{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T22:13:42Z","timestamp":1761948822649,"version":"3.37.3"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"16","license":[{"start":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T00:00:00Z","timestamp":1692144000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T00:00:00Z","timestamp":1692144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Ph.D. Martina Hamb\u00f6ck Grant of the Vienna Medical Chamber","award":["0007-WS 2020"],"award-info":[{"award-number":["0007-WS 2020"]}]},{"name":"Medical Scientific Fund of the Mayor of the city of Vienna","award":["19066"],"award-info":[{"award-number":["19066"]}]},{"DOI":"10.13039\/501100005788","name":"Medical University of Vienna","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005788","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Cancer Res Clin Oncol"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Purpose<\/jats:title>\n                <jats:p>Gamma-secretase inhibitor MK0752 has shown a\u00a0high therapeutic potential in different solid malignant tumors. Up to now, its antineoplastic effects were not investigated in head and neck squamous cell carcinoma (HNSCC) and particularly in human-papillomavirus (HPV)-positive tumors.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We conducted cytotoxic, migration, and clonogenic assays in two HPV-negative HNSCC cell lines (Cal27 and FaDu) and one HPV-positive cell line (SCC154). Furthermore, in order to assess the pro-apoptotic effects of MK0752, a Caspase 3\/7 Glo assay was performed.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Our experiments revealed antineoplastic effects of MK0752 in all three cell lines. Strong cytotoxic and antimigratory potential was shown in all cell lines, with strongest effects observed in the HPV-positive cell line. Meanwhile, anticlonogenic effects were only shown in Cal27 and SCC154. Most importantly, MK0752 induced apoptosis solely in HPV-positive SCC154.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our novel findings indicate a therapeutic potential of MK0752 in HPV-positive HNSCC. Indeed, further investigation is needed for validation of our results and for the assessment of the mechanistic background.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00432-023-05269-x","type":"journal-article","created":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T16:02:22Z","timestamp":1692201742000},"page":"14691-14699","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["In vitro antineoplastic effects of MK0752 in HPV-positive head and neck squamous cell carcinoma"],"prefix":"10.1007","volume":"149","author":[{"given":"Sara","family":"Varatanovic","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Stoiber","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Haas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Lein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenz","family":"Kadletz-Wanke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faris F.","family":"Brkic","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,8,16]]},"reference":[{"issue":"11","key":"5269_CR1","doi-asserted-by":"publisher","first-page":"5980","DOI":"10.3390\/ijms23115980","volume":"23","author":"Y Abedin","year":"2022","unstructured":"Abedin Y, Gabrilovich S, Alpert E, Rego E, Begum S, Zhao Q, Heller D, Einstein MH, Douglas NC (2022) Gamma secretase inhibitors as potential therapeutic targets for notch signaling in Uterine Leiomyosarcoma. Int J Mol Sci 23(11):5980. https:\/\/doi.org\/10.3390\/ijms23115980","journal-title":"Int J Mol Sci"},{"issue":"3","key":"5269_CR2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0091983","volume":"9","author":"EV Abel","year":"2014","unstructured":"Abel EV, Kim EJ, Wu J, Hynes M, Bednar F, Proctor E, Wang L, Dziubinski ML, Simeone DM (2014) The Notch pathway is im-portant in maintaining the cancer stem cell population in pancreatic cancer. PLoS ONE 9(3):e91983. https:\/\/doi.org\/10.1371\/journal.pone.0091983","journal-title":"PLoS ONE"},{"issue":"6046","key":"5269_CR3","doi-asserted-by":"publisher","first-page":"1154","DOI":"10.1126\/science.1206923","volume":"333","author":"N Agrawal","year":"2011","unstructured":"Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ, Fakhry C, Xie TX, Zhang J, Wang J, Zhang N, El-Naggar AK, Jasser SA, Weinstein JN, Trevi\u00f1o L, Drummond JA, Muzny DM, Wu Y, Wood LD, Hruban RH, Westra WH, Koch WM, Califano JA, Gibbs RA, Sidransky D, Vogelstein B, Velculescu VE, Papadopoulos N, Wheeler DA, Kinzler KW, Myers JN (2011) Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 333(6046):1154\u20131157. https:\/\/doi.org\/10.1126\/science.1206923","journal-title":"Science"},{"issue":"4","key":"5269_CR4","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.jcms.2021.01.012","volume":"49","author":"FF Brkic","year":"2021","unstructured":"Brkic FF, Kadletz-Wanke L, Kenner L, F\u00fcreder T, Jank B, Brunner M, Heiduschka G (2021) An analysis of distant metastasis cases from HPV-associated oropharyngeal squamous cell carcinoma. J Craniomaxillofac Surg 49(4):312\u2013316","journal-title":"J Craniomaxillofac Surg"},{"issue":"3","key":"5269_CR5","doi-asserted-by":"publisher","first-page":"378","DOI":"10.3390\/ph15030378","volume":"15","author":"FF Brkic","year":"2022","unstructured":"Brkic FF, Stoiber S, Maier T, Gurnhofer E, Kenner L, Heiduschka G, Kadletz-Wanke L (2022) Targeting Wnt\/\u03b2-Catenin signaling in HPV-positive head and neck squamous cell carcinoma. Pharmaceuticals (basel) 15(3):378. https:\/\/doi.org\/10.3390\/ph15030378","journal-title":"Pharmaceuticals (basel)"},{"issue":"3","key":"5269_CR6","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1016\/j.ygyno.2015.12.011","volume":"140","author":"X Chen","year":"2016","unstructured":"Chen X, Gong L, Ou R, Zheng Z, Chen J, Xie F, Huang X, Qiu J, Zhang W, Jiang Q, Yang Y, Zhu H, Shi Z, Yan X (2016) Sequential combination therapy of ovarian cancer with cisplatin and \u03b3-secretase inhibitor MK-0752. Gynecol Oncol 140(3):537\u2013544. https:\/\/doi.org\/10.1016\/j.ygyno.2015.12.011","journal-title":"Gynecol Oncol"},{"key":"5269_CR7","unstructured":"ClinicalTrials.gov, \"Study Of MK-0752 In combination with tamoxifen or letrozole to treat early stage breast cancer (MK-0752) - NCT00756717,\" U.S. National Library of Medicine, 2019. Available: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT00756717. (accessed on Jan 2nd 2023)"},{"key":"5269_CR8","doi-asserted-by":"publisher","unstructured":"Cook N, Basu B, Smith DM, Gopinathan A, Evans J, Steward WP, Palmer D, Propper D, Venugopal B, Hategan M, Antho-ney DA, Hampson LV, Nebozhyn M, Tuveson D, Farmer-Hall H, Turner H, Das T, Zhong R, Spiotto MT (2020) Notch signaling and human papillomavirus\u2013associated oral tumorigenesis. Notch Signalling in Embriology and Cancer. pp 105\u2013122. https:\/\/doi.org\/10.1007\/978-3-030-55031-8_14","DOI":"10.1007\/978-3-030-55031-8_14"},{"issue":"18","key":"5269_CR9","doi-asserted-by":"publisher","first-page":"6585","DOI":"10.1200\/jco.2006.24.18_suppl.6585","volume":"24","author":"DJ Deangelo","year":"2006","unstructured":"Deangelo DJ, Stone RM, Silverman LB, Stock W, Attar EC, Fearen I, Dallob A, Matthews C, Stone J, Freedman SJ, Aster J (2006) A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia\/lymphoma (T-ALL) and other leukemias. J Clin Oncol 24(18):6585\u20136585","journal-title":"J Clin Oncol"},{"issue":"6","key":"5269_CR10","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1177\/0022034518760297","volume":"97","author":"T Fukusumi","year":"2018","unstructured":"Fukusumi T, Califano JA (2018) The NOTCH pathway in head and neck squamous cell carcinoma. J Dent Res 97(6):645\u2013653. https:\/\/doi.org\/10.1177\/0022034518760297","journal-title":"J Dent Res"},{"issue":"4","key":"5269_CR11","doi-asserted-by":"publisher","first-page":"2900","DOI":"10.3892\/ol.2016.5011","volume":"12","author":"LM Greene","year":"2016","unstructured":"Greene LM, Nathwani SM, Zisterer DM (2016) Inhibition of \u03b3-secretase activity synergistically enhances tumour necrosis fac-tor-related apoptosis-inducing ligand induced apoptosis in T-cell acute lymphoblastic leukemia cells via upregulation of death receptor 5. Oncol Lett 12(4):2900\u20132905. https:\/\/doi.org\/10.3892\/ol.2016.5011","journal-title":"Oncol Lett"},{"issue":"1","key":"5269_CR12","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41572-020-00224-3","volume":"6","author":"DE Johnson","year":"2020","unstructured":"Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR (2020) Head and neck squamous cell carcinoma. Nat Rev Dis Primers 6(1):92. https:\/\/doi.org\/10.1038\/s41572-020-00224-3","journal-title":"Nat Rev Dis Primers"},{"issue":"9","key":"5269_CR13","doi-asserted-by":"publisher","first-page":"241","DOI":"10.3390\/jcm7090241","volume":"7","author":"K Kobayashi","year":"2018","unstructured":"Kobayashi K, Hisamatsu K, Suzui N, Hara A, Tomita H, Miyazaki T (2018) A review of HPV-related head and neck cancer. J Clin Med 7(9):241. https:\/\/doi.org\/10.3390\/jcm7090241","journal-title":"J Clin Med"},{"issue":"1","key":"5269_CR14","doi-asserted-by":"publisher","first-page":"3000","DOI":"10.1038\/s41598-022-06922-0","volume":"12","author":"J Lim","year":"2022","unstructured":"Lim J, Straub E, Stubenrauch F, Iftner T, Schindler M, Simon C (2022) An enhanced triple fluorescence flow-cytometry-based assay shows differential activation of the Notch signaling pathway by human papillomavirus E6 proteins. Sci Rep 12(1):3000. https:\/\/doi.org\/10.1038\/s41598-022-06922-0","journal-title":"Sci Rep"},{"issue":"11","key":"5269_CR15","doi-asserted-by":"publisher","first-page":"2976","DOI":"10.1245\/s10434-010-1118-9","volume":"17","author":"JT Lin","year":"2010","unstructured":"Lin JT, Chen MK, Yeh KT, Chang CS, Chang TH, Lin CY, Wu YC, Su BW, Lee KD, Chang PJ (2010) Association of high levels of Jagged-1 and Notch-1 expression with poor prognosis in head and neck cancer. Ann Surg Oncol 17(11):2976\u20132983. https:\/\/doi.org\/10.1245\/s10434-010-1118-9","journal-title":"Ann Surg Oncol"},{"issue":"1","key":"5269_CR16","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1007\/s00405-022-07598-y","volume":"280","author":"T Maier","year":"2023","unstructured":"Maier T, Stoiber S, Gurnhofer E, Haas M, Kenner L, Heiduschka G, Kadletz-Wanke L, Brkic FF (2023) Inhibition of beta-catenin shows therapeutic potential in head and neck squamous cell carcinoma in vitro. Eur Arch Otorhinolaryngol 280(1):399\u2013408. https:\/\/doi.org\/10.1007\/s00405-022-07598-y","journal-title":"Eur Arch Otorhinolaryngol"},{"issue":"6","key":"5269_CR17","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1038\/bjc.2017.495","volume":"118","author":"R McLeod","year":"2018","unstructured":"McLeod R, Halford S, Jodrell D (2018) A phase I trial of the \u03b3-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma. Br J Cancer 118(6):793\u2013801. https:\/\/doi.org\/10.1038\/bjc.2017.495","journal-title":"Br J Cancer"},{"issue":"24","key":"5269_CR18","doi-asserted-by":"publisher","first-page":"6308","DOI":"10.1158\/1078-0432.CCR-17-3535","volume":"24","author":"PE Nyman","year":"2018","unstructured":"Nyman PE, Buehler D, Lambert PF (2018) Loss of function of canonical notch signaling drives head and neck carcinogenesis. Clin Cancer Res 24(24):6308\u20136318. https:\/\/doi.org\/10.1158\/1078-0432.CCR-17-3535","journal-title":"Clin Cancer Res"},{"issue":"14","key":"5269_CR19","doi-asserted-by":"publisher","first-page":"1865","DOI":"10.1016\/j.ejca.2015.06.115","volume":"51","author":"SA Piha-Paul","year":"2015","unstructured":"Piha-Paul SA, Munster PN, Hollebecque A, Argil\u00e9s G, Dajani O, Cheng JD, Wang R, Swift A, Tosolini A, Gupta S (2015) Results of a phase 1 trial combining ridaforolimus and MK-0752 in patients with advanced solid tumours. Eur J Cancer 51(14):1865\u20131873. https:\/\/doi.org\/10.1016\/j.ejca.2015.06.115","journal-title":"Eur J Cancer"},{"issue":"5","key":"5269_CR20","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1016\/j.oraloncology.2013.07.011","volume":"50","author":"T Rampias","year":"2014","unstructured":"Rampias T, Sasaki C, Psyrri A (2014) Molecular mechanisms of HPV induced carcinogenesis in head and neck. Oral Oncol 50(5):356\u2013363. https:\/\/doi.org\/10.1016\/j.oraloncology.2013.07.011","journal-title":"Oral Oncol"},{"issue":"7","key":"5269_CR21","doi-asserted-by":"publisher","first-page":"950","DOI":"10.15252\/emmm.201607265","volume":"9","author":"Y Ran","year":"2017","unstructured":"Ran Y, Hossain F, Pannuti A, Lessard CB, Ladd GZ, Jung JI, Minter LM, Osborne BA, Miele L, Golde TE (2017) \u03b3-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct. EMBO Mol Med 9(7):950\u2013966. https:\/\/doi.org\/10.15252\/emmm.201607265","journal-title":"EMBO Mol Med"},{"issue":"1","key":"5269_CR22","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.neo.2018.10.011","volume":"21","author":"I Saltarella","year":"2019","unstructured":"Saltarella I, Frassanito MA, Lamanuzzi A, Brevi A, Leone P, Desantis V, Di Marzo L, Bellone M, Derudas D, Ribatti D, Chi-aramonte R, Palano MT, Neri A, Mariggi\u00f2 MA, Fumarulo R, Dammacco F, Racanelli V, Vacca A, Ria R (2019) Homotypic and heterotypic activation of the notch pathway in multiple myeloma-enhanced angiogenesis: a novel therapeutic target? Neoplasia 21(1):93\u2013105. https:\/\/doi.org\/10.1016\/j.neo.2018.10.011","journal-title":"Neoplasia"},{"key":"5269_CR23","doi-asserted-by":"publisher","DOI":"10.1099\/jgv.0.001540","author":"JA Scarth","year":"2021","unstructured":"Scarth JA, Patterson MR, Morgan EL, Maxdonald A (2021) The human papillomavirus oncoproteins: a review of the host path-ways targeted on the road to transformation. Microbiol Soc. https:\/\/doi.org\/10.1099\/jgv.0.001540","journal-title":"Microbiol Soc"},{"issue":"6","key":"5269_CR24","doi-asserted-by":"publisher","first-page":"1512","DOI":"10.1158\/1078-0432.CCR-11-3326","volume":"19","author":"AF Schott","year":"2013","unstructured":"Schott AF, Landis MD, Dontu G, Griffith KA, Layman RM, Krop I, Paskett LA, Wong H, Dobrolecki LE, Lewis MT, Froeh-lich AM, Paranilam J, Hayes DF, Wicha MS, Chang JC (2013) Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors. Clin Cancer Res 19(6):1512\u20131524. https:\/\/doi.org\/10.1158\/1078-0432.CCR-11-3326","journal-title":"Clin Cancer Res"},{"issue":"4","key":"5269_CR25","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1158\/0008-5472.CAN-13-1259","volume":"74","author":"W Sun","year":"2014","unstructured":"Sun W, Gaykalova DA, Ochs MF, Mambo E, Arnaoutakis D, Liu Y, Loyo M, Agrawal N, Howard J, Li R, Ahn S, Fertig E, Sidransky D, Houghton J, Buddavarapu K, Sanford T, Choudhary A, Darden W, Adai A, Latham G, Bishop J, Sharma R, Westra WH, Hennessey P, Chung CH, Califano JA (2014) Activation of the NOTCH pathway in head and neck cancer. Cancer Res 74(4):1091\u20131104. https:\/\/doi.org\/10.1158\/0008-5472.CAN-13-1259","journal-title":"Cancer Res"},{"key":"5269_CR26","unstructured":"Uniprot, \"Q96BI3 \u00b7 APH1A_HUMAN,\" UniProt. Available: https:\/\/www.uniprot.org\/uniprotkb\/Q96BI3\/entry. (accessed on Jan 2nd 2023)"},{"key":"5269_CR27","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.virol.2015.02.002","volume":"478","author":"PA Vliet-Gregg","year":"2015","unstructured":"Vliet-Gregg PA, Hamilton JR, Katzenellenbogen RA (2015) Human papillomavirus 16E6 and NFX1-123 potentiate Notch signaling and differentiation without activating cellular arrest. Virology 478:50\u201360. https:\/\/doi.org\/10.1016\/j.virol.2015.02.002","journal-title":"Virology"},{"key":"5269_CR28","unstructured":"World Health Organisation (2023) Cancer Tomorrow,\" Global cancer observatory. Available: https:\/\/gco.iarc.fr\/. (accessed on Jan 2nd 2023)"},{"key":"5269_CR29","unstructured":"Yuwei L, Kaiqi L, Tianyi W, Weirong K, Weiping W (2022) Carrier-free nanodrugs for stemness inhibition-enhanced photodynamic therapy. Wiley Online Library. https:\/\/onlinelibrary.wiley.com (accessed on Jan 2nd 2023)"},{"issue":"1","key":"5269_CR30","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.ccr.2005.06.004","volume":"8","author":"Q Zeng","year":"2005","unstructured":"Zeng Q, Li S, Chepeha DB, Giordano TJ, Li J, Zhang H, Polverini PJ, Nor J, Kitajewski J, Wang CY (2005) Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell 8(1):13\u201323. https:\/\/doi.org\/10.1016\/j.ccr.2005.06.004","journal-title":"Cancer Cell"}],"container-title":["Journal of Cancer Research and Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00432-023-05269-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00432-023-05269-x\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00432-023-05269-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,26]],"date-time":"2023-10-26T11:14:54Z","timestamp":1698318894000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00432-023-05269-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,16]]},"references-count":30,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2023,11]]}},"alternative-id":["5269"],"URL":"https:\/\/doi.org\/10.1007\/s00432-023-05269-x","relation":{},"ISSN":["0171-5216","1432-1335"],"issn-type":[{"type":"print","value":"0171-5216"},{"type":"electronic","value":"1432-1335"}],"subject":[],"published":{"date-parts":[[2023,8,16]]},"assertion":[{"value":"9 July 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 August 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 August 2023","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 conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}