{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T13:07:50Z","timestamp":1779455270754,"version":"3.53.1"},"reference-count":48,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003065","name":"University of Vienna","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003065","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Chemother Pharmacol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>BOLD-100, a ruthenium(III) prodrug also known as KP1339, is currently under clinical investigation for its suitability as a co-therapeutic anticancer drug. Unlike platinum-based chemotherapeutics, it has unique non-DNA targets, mainly GRP78, an enzyme responsible for signaling related to protein folding in the ER. Inhibition of this key mediator of the \u201cunfolded protein response\u201d may lead to cell death eventually. The purpose of this study was to assess in vitro the impact of BOLD-100 combinations with oxaliplatin, 5-FU, cisplatin or SN38 in multicellular tumor spheroids (MCTSs) compared to single-drug treatments. Gastric (MKN45, NCI-N87) and colorectal cancer (HCT116, HT29) cell lines were chosen, corresponding to the clinical trial in which patients with tumors of these origins are being treated. Biological effects investigated in this study include cytotoxic activity, synergism\/antagonism based on Chou and Talalay\u2019s algorithm, formation of reactive oxygen species (ROS) and induction of apoptosis and necrosis. Cytotoxicity tests showed vastly different chemosensitivities in MCTSs of the same tumor origin. In both tumor entities, partially synergistic effects were revealed when BOLD-100 was combined with the drugs mentioned above. The DCFH-DA assay suggested consistent increases of ROS levels after treatment with oxaliplatin and, with restrictions, its combination with BOLD-100. Apoptosis and necrosis were induced in the spheroid models by single-drug and combined treatment, with no hints at antagonism in the combination settings. In conclusion, these findings emphasize the potential of BOLD-100 for combination therapy of gastric and colorectal cancers.<\/jats:p>","DOI":"10.1007\/s00280-026-04902-z","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T12:33:53Z","timestamp":1779453233000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Combinational studies of BOLD-100\/KP1339 with established chemotherapeutics in gastrointestinal multicellular tumor spheroids"],"prefix":"10.1007","volume":"96","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5305-2048","authenticated-orcid":false,"given":"Dominik","family":"Wenisch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Slavica","family":"\u017ddravac","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7945-1426","authenticated-orcid":false,"given":"Michael A.","family":"Jakupec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4926-3261","authenticated-orcid":false,"given":"Franz","family":"Jirsa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0877-1822","authenticated-orcid":false,"given":"Bernhard K.","family":"Keppler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"issue":"1","key":"4902_CR1","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/s41568-020-00308-y","volume":"21","author":"S Rottenberg","year":"2021","unstructured":"Rottenberg S, Disler C, Perego P (2021) The rediscovery of platinum-based cancer therapy. Nat Rev Cancer 21(1):37\u201350. https:\/\/doi.org\/10.1038\/s41568-020-00308-y","journal-title":"Nat Rev Cancer"},{"issue":"23","key":"4902_CR2","doi-asserted-by":"publisher","first-page":"7848","DOI":"10.1039\/c8dt90088d","volume":"47","author":"R Oun","year":"2018","unstructured":"Oun R, Moussa YE, Wheate NJ (2018) The side effects of platinum-based chemotherapy drugs: a review for chemists. Dalton Trans 47(23):7848. https:\/\/doi.org\/10.1039\/c8dt90088d","journal-title":"Dalton Trans"},{"issue":"9","key":"4902_CR3","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13092073","volume":"13","author":"B K\u00f6berle","year":"2021","unstructured":"K\u00f6berle B, Schoch S (2021) Platinum complexes in colorectal cancer and other solid tumors. Cancers 2073. https:\/\/doi.org\/10.3390\/cancers13092073","journal-title":"Cancers"},{"key":"4902_CR4","doi-asserted-by":"publisher","unstructured":"Tsai HJ, Yang SH, Hsiao CF, Kao HF, Su YY, Shan YS, Yen CJ, Du JS, Hsu C, Wu IC, Chen LT (2024) A phase 1 study of biweekly nab-paclitaxel\/oxaliplatin\/S-1\/LV for advanced upper gastrointestinal cancers: TCOG T1216 study. Oncologist 29(10):e1396\u2013e1405. https:\/\/doi.org\/10.1093\/oncolo\/oyae109","DOI":"10.1093\/oncolo\/oyae109"},{"issue":"1","key":"4902_CR5","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1186\/s12957-025-03723-3","volume":"23","author":"FY Wang","year":"2025","unstructured":"Wang FY, Huang XM, Cao YQ, Cao J, Song M, Fang ZJ, Huang XE (2025) Comparison of PSOX (paclitaxel, oxaliplatin, S-1) and SOX (oxaliplatin, S-1) as postoperative adjuvant chemotherapy for stage II-III gastric cancer. World J Surg Oncol 23(1):75. https:\/\/doi.org\/10.1186\/s12957-025-03723-3","journal-title":"World J Surg Oncol"},{"issue":"12","key":"4902_CR6","doi-asserted-by":"publisher","first-page":"5567","DOI":"10.1039\/D4DT00245H","volume":"53","author":"P Getreuer","year":"2024","unstructured":"Getreuer P, Marretta L, Toyoglu E, D\u00f6m\u00f6t\u00f6r O, Hejl M, Prado-Roller A, Cseh K, Legin AA, Jakupec MA, Barone G, Terenzi A, Keppler BK, Kandioller W (2024) Investigating the anticancer potential of 4-phenylthiazole derived Ru(II) and Os(II) metalacycles. Dalton Trans 53(12):5567\u20135579. https:\/\/doi.org\/10.1039\/D4DT00245H","journal-title":"Dalton Trans"},{"issue":"13","key":"4902_CR7","doi-asserted-by":"publisher","first-page":"9805","DOI":"10.1021\/acs.inorgchem.1c01083","volume":"60","author":"H Geisler","year":"2021","unstructured":"Geisler H, Westermayr J, Cseh K, Wenisch D, Fuchs V, Harringer S, Plutzar S, Gajic N, Hejl M, Jakupec MA, Marquetand P, Kandioller W (2021) Tridentate 3-substituted naphthoquinone ruthenium arene complexes: synthesis, characterization, aqueous behavior, and theoretical and biological studies. Inorg Chem 60(13):9805\u20139819. https:\/\/doi.org\/10.1021\/acs.inorgchem.1c01083","journal-title":"Inorg Chem"},{"issue":"7","key":"4902_CR8","doi-asserted-by":"publisher","DOI":"10.1002\/open.202200019","volume":"11","author":"H Geisler","year":"2022","unstructured":"Geisler H, Harringer S, Wenisch D, Urban R, Jakupec MA, Kandioller W, Keppler BK (2022) Systematic study on the cytotoxic potency of commonly used dimeric metal precursors in human cancer cell lines. ChemistryOpen 11(7):e202200019. https:\/\/doi.org\/10.1002\/open.202200019","journal-title":"ChemistryOpen"},{"key":"4902_CR9","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2022.40.16_suppl.3031","volume":"40","author":"JL Spratlin","year":"2022","unstructured":"Spratlin JL, O\u00b4Kane G, Goodwin RA, McWhirter E, Thompson D, Halani K, Jones M, Snow M, McAllister ER, Machado A, Lemmerick Y, Pankovich J (2022) BOLD-100-001 (TRIO039): a phase 1b dose-escalation study of BOLD-100 in combination with FOLFOX chemotherapy in patients with advanced gastrointestinal solid cancers: interim safety, tolerability, and efficacy. J Clin Oncol 40:3031. https:\/\/doi.org\/10.1200\/JCO.2022.40.16_suppl.3031","journal-title":"J Clin Oncol"},{"key":"4902_CR10","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2024.42.3_suppl.143","volume":"42","author":"JL Spratlin","year":"2024","unstructured":"Spratlin JL, O\u2019Kane GM, Oh D-Y, Rha SY, McWhirter E, Elimova E, Kavan P, Choi MK, Kim DW, Goodwin RA, Hecht JR, Kim ST, Koo DH, Halani K, McAllister ER, Jones M, Snow M, Lemmerick Y, Spera G, Pankovich J (2024) BOLD-100-001 (TRIO039): a phase 2 study of BOLD-100 in combination with FOLFOX in patients with advanced mCRC previously treated with FOLFOX\/CAPOX\u2014efficacy and safety analysis. J Clin Oncol 42:143. https:\/\/doi.org\/10.1200\/JCO.2024.42.3_suppl.143","journal-title":"J Clin Oncol"},{"key":"4902_CR11","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2024.42.16_suppl.4059","volume":"42","author":"J Spratlin","year":"2024","unstructured":"Spratlin J, Rha SY, O\u2019Kane GM, Oh D-Y, Elimova E, Goodwin RA, Kim ST, Koo DH, McAllister ER, Jones M, Snow M, Lemmerick Y, Spera G, Pankovich J (2024) A phase 2 study of BOLD-100 in combination with FOLFOX chemotherapy in patients with advanced gastric cancer: efficacy and safety analysis (BOLD-100-001). J Clin Oncol 42:4059. https:\/\/doi.org\/10.1200\/JCO.2024.42.16_suppl.4059","journal-title":"J Clin Oncol"},{"key":"4902_CR12","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2024.42.16_suppl.4115","volume":"42","author":"GM O'Kane","year":"2024","unstructured":"O\u2019Kane GM, Oh DY, Spratlin J, Rha SY, Elimova E, Kavan P, Goodwin RA, Cha Y, Kim ST, McAllister ER, Jones M, Snow M, Lemmerick Y, Spera G, Pankovich J (2024) A phase 2 study of BOLD-100 in combination with FOLFOX chemotherapy in patients with pretreated advanced biliary tract cancer: efficacy and safety analysis (BOLD-100-001). J Clin Oncol 42:4115. https:\/\/doi.org\/10.1200\/JCO.2024.42.16_suppl.4115","journal-title":"J Clin Oncol"},{"issue":"9","key":"4902_CR13","doi-asserted-by":"publisher","DOI":"10.3390\/biology10090854","volume":"10","author":"S Azwar","year":"2021","unstructured":"Azwar S, Seow HF, Abdullah M, Faisal Jabar M, Mohtarrudin N (2021) Recent updates on mechanisms of resistance to 5-Fluorouracil and reversal strategies in colon cancer treatment. Biology (Basel) 854. https:\/\/doi.org\/10.3390\/biology10090854","journal-title":"Biology (Basel)"},{"issue":"20","key":"4902_CR14","doi-asserted-by":"publisher","first-page":"2006","DOI":"10.18632\/oncotarget.28075","volume":"12","author":"L Carlsen","year":"2021","unstructured":"Carlsen L, Schorl C, Huntington K, Hernandez-Borrero L, Jhaveri A, Zhang S, Zhou L, El-Deiry WS (2021) Pan-drug and drug-specific mechanisms of 5-FU, irinotecan (CPT-11), oxaliplatin, and cisplatin identified by comparison of transcriptomic and cytokine responses of colorectal cancer cells. Oncotarget 12(20):2006\u20132021. https:\/\/doi.org\/10.18632\/oncotarget.28075","journal-title":"Oncotarget"},{"issue":"10","key":"4902_CR15","doi-asserted-by":"publisher","first-page":"5063","DOI":"10.1002\/anie.202015962","volume":"60","author":"B Neuditschko","year":"2021","unstructured":"Neuditschko B, Legin AA, Baier D, Schintlmeister A, Reipert S, Wagner M, Keppler BK, Berger W, Meier-Menches SM, Gerner C (2021) Interaction with ribosomal proteins accompanies stress induction of the anticancer metallodrug BOLD-100\/KP1339 in the endoplasmic reticulum. Angew Chem Int Ed Engl 60(10):5063\u20138. https:\/\/doi.org\/10.1002\/anie.202015962","journal-title":"Angew Chem Int Ed Engl"},{"issue":"3","key":"4902_CR16","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1007\/s10637-016-0337-8","volume":"34","author":"LS Flocke","year":"2016","unstructured":"Flocke LS, Trondl R, Jakupec MA, Keppler BK (2016) Molecular mode of action of NKP-1339 - a clinically investigated ruthenium-based drug - involves ER- and ROS-related effects in colon carcinoma cell lines. Invest New Drugs 34(3):261\u2013268. https:\/\/doi.org\/10.1007\/s10637-016-0337-8","journal-title":"Invest New Drugs"},{"key":"4902_CR17","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14020238","author":"D Baier","year":"2022","unstructured":"Baier D, Schoenhacker-Alte B, Rusz M, Pirker C, Mohr T, Mendrina T, Kirchhofer D, Meier-Menches SM, Hohenwallner K, Schaier M, Rampler E, Koellensperger G, Heffeter P, Keppler B, Berger W (2022) The anticancer Ruthenium compound BOLD-100 targets glycolysis and generates a metabolic vulnerability towards glucose deprivation. Pharmaceutics. https:\/\/doi.org\/10.3390\/pharmaceutics14020238","journal-title":"Pharmaceutics"},{"issue":"6","key":"4902_CR18","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1039\/c9mt00051h","volume":"11","author":"D Wernitznig","year":"2019","unstructured":"Wernitznig D, Kiakos K, Del Favero G, Harrer N, Machat H, Osswald A, Jakupec MA, Wernitznig A, Sommergruber W, Keppler BK (2019) First-in-class ruthenium anticancer drug (KP1339\/IT-139) induces an immunogenic cell death signature in colorectal spheroids in vitro. Metallomics 11(6):1044\u20131048. https:\/\/doi.org\/10.1039\/c9mt00051h","journal-title":"Metallomics"},{"issue":"6","key":"4902_CR19","doi-asserted-by":"publisher","DOI":"10.1136\/esmoopen-2016-000154","volume":"1","author":"HA Burris","year":"2016","unstructured":"Burris HA, Bakewell S, Bendell JC, Infante J, Jones SF, Spigel DR, Weiss GJ, Ramanathan RK, Ogden A, Von Hoff D (2016) Safety and activity of IT-139, a ruthenium-based compound, in patients with advanced solid tumours: a first-in-human, open-label, dose-escalation phase I study with expansion cohort. ESMO Open 1(6):e000154. https:\/\/doi.org\/10.1136\/esmoopen-2016-000154","journal-title":"ESMO Open"},{"issue":"4","key":"4902_CR20","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1053\/gast.2001.27989","volume":"121","author":"B Mayer","year":"2001","unstructured":"Mayer B, Klement G, Kaneko M, Man S, Jothy S, Rak J, Kerbel RS (2001) Multicellular gastric cancer spheroids recapitulate growth pattern and differentiation phenotype of human gastric carcinomas. Gastroenterology 121(4):839\u201352. https:\/\/doi.org\/10.1053\/gast.2001.27989","journal-title":"Gastroenterology"},{"issue":"8","key":"4902_CR21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1007961","volume":"16","author":"JA Bull","year":"2020","unstructured":"Bull JA, Mech F, Quaiser T, Waters SL, Byrne HM (2020) Mathematical modelling reveals cellular dynamics within tumour spheroids. PLoS Comput Biol 16(8):e1007961. https:\/\/doi.org\/10.1371\/journal.pcbi.1007961","journal-title":"PLoS Comput Biol"},{"issue":"1","key":"4902_CR22","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-023-04778-0","volume":"21","author":"C Yu","year":"2023","unstructured":"Yu C, Huang F, Wang K, Liu M, Chow WA, Ling X, Li F, Causey JL, Huang X, Cook-Wiens G, Cui X (2023) Single protein encapsulated SN38 for tumor-targeting treatment. J Transl Med 21(1):897. https:\/\/doi.org\/10.1186\/s12967-023-04778-0","journal-title":"J Transl Med"},{"issue":"12","key":"4902_CR23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0083022","volume":"8","author":"F Petrelli","year":"2013","unstructured":"Petrelli F, Zaniboni A, Coinu A, Cabiddu M, Ghilardi M, Sgroi G, Barni S (2013) Cisplatin or not in advanced gastric cancer: a systematic review and meta-analysis. PLoS One 8(12):e83022. https:\/\/doi.org\/10.1371\/journal.pone.0083022","journal-title":"PLoS One"},{"key":"4902_CR24","doi-asserted-by":"publisher","first-page":"1493","DOI":"10.3892\/or.19.6.1493","volume":"19","author":"X-F Sun","year":"2008","unstructured":"Sun X-F, Ferreud L, Svanvik J, Holmlund B, Wallin \u00c5 (2008) Anticancer effect of SN-38 on colon cancer cell lines with different metastatic potential. Oncol Rep 19:1493\u20131498. https:\/\/doi.org\/10.3892\/or.19.6.1493","journal-title":"Oncol Rep"},{"issue":"13","key":"4902_CR25","doi-asserted-by":"publisher","first-page":"16948","DOI":"10.18632\/oncotarget.7659","volume":"7","author":"S Raghavan","year":"2016","unstructured":"Raghavan S, Mehta P, Horst EN, Ward MR, Rowley KR, Mehta G (2016) Comparative analysis of tumor spheroid generation techniques for differential in vitro drug toxicity. Oncotarget 7(13):16948\u201316961. https:\/\/doi.org\/10.18632\/oncotarget.7659","journal-title":"Oncotarget"},{"issue":"3","key":"4902_CR26","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1038\/nprot.2008.226","volume":"4","author":"J Friedrich","year":"2009","unstructured":"Friedrich J, Seidel C, Ebner R, Kunz-Schughart LA (2009) Spheroid-based drug screen: considerations and practical approach. Nat Protoc 4(3):309\u2013324. https:\/\/doi.org\/10.1038\/nprot.2008.226","journal-title":"Nat Protoc"},{"key":"4902_CR27","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/0065-2571(84)90007-4","volume":"22","author":"TC Chou","year":"1984","unstructured":"Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27\u201355. https:\/\/doi.org\/10.1016\/0065-2571(84)90007-4","journal-title":"Adv Enzyme Regul"},{"issue":"5","key":"4902_CR28","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.18070","volume":"28","author":"B Qu","year":"2024","unstructured":"Qu B, Liu J, Peng Z, Xiao Z, Li S, Wu J, Li S, Luo J (2024) Macrophages enhance cisplatin resistance in gastric cancer through the transfer of circTEX2. J Cell Mol Med 28(5):e18070. https:\/\/doi.org\/10.1111\/jcmm.18070","journal-title":"J Cell Mol Med"},{"issue":"24","key":"4902_CR29","doi-asserted-by":"publisher","first-page":"4223","DOI":"10.1002\/cncr.28358","volume":"119","author":"CR Garrett","year":"2013","unstructured":"Garrett CR, Bekaii-Saab TS, Ryan T, Fisher GA, Clive S, Kavan P, Shacham-Shmueli E, Buchbinder A, Goldberg RM (2013) Randomized phase 2 study of pegylated SN-38 (EZN-2208) or irinotecan plus cetuximab in patients with advanced colorectal cancer. Cancer 119(24):4223\u20134230. https:\/\/doi.org\/10.1002\/cncr.28358","journal-title":"Cancer"},{"issue":"10","key":"4902_CR30","doi-asserted-by":"publisher","first-page":"3945","DOI":"10.1111\/cas.15068","volume":"112","author":"H Nakamura","year":"2021","unstructured":"Nakamura H, Takada K (2021) Reactive oxygen species in cancer: current findings and future directions. Cancer Sci 112(10):3945\u20133952. https:\/\/doi.org\/10.1111\/cas.15068","journal-title":"Cancer Sci"},{"issue":"1","key":"4902_CR31","doi-asserted-by":"publisher","DOI":"10.1208\/s12249-024-03011-5","volume":"26","author":"A Chauhan","year":"2024","unstructured":"Chauhan A, Kamal R, Bhatia R, Singh TG, Awasthi A (2024) From bench to bedside: ROS-responsive nanocarriers in cancer therapy. AAPS PharmSciTech 26(1):10. https:\/\/doi.org\/10.1208\/s12249-024-03011-5","journal-title":"AAPS PharmSciTech"},{"issue":"31","key":"4902_CR32","doi-asserted-by":"publisher","first-page":"33888","DOI":"10.1021\/acsomega.4c03865","volume":"9","author":"W Songoen","year":"2024","unstructured":"Songoen W, Wenisch D, Jakupec MA, Phanchai W, Sukkhaeng S, Brecker L, Schinnerl J, Tharamak S, Pluempanupat W (2024) Flavan-Benzofurans from Artocarpus lacucha: their intracellular antioxidant activity and molecular docking to glutathione reductase. ACS Omega 9(31):33888\u201333899. https:\/\/doi.org\/10.1021\/acsomega.4c03865","journal-title":"ACS Omega"},{"issue":"2","key":"4902_CR33","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1158\/1535-7163.169.3.2","volume":"3","author":"RL Hayward","year":"2004","unstructured":"Hayward RL, Macpherson JS, Cummings J, Monia BP, Smyth JF, Jodrell DI (2004) Enhanced oxaliplatin-induced apoptosis following antisense Bcl-xl down-regulation is p53 and Bax dependent: genetic evidence for specificity of the antisense effect. Mol Cancer Ther 3(2):169\u2013178. https:\/\/doi.org\/10.1158\/1535-7163.169.3.2","journal-title":"Mol Cancer Ther"},{"key":"4902_CR34","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s12885-015-1550-0","volume":"15","author":"VV Subhash","year":"2015","unstructured":"Subhash VV, Tan SH, Tan WL, Yeo MS, Xie C, Wong FY, Kiat ZY, Lim R, Yong WP (2015) GTSE1 expression represses apoptotic signaling and confers cisplatin resistance in gastric cancer cells. BMC Cancer 15:550. https:\/\/doi.org\/10.1186\/s12885-015-1550-0","journal-title":"BMC Cancer"},{"issue":"1","key":"4902_CR35","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-022-02717-5","volume":"22","author":"P Su","year":"2022","unstructured":"Su P, Jiang L, Zhang Y, Yu T, Kang W, Liu Y, Yu J (2022) Crosstalk between tumor-associated macrophages and tumor cells promotes chemoresistance via CXCL5\/PI3K\/AKT\/mTOR pathway in gastric cancer. Cancer Cell Int 22(1):290. https:\/\/doi.org\/10.1186\/s12935-022-02717-5","journal-title":"Cancer Cell Int"},{"issue":"1","key":"4902_CR36","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1186\/s12935-021-01853-8","volume":"21","author":"SJ Han","year":"2021","unstructured":"Han SJ, Kwon S, Kim KS (2021) Challenges of applying multicellular tumor spheroids in preclinical phase. Cancer Cell Int 21(1):152. https:\/\/doi.org\/10.1186\/s12935-021-01853-8","journal-title":"Cancer Cell Int"},{"issue":"10","key":"4902_CR37","doi-asserted-by":"publisher","first-page":"6922","DOI":"10.1021\/acs.jmedchem.3c00322","volume":"66","author":"NA Yusoh","year":"2023","unstructured":"Yusoh NA, Tiley PR, James SD, Harun SN, Thomas JA, Saad N, Hii LW, Chia SL, Gill MR, Ahmad H (2023) Discovery of Ruthenium(II) metallocompound and Olaparib synergy for cancer combination therapy. J Med Chem 66(10):6922\u20136937. https:\/\/doi.org\/10.1021\/acs.jmedchem.3c00322","journal-title":"J Med Chem"},{"key":"4902_CR38","doi-asserted-by":"publisher","first-page":"141","DOI":"10.3389\/fonc.2020.00141","volume":"10","author":"K Lin","year":"2020","unstructured":"Lin K, Rong Y, Chen D, Zhao Z, Bo H, Qiao A, Hao X, Wang J (2020) Combination of Ruthenium complex and Doxorubicin synergistically inhibits cancer cell growth by down-regulating PI3K\/AKT signaling pathway. Front Oncol 10:141. https:\/\/doi.org\/10.3389\/fonc.2020.00141","journal-title":"Front Oncol"},{"issue":"1","key":"4902_CR39","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1093\/glycob\/cwac075","volume":"33","author":"Q Zhou","year":"2023","unstructured":"Zhou Q, Alvarez MRS, Solakyildirim K, Tena J, Serrano LMN, Lam M, Nguyen C, Tobias F, Hummon AB, Nacario RC, Lebrilla CB (2023) Multi-glycomic analysis of spheroid glycocalyx differentiates 2- and 3-dimensional cell models. Glycobiology 33(1):2\u201316. https:\/\/doi.org\/10.1093\/glycob\/cwac075","journal-title":"Glycobiology"},{"issue":"11","key":"4902_CR40","doi-asserted-by":"publisher","DOI":"10.3390\/molecules23112815","volume":"23","author":"M Balma\u00f1a","year":"2018","unstructured":"Balma\u00f1a M, Mereiter S, Diniz F, Feij\u00e3o T, Barrias CC, Reis CA (2018) Multicellular human gastric-cancer spheroids mimic the glycosylation phenotype of gastric carcinomas. Molecules 23(11):2815. https:\/\/doi.org\/10.3390\/molecules23112815","journal-title":"Molecules"},{"issue":"6","key":"4902_CR41","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1080\/15376516.2022.2029656","volume":"32","author":"M Boyles","year":"2022","unstructured":"Boyles M, Murphy F, Mueller W, Wohlleben W, Jacobsen NR, Braakhuis H, Giusti A, Stone V (2022) Development of a standard operating procedure for the DCFH2-DA acellular assessment of reactive oxygen species produced by nanomaterials. Toxicol Mech Methods 32(6):439\u2013452. https:\/\/doi.org\/10.1080\/15376516.2022.2029656","journal-title":"Toxicol Mech Methods"},{"issue":"8","key":"4902_CR42","doi-asserted-by":"publisher","DOI":"10.3390\/antiox11081424","volume":"11","author":"LR De Haan","year":"2022","unstructured":"De Haan LR, Reiniers MJ, Reeskamp LF, Belkouz A, Ao L, Cheng S, Ding B, Van Golen RF, Heger M (2022) Experimental conditions that influence the utility of 2\u20197\u2019-Dichlorodihydrofluorescein Diacetate (DCFH2-DA) as a fluorogenic biosensor for mitochondrial redox status. Antioxidants 11(8):1424. https:\/\/doi.org\/10.3390\/antiox11081424","journal-title":"Antioxidants"},{"key":"4902_CR43","doi-asserted-by":"publisher","first-page":"1796","DOI":"10.1039\/B511792E","volume":"14","author":"P Schluga","year":"2006","unstructured":"Schluga P, Hartinger CG, Egger A, Reisner E, Galanski MS, Jakupec MA, Keppler BK (2006) Redox behavior of tumor-inhibiting Ruthenium(III) complexes and effects of physiological reductants on their binding to GMP. Dalton Trans 14:1796\u2013802. https:\/\/doi.org\/10.1039\/B511792E","journal-title":"Dalton Trans"},{"issue":"12","key":"4902_CR44","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1158\/1541-7786.MCR-24-0151","volume":"22","author":"D Griffin","year":"2024","unstructured":"Griffin D, Carson R, Moss D, Sessler T, Lavin D, Tiwari VK, Karelia S, Kennedy R, Savage KI, McDade S, Carie A, Pankovich J, Bazett M, van Schaeybroeck S (2024) Ruthenium drug BOLD-100 regulates BRAFMT colorectal cancer cell apoptosis through AhR\/ROS\/ATR signaling axis modulation. Mol Cancer Res 22(12):1088\u2013101. https:\/\/doi.org\/10.1158\/1541-7786.MCR-24-0151","journal-title":"Mol Cancer Res"},{"issue":"6","key":"4902_CR45","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djv394","volume":"108","author":"V Santoro","year":"2016","unstructured":"Santoro V, Jia R, Thompson H, Nijhuis A, Jeffery R, Kiakos K, Silver AR, Hartley JA, Hochhauser D (2016) Role of reactive oxygen species in the abrogation of Oxaliplatin activity by Cetuximab in colorectal cancer. J Natl Cancer Inst 108(6):djv394. https:\/\/doi.org\/10.1093\/jnci\/djv394","journal-title":"J Natl Cancer Inst"},{"issue":"11","key":"4902_CR46","doi-asserted-by":"publisher","first-page":"6163","DOI":"10.21873\/anticanres.12969","volume":"38","author":"S Miyoshi","year":"2018","unstructured":"Miyoshi S, Tsugawa H, Matsuzaki J, Hirata K, Mori H, Saya H, Kanai T, Suzuki H (2018) Inhibiting xCT improves 5-Fluorouracil resistance of gastric cancer induced by CD44 variant 9 expression. Anticancer Res 38(11):6163\u20136170. https:\/\/doi.org\/10.21873\/anticanres.12969","journal-title":"Anticancer Res"},{"issue":"1","key":"4902_CR47","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1007\/s12032-022-01879-6","volume":"40","author":"H Wang","year":"2022","unstructured":"Wang H, Lu Y, Wang M, Shen A, Wu Y, Xu X, Li Y (2022) Src inhibitor dasatinib sensitized gastric cancer cells to cisplatin. Med Oncol 40(1):49. https:\/\/doi.org\/10.1007\/s12032-022-01879-6","journal-title":"Med Oncol"},{"key":"4902_CR48","doi-asserted-by":"publisher","first-page":"945","DOI":"10.2147\/IJN.S435407","volume":"19","author":"Q-R Qi","year":"2024","unstructured":"Qi Q-R, Tian H, Yue B-S, Zhai B-T, Zhao F (2024) Research progress of SN38 drug delivery system in cancer treatment. Int J Nanomedicine 19:945\u201364. https:\/\/doi.org\/10.2147\/IJN.S435407","journal-title":"Int J Nanomedicine"}],"container-title":["Cancer Chemotherapy and Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00280-026-04902-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00280-026-04902-z","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00280-026-04902-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T12:33:55Z","timestamp":1779453235000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00280-026-04902-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,22]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["4902"],"URL":"https:\/\/doi.org\/10.1007\/s00280-026-04902-z","relation":{},"ISSN":["1432-0843"],"issn-type":[{"value":"1432-0843","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,22]]},"assertion":[{"value":"18 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 May 2026","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 no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"57"}}