{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T01:08:32Z","timestamp":1773018512310,"version":"3.50.1"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2021,8,6]],"date-time":"2021-08-06T00:00:00Z","timestamp":1628208000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2021,8,6]],"date-time":"2021-08-06T00:00:00Z","timestamp":1628208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"funder":[{"DOI":"10.13039\/501100004006","name":"Bilimsel Ara\u015ftirma Projeleri Birimi, Istanbul \u00dcniversitesi","doi-asserted-by":"publisher","award":["32763"],"award-info":[{"award-number":["32763"]}],"id":[{"id":"10.13039\/501100004006","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Med Oncol"],"published-print":{"date-parts":[[2021,9]]},"DOI":"10.1007\/s12032-021-01560-4","type":"journal-article","created":{"date-parts":[[2021,8,6]],"date-time":"2021-08-06T15:03:24Z","timestamp":1628262204000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Combined evaluation of proliferation and apoptosis to calculate IC50 of VPA-induced PANC-1 cells and assessing its effect on the Wnt signaling pathway"],"prefix":"10.1007","volume":"38","author":[{"given":"Yeliz","family":"Ekici","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdullah","family":"Yilmaz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Umut Can","family":"Kucuksezer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sema Bilgic","family":"Gazioglu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeynep Dogusan","family":"Yamalioglu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali Osman","family":"Gurol","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Linn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8233-1839","authenticated-orcid":false,"given":"Feyza Nur","family":"Tuncer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,8,6]]},"reference":[{"key":"1560_CR1","doi-asserted-by":"publisher","DOI":"10.3945\/an.116.012211","author":"S McGuire","year":"2014","unstructured":"McGuire S, World Cancer Report. Geneva, Switzerland: World Health Organization, International Agency for Research on Cancer, WHO Press, 2015. Adv Nutr. 2014. https:\/\/doi.org\/10.3945\/an.116.012211.","journal-title":"Adv Nutr"},{"key":"1560_CR2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21492","author":"F Bray","year":"2018","unstructured":"Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018. https:\/\/doi.org\/10.3322\/caac.21492.","journal-title":"CA Cancer J Clin"},{"key":"1560_CR3","doi-asserted-by":"publisher","DOI":"10.1007\/s13402-017-0314-z","author":"MS Gilardini Montani","year":"2017","unstructured":"Gilardini Montani MS, Granato M, Santoni C, Del Porto P, Merendino N, D\u2019Orazi G, et al. Histone deacetylase inhibitors VPA and TSA induce apoptosis and autophagy in pancreatic cancer cells. Cell Oncol (Dordr). 2017. https:\/\/doi.org\/10.1007\/s13402-017-0314-z.","journal-title":"Cell Oncol (Dordr)"},{"key":"1560_CR4","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdu013","author":"A Kleger","year":"2014","unstructured":"Kleger A, Perkhofer L, Seufferlein T. Smarter drugs emerging in pancreatic cancer therapy. Ann Oncol. 2014. https:\/\/doi.org\/10.1093\/annonc\/mdu013.","journal-title":"Ann Oncol"},{"key":"1560_CR5","doi-asserted-by":"publisher","DOI":"10.1038\/nrg816","author":"PA Jones","year":"2002","unstructured":"Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002. https:\/\/doi.org\/10.1038\/nrg816.","journal-title":"Nat Rev Genet"},{"key":"1560_CR6","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2008.08.027","author":"S Spange","year":"2009","unstructured":"Spange S, Wagner T, Heinzel T, Kr\u00e4mer OH. Acetylation of non-histone proteins modulates cellular signalling at multiple levels. Int J Biochem Cell Biol. 2009. https:\/\/doi.org\/10.1016\/j.biocel.2008.08.027.","journal-title":"Int J Biochem Cell Biol"},{"key":"1560_CR7","doi-asserted-by":"publisher","DOI":"10.1002\/med.10017","author":"RA Blaheta","year":"2002","unstructured":"Blaheta RA, Cinatl J Jr. Anti-tumor mechanisms of valproate: a novel role for an old drug. Med Res Rev. 2002. https:\/\/doi.org\/10.1002\/med.10017.","journal-title":"Med Res Rev"},{"key":"1560_CR8","doi-asserted-by":"publisher","DOI":"10.1124\/mol.65.3.520","author":"M Michaelis","year":"2004","unstructured":"Michaelis M, Michaelis UR, Fleming I, Suhan T, Cinatl J, Blaheta RA, Hoffmann K, Kotchetkov R, Busse R, Nau H, Cinatl J Jr. Valproic acid inhibits angiogenesis in vitro and in vivo. Mol Pharmacol. 2004. https:\/\/doi.org\/10.1124\/mol.65.3.520.","journal-title":"Mol Pharmacol"},{"key":"1560_CR9","doi-asserted-by":"publisher","DOI":"10.1002\/med.20027","author":"RA Blaheta","year":"2005","unstructured":"Blaheta RA, Michaelis M, Driever PH, Cinatl J Jr. Evolving anticancer drug valproic acid: insights into the mechanism and clinical studies. Med Res Rev. 2005. https:\/\/doi.org\/10.1002\/med.20027.","journal-title":"Med Res Rev"},{"key":"1560_CR10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2007.11.003","author":"A Duenas-Gonzalez","year":"2008","unstructured":"Duenas-Gonzalez A, Candelaria M, Perez-Plascencia C, Perez-Cardenas E, de la Cruz-Hernandez E, Herrera LA. Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors. Cancer Treat Rev. 2008. https:\/\/doi.org\/10.1016\/j.ctrv.2007.11.003.","journal-title":"Cancer Treat Rev"},{"key":"1560_CR11","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2013.00058","author":"Y Li","year":"2013","unstructured":"Li Y, Liu T, Ivan C, Huang J, Shen DY, Kavanagh JJ, et al. Enhanced cytotoxic effects of combined valproic acid and the aurora kinase inhibitor VE465 on gynecologic cancer cells. Front Oncol. 2013. https:\/\/doi.org\/10.3389\/fonc.2013.00058.","journal-title":"Front Oncol"},{"key":"1560_CR12","first-page":"37","volume":"53","author":"M Kostrouchov\u00e1","year":"2007","unstructured":"Kostrouchov\u00e1 M, Kostrouch Z, Kostrouchov\u00e1 M. Valproic acid, a molecular lead to multiple regulatory pathways. Folia Biol (Praha). 2007;53:37\u201349.","journal-title":"Folia Biol (Praha)"},{"key":"1560_CR13","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2014.04.012","author":"C Jamieson","year":"2014","unstructured":"Jamieson C, Sharma M, Henderson BR. Targeting the \u03b2-catenin nuclear transport pathway in cancer. Semin Cancer Biol. 2014. https:\/\/doi.org\/10.1016\/j.semcancer.2014.04.012.","journal-title":"Semin Cancer Biol"},{"key":"1560_CR14","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-13-0315","author":"S Sarkar","year":"2014","unstructured":"Sarkar S, Mandal C, Sangwan R, Mandal C. Coupling G2\/M arrest to the Wnt\/\u03b2-catenin pathway restrains pancreatic adenocarcinoma. Endocr Relat Cancer. 2014. https:\/\/doi.org\/10.1530\/ERC-13-0315.","journal-title":"Endocr Relat Cancer"},{"key":"1560_CR15","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440-1711.1999.00877.x","author":"CR Parish","year":"1999","unstructured":"Parish CR. Fluorescent dyes for lymphocyte migration and proliferation studies. Immunol Cell Biol. 1999. https:\/\/doi.org\/10.1046\/j.1440-1711.1999.00877.x.","journal-title":"Immunol Cell Biol"},{"key":"1560_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.39","author":"S Raz","year":"2014","unstructured":"Raz S, Sheban D, Gonen N, Stark M, Berman B, Assaraf YG. Severe hypoxia induces complete antifolate resistance in carcinoma cells due to cell cycle arrest. Cell Death Dis. 2014. https:\/\/doi.org\/10.1038\/cddis.2014.39.","journal-title":"Cell Death Dis"},{"key":"1560_CR17","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-09-178475","author":"MT Ahlen","year":"2009","unstructured":"Ahlen MT, Husebekk A, Killie MK, Skogen B, Stuge TB. T-cell responses associated with neonatal alloimmune thrombocytopenia: isolation of HPA-1a-specific, HLA-DRB3*0101-restricted CD4+ T cells. Blood. 2009. https:\/\/doi.org\/10.1182\/blood-2008-09-178475.","journal-title":"Blood"},{"key":"1560_CR18","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(95)00072-i","author":"I Vermes","year":"1995","unstructured":"Vermes I, Haanen C, Steffens-Nakken H, Reutelingsperger C. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J Immunol Methods. 1995. https:\/\/doi.org\/10.1016\/0022-1759(95)00072-i.","journal-title":"J Immunol Methods"},{"key":"1560_CR19","doi-asserted-by":"publisher","first-page":"277","DOI":"10.3322\/caac.20073","volume":"60","author":"A Jemal","year":"2010","unstructured":"Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277\u2013300.","journal-title":"CA Cancer J Clin"},{"key":"1560_CR20","doi-asserted-by":"publisher","DOI":"10.2174\/1570159X17666181227165722","author":"M Romoli","year":"2019","unstructured":"Romoli M, Mazzocchetti P, D\u2019Alonzo R, Siliquini S, Rinaldi VE, Verrotti A, et al. Valproic acid and epilepsy: from molecular mechanisms to clinical evidences. Curr Neuropharmacol. 2019. https:\/\/doi.org\/10.2174\/1570159X17666181227165722.","journal-title":"Curr Neuropharmacol"},{"key":"1560_CR21","doi-asserted-by":"publisher","DOI":"10.4172\/2329-6798.1000118","author":"S Lichun","year":"2014","unstructured":"Lichun S, David H. Anti-convulsant drug valproic acid in cancers and in combination anti-cancer therapeutics. Mod Chem Appl. 2014. https:\/\/doi.org\/10.4172\/2329-6798.1000118.","journal-title":"Mod Chem Appl"},{"key":"1560_CR22","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.08.6165","author":"P M\u00fcnster","year":"2007","unstructured":"M\u00fcnster P, Marchion D, Bicaku E, Schmitt M, Lee JH, DeConti R, et al. Phase I trial of histone deacetylase inhibition by valproic acid followed by the topoisomerase II inhibitor epirubicin in advanced solid tumors: a clinical and translational study. J Clin Oncol. 2007. https:\/\/doi.org\/10.1200\/JCO.2006.08.6165.","journal-title":"J Clin Oncol"},{"key":"1560_CR23","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-011-1213-7","author":"B Lehner","year":"2011","unstructured":"Lehner B, Sandner B, Marschallinger J, Lehner C, Furtner T, Couillard-Despres S, et al. The dark side of BrdU in neural stem cell biology: detrimental effects on cell cycle, differentiation and survival. Cell Tissue Res. 2011. https:\/\/doi.org\/10.1007\/s00441-011-1213-7.","journal-title":"Cell Tissue Res"},{"key":"1560_CR24","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(83)90303-4","author":"T Mosmann","year":"1983","unstructured":"Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983. https:\/\/doi.org\/10.1016\/0022-1759(83)90303-4.","journal-title":"J Immunol Methods"},{"key":"1560_CR25","doi-asserted-by":"publisher","DOI":"10.5246\/jcps.2010.03.027","author":"M Han","year":"2010","unstructured":"Han M, Li JF, Tan Q, Sun YY. Limitations of the use of MTT assay for screening in drug discovery. J Chin Pharmaceutical Sci. 2010. https:\/\/doi.org\/10.5246\/jcps.2010.03.027.","journal-title":"J Chin Pharmaceutical Sci"},{"key":"1560_CR26","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2012.02.006","author":"L L\u00fc","year":"2012","unstructured":"L\u00fc L, Zhang L, Wai MS, Yew DT, Xu J. Exocytosis of MTT formazan could exacerbate cell injury. Toxicol In Vitro. 2012. https:\/\/doi.org\/10.1016\/j.tiv.2012.02.006.","journal-title":"Toxicol In Vitro"},{"key":"1560_CR27","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2017.6943","author":"T Miyashita","year":"2017","unstructured":"Miyashita T, Miki K, Kamigaki T, Makino I, Tajima H, Nakanuma S, et al. Low-dose valproic acid with low-dose gemcitabine augments MHC class I-related chain A\/B expression without inducing the release of soluble MHC class I-related chain A\/B. Oncol Lett. 2017. https:\/\/doi.org\/10.3892\/ol.2017.6943.","journal-title":"Oncol Lett"},{"key":"1560_CR28","doi-asserted-by":"publisher","DOI":"10.1186\/s13578-019-0312-0","author":"H Li","year":"2019","unstructured":"Li H, Zhang Z, Gao C, Wu S, Duan Q, Wu H, et al. Combination chemotherapy of valproic acid (VPA) and gemcitabine regulates STAT3\/Bmi1 pathway to differentially potentiate the motility of pancreatic cancer cells. Cell Biosci. 2019. https:\/\/doi.org\/10.1186\/s13578-019-0312-0.","journal-title":"Cell Biosci"},{"key":"1560_CR29","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.057836","author":"V Venkataramani","year":"2010","unstructured":"Venkataramani V, Rossner C, Iffland L, Schweyer S, Tamboli IY, Walter J, et al. Histone deacetylase inhibitor valproic acid inhibits cancer cell proliferation via down-regulation of the alzheimer amyloid precursor protein. J Biol Chem. 2010. https:\/\/doi.org\/10.1074\/jbc.M109.057836.","journal-title":"J Biol Chem"},{"key":"1560_CR30","doi-asserted-by":"publisher","first-page":"1912","DOI":"10.1158\/1535-7163.MCT-05-0184","volume":"4","author":"XN Li","year":"2005","unstructured":"Li XN, Shu Q, Su JM, Perlaky L, Blaney SM, Lau CC. Valproic acid induces growth arrest, apoptosis, and senescence in medulloblastomas by increasing histone hyperacetylation and regulating expression of p21Cip1, CDK4, and CMYC. Mol Cancer Ther. 2005;4:1912\u201322.","journal-title":"Mol Cancer Ther"},{"key":"1560_CR31","doi-asserted-by":"publisher","DOI":"10.1038\/nature11005","author":"MJ Garnett","year":"2012","unstructured":"Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012. https:\/\/doi.org\/10.1038\/nature11005.","journal-title":"Nature"},{"key":"1560_CR32","doi-asserted-by":"publisher","DOI":"10.1038\/nature11003","author":"J Barretina","year":"2012","unstructured":"Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012. https:\/\/doi.org\/10.1038\/nature11003.","journal-title":"Nature"},{"key":"1560_CR33","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.06.089","author":"PW Heiser","year":"2008","unstructured":"Heiser PW, Cano DA, Landsman L, Kim GE, Kench JG, Klimstra DS, et al. Stabilization of beta-catenin induces pancreas tumor formation. Gastroenterology. 2008. https:\/\/doi.org\/10.1053\/j.gastro.2008.06.089.","journal-title":"Gastroenterology"},{"key":"1560_CR34","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2009.01.018","author":"L Wang","year":"2009","unstructured":"Wang L, Heidt DG, Lee CJ, Yang H, Logsdon CD, Zhang L, et al. Oncogenic function of ATDC in pancreatic cancer through Wnt pathway activation and beta-catenin stabilization. Cancer Cell. 2009. https:\/\/doi.org\/10.1016\/j.ccr.2009.01.018.","journal-title":"Cancer Cell"},{"key":"1560_CR35","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.24802","author":"S Jesse","year":"2010","unstructured":"Jesse S, Koenig A, Ellenrieder V, Menke A. Lef-1 isoforms regulate different target genes and reduce cellular adhesion. Int J Cancer. 2010. https:\/\/doi.org\/10.1002\/ijc.24802.","journal-title":"Int J Cancer"},{"key":"1560_CR36","first-page":"1389","volume":"7","author":"L Santiago","year":"2017","unstructured":"Santiago L, Daniels G, Wang D, Deng FM, Lee P. Wnt signaling pathway protein LEF1 in cancer, as a biomarker for prognosis and a target for treatment. Am J Cancer Res. 2017;7:1389\u2013406.","journal-title":"Am J Cancer Res"},{"key":"1560_CR37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0001155","author":"M Pasca di Magliano","year":"2007","unstructured":"Pasca di Magliano M, Biankin AV, Heiser PW, Cano DA, Gutierrez PJ, Deramaudt T, et al. Common activation of canonical Wnt signaling in pancreatic adenocarcinoma. PLoS ONE. 2007. https:\/\/doi.org\/10.1371\/journal.pone.0001155.","journal-title":"PLoS ONE"}],"container-title":["Medical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12032-021-01560-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12032-021-01560-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12032-021-01560-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,24]],"date-time":"2021-08-24T06:51:33Z","timestamp":1629787893000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12032-021-01560-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,6]]},"references-count":37,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2021,9]]}},"alternative-id":["1560"],"URL":"https:\/\/doi.org\/10.1007\/s12032-021-01560-4","relation":{},"ISSN":["1357-0560","1559-131X"],"issn-type":[{"value":"1357-0560","type":"print"},{"value":"1559-131X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,6]]},"assertion":[{"value":"6 April 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 July 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 August 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no competing or conflicting interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"109"}}