Interrupt the Interplay between mutp53 and HSP70, Leading to CHK1 and RAD51 Down-Regulation and Sensitizing Pancreatic Cancer Cells to AZD2461 PARP Inhibitor. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23042268"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/s41419-022-04751-7","article-title":"Class I HDAC overexpression promotes temozolomide resistance in glioma cells by regulating RAD18 expression","volume":"13","author":"Hanisch","year":"2022","journal-title":"Cell Death Dis."}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/13\/9\/1315\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:40:07Z","timestamp":1760128807000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/13\/9\/1315"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,27]]},"references-count":40,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["jpm13091315"],"URL":"https:\/\/doi.org\/10.3390\/jpm13091315","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,27]]}}}