{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T02:49:51Z","timestamp":1788058191787,"version":"build-2784847793"},"reference-count":45,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T00:00:00Z","timestamp":1656547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Georgius Agricola Stiftung Ruhr","award":["01.017.-92903"],"award-info":[{"award-number":["01.017.-92903"]}]},{"name":"DFG Open Access Publication Funds of the Ruhr-Universit\u00e4t Bochum","award":["01.017.-92903"],"award-info":[{"award-number":["01.017.-92903"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Malignant peritoneal mesothelioma is a rare tumor entity. Although cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have increased overall survival, its prognosis remains poor. Established chemotherapeutics include mitomycin C (MMC) and cisplatin (CP), both characterized by severe side effects. GP-2250 is a novel antineoplastic agent, currently under clinical investigation. This in vitro study aims to investigate effects of GP-2250 including combinations with CP and MMC on malignant mesothelioma. JL-1 and MSTO-211H mesothelioma cell lines were treated with increasing doses of GP-2250, CP, MMC and combination therapies of GP-2250 + CP\/MMC. Microscopic effects were documented, and a flow-cytometric apoptosis\/necrosis assay was performed. Synergistic and antagonistic effects were analyzed by computing the combination index by Chou-Talalay. GP-2250 showed an antiadhesive effect on JL-1 and MSTO-211H spheroids. It had a dose-dependent cytotoxic effect on both monolayer and spheroid cultured cells, inducing apoptosis and necrosis. Combination treatments of GP-2250 with MMC and CP led to significant reductions of the effective doses of CP\/MMC. Synergistic and additive effects were observed. GP-2250 showed promising antineoplastic effects on malignant mesothelioma cells in vitro especially in combination with CP\/MMC. This forms the basis for further in vivo and clinical investigations in order to broaden treatment options.<\/jats:p>","DOI":"10.3390\/ijms23137293","type":"journal-article","created":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T00:21:50Z","timestamp":1656634910000},"page":"7293","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Substance GP-2250 as a New Therapeutic Agent for Malignant Peritoneal Mesothelioma\u2014A 3-D In Vitro Study"],"prefix":"10.3390","volume":"23","author":[{"given":"Claudia","family":"Baron","sequence":"first","affiliation":[{"name":"Department of General-, Visceral-, Thoracic- and Vascular Surgery, Prosper Hospital, Stiftungsklinikum PROSELIS, 45659 Recklinghausen, Germany"},{"name":"Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9414-9807","authenticated-orcid":false,"given":"Marie","family":"Buchholz","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2169-9880","authenticated-orcid":false,"given":"Britta","family":"Majchrzak-Stiller","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2259-2337","authenticated-orcid":false,"given":"Ilka","family":"Peters","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Fein","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Geistlich Pharma AG, CH-6110 Wolhusen, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waldemar","family":"Uhl","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2913-9690","authenticated-orcid":false,"given":"Philipp","family":"H\u00f6hn","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7847-6138","authenticated-orcid":false,"given":"Johanna","family":"Strotmann","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Braumann","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany"},{"name":"Department of General, Visceral and Vascular Surgery, Evangelische Kliniken Gelsenkirchen, Akademisches Lehrkrankenhaus der Universit\u00e4t Duisburg-Essen, 45878 Gelsenkirchen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1007\/s00292-017-0364-z","article-title":"Mesotheliom","volume":"38","author":"Tischoff","year":"2017","journal-title":"Pathologe"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Hiriart, E., Deepe, R., and Wessels, A. (2019). Mesothelium and Malignant Mesothelioma. JDB, 7.","DOI":"10.3390\/jdb7020007"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1046\/j.1440-1843.2002.00404.x","article-title":"Mesothelial cells: Their structure, function and role in serosal repair","volume":"7","author":"Mutsaers","year":"2002","journal-title":"Respirology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.freeradbiomed.2015.05.002","article-title":"Malignant mesothelioma as an oxidative stress-induced cancer: An update","volume":"86","author":"Chew","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref_5","first-page":"659","article-title":"Malignant peritoneal mesothelioma: Clinical aspects, and therapeutic perspectives","volume":"31","author":"Boussios","year":"2018","journal-title":"AOG"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.12688\/f1000research.15512.2","article-title":"Factors influencing malignant mesothelioma survival: A retrospective review of the National Mesothelioma Virtual Bank cohort","volume":"7","author":"Amin","year":"2018","journal-title":"F1000Research"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"537","DOI":"10.21037\/tlcr.2018.10.04","article-title":"Malignant peritoneal mesothelioma: A review","volume":"7","author":"Broeckx","year":"2018","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4231","DOI":"10.2147\/CMAR.S170300","article-title":"Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal mesothelioma: Patient selection and special considerations","volume":"11","author":"Enomoto","year":"2019","journal-title":"Cancer Manag. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"599","DOI":"10.21037\/tlcr.2018.08.03","article-title":"Update on the management of malignant peritoneal mesothelioma","volume":"7","author":"Sugarbaker","year":"2018","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1245\/s10434-008-0219-1","article-title":"Diffuse malignant peritoneal mesothelioma: Failure analysis following cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC)","volume":"16","author":"Baratti","year":"2009","journal-title":"Ann. Surg. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Rau, B., Piso, P., and K\u00f6nigsrainer, A. (2018). Peritoneale Tumoren und Metastasen, Springer.","DOI":"10.1007\/978-3-662-54500-3"},{"key":"ref_12","first-page":"29","article-title":"Surgical technology and pharmacology of hyperthermic perioperative chemotherapy","volume":"7","author":"Sugarbaker","year":"2016","journal-title":"J. Gastrointest. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00384-014-2029-1","article-title":"Advances in malignant peritoneal mesothelioma","volume":"30","author":"Cao","year":"2015","journal-title":"Int. J. Colorectal. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3271","DOI":"10.1245\/s10434-018-6631-2","article-title":"Impact of Combination Chemotherapy in Peritoneal Mesothelioma Hyperthermic Intraperitoneal Chemotherapy (HIPEC): The RENAPE Study","volume":"25","author":"Malgras","year":"2018","journal-title":"Ann. Surg. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Buchholz, M., Majchrzak-Stiller, B., Hahn, S., Vangala, D., Pfirrmann, R.W., Uhl, W., Braumann, C., and Chromik, A.M. (2017). Innovative substance 2250 as a highly promising anti-neoplastic agent in malignant pancreatic carcinoma\u2014In vitro and in vivo. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3204-x"},{"key":"ref_16","unstructured":"Geistlich Pharma, A.G. (2020, December 08). Translational Drug Development. A Phase 1\/2 Trial of GP-2250 in Combination with Gemcitabine in Pancreatic Adenocarcinoma after FOLFIRINOX Chemotherapy: NCT03854110, GP-2250-1001, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03854110."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Barisam, M., Saidi, M., Kashaninejad, N., and Nguyen, N.-T. (2018). Prediction of Necrotic Core and Hypoxic Zone of Multicellular Spheroids in a Microbioreactor with a U-Shaped Barrier. Micromachines, 9.","DOI":"10.3390\/mi9030094"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/S1040-8428(00)00077-9","article-title":"Spheroids and cell survival","volume":"36","author":"Bates","year":"2000","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1111\/brv.12293","article-title":"Three-dimensional cell culture model utilization in cancer stem cell research","volume":"92","author":"Bielecka","year":"2017","journal-title":"Biol. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Desmaison, A., Frongia, C., Grenier, K., Ducommun, B., and Lobjois, V. (2013). Mechanical stress impairs mitosis progression in multi-cellular tumor spheroids. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0080447"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1111\/cas.13155","article-title":"Tumor-derived spheroids: Relevance to cancer stem cells and clinical applications","volume":"108","author":"Ishiguro","year":"2017","journal-title":"Cancer Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1080\/09553000701727531","article-title":"Experimental anti-tumor therapy in 3-D: Spheroids--old hat or new challenge?","volume":"83","author":"Friedrich","year":"2007","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1186\/s13046-017-0570-9","article-title":"Modeling tumor cell adaptations to hypoxia in multicellular tumor spheroids","volume":"36","author":"Riffle","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2240","DOI":"10.1016\/j.ejca.2011.04.032","article-title":"Curcumin improves MMC-based chemotherapy by simultaneously sensitising cancer cells to MMC and reducing MMC-associated side-effects","volume":"47","author":"Zhou","year":"2011","journal-title":"Eur. J. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Cortes-Dericks, L., Froment, L., Boesch, R., Schmid, R.A., and Karoubi, G. (2014). Cisplatin-resistant cells in malignant pleural mesothelioma cell lines show ALDHhighCD44+ phenotype and sphere-forming capacity. BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-304"},{"key":"ref_26","unstructured":"Buchholz, M. (2016). Vergleichende Anti-Neoplastische Charakterisierung der Substanz 2250 mit ihrer Muttersubstanz Taurolidin\u2014In Vitro und In Vivo. [Dissertation, Ruhr-Universit\u00e4t Bochum]."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.tibtech.2012.12.003","article-title":"Spheroid culture as a tool for creating 3D complex tissues","volume":"31","author":"Fennema","year":"2013","journal-title":"Trends Biotechnol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ryu, N.-E., Lee, S.-H., and Park, H. (2019). Spheroid Culture System Methods and Applications for Mesenchymal Stem Cells. Cells, 8.","DOI":"10.3390\/cells8121620"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1111\/j.1365-2184.2012.00845.x","article-title":"Programmed cell death pathways in cancer: A review of apoptosis, autophagy and programmed necrosis","volume":"45","author":"Ouyang","year":"2012","journal-title":"Cell Prolif."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1038\/nm1196-1204","article-title":"Impact of the cyclin-dependent kinase inhibitor p27Kip1 on resistance of tumor cells to anticancer agents","volume":"2","author":"Rak","year":"1996","journal-title":"Nat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1093\/jnci\/86.13.975","article-title":"Rapid acquisition of multicellular drug resistance after a single exposure of mammary tumor cells to antitumor alkylating agents","volume":"86","author":"Graham","year":"1994","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3294","DOI":"10.1073\/pnas.90.8.3294","article-title":"Acquired multicellular-mediated resistance to alkylating agents in cancer","volume":"90","author":"Kobayashi","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","unstructured":"Sinawe, H., and Casadesus, D. (2021). Mitomycin. StatPearls [Internet], StatPearls Publishing."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1042\/bse0340191","article-title":"Cisplatin","volume":"34","author":"Trimmer","year":"1999","journal-title":"Essays Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1200\/JCO.1996.14.3.1007","article-title":"Chemotherapy in malignant pleural mesothelioma. A review","volume":"14","author":"Ong","year":"1996","journal-title":"J. Clin. Oncol."},{"key":"ref_36","first-page":"1688","article-title":"Experimental and Clinical Activity of Mitomycin C and c\/s- Diamminedichloroplatinum in Malignant Mesothelioma","volume":"44","author":"Chahinian","year":"1984","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1002\/jso.21787","article-title":"Diffuse malignant peritoneal mesothelioma: Systematic review of clinical management and biological research","volume":"103","author":"Baratti","year":"2011","journal-title":"J. Surg. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1080\/02656736.2017.1345014","article-title":"Platinum agents and mitomycin C-specific complications in cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC)","volume":"34","author":"Tan","year":"2018","journal-title":"Int. J. Hyperth."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"159","DOI":"10.2147\/DDDT.S150201","article-title":"Diminishing the side effect of mitomycin C by using pH-sensitive liposomes: In vitro characterization and in vivo pharmacokinetics","volume":"12","author":"Fang","year":"2018","journal-title":"DDDT"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/nrc1893","article-title":"Drug penetration in solid tumours","volume":"6","author":"Minchinton","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_41","first-page":"437","article-title":"Putative cancer stem cells in malignant pleural mesothelioma show resistance to cisplatin and pemetrexed","volume":"37","author":"Carboni","year":"2010","journal-title":"Int. J. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1080\/02656736.2017.1291999","article-title":"Drugs, doses, and durations of intraperitoneal chemotherapy: Standardising HIPEC and EPIC for colorectal, appendiceal, gastric, ovarian peritoneal surface malignancies and peritoneal mesothelioma","volume":"33","author":"Lemoine","year":"2017","journal-title":"Int. J. Hyperth."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.ejphar.2014.07.025","article-title":"Cisplatin in cancer therapy: Molecular mechanisms of action","volume":"740","author":"Dasari","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1124\/pr.58.3.10","article-title":"Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies","volume":"58","author":"Chou","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_45","first-page":"294","article-title":"Rational approach to the clinical protocol design for drug combinations: A review","volume":"41","author":"Chang","year":"2000","journal-title":"Acta Paediatr. Taiwanica Taiwan Er Ke Yi Xue Hui Za Zhi"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/13\/7293\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:41:17Z","timestamp":1760139677000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/13\/7293"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,30]]},"references-count":45,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ijms23137293"],"URL":"https:\/\/doi.org\/10.3390\/ijms23137293","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,30]]}}}