{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T00:44:03Z","timestamp":1768783443198,"version":"3.49.0"},"reference-count":47,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Association Against Cancer (AIRC)","award":["IG 24815"],"award-info":[{"award-number":["IG 24815"]}]},{"name":"Italian Association Against Cancer (AIRC)","award":["IG 23117"],"award-info":[{"award-number":["IG 23117"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver tumor. Due to its aggressive nature and resistance to conventional treatments, there is a pressing need to develop novel and more effective therapies for this deadly malignancy. Here, we explored the therapeutic potential of the DNA minor groove binders trabectedin (TRB) and lurbinectedin (LUR) for the treatment of iCCA using cell lines, spheroids, cancer-associated fibroblasts (CAFs), patient-derived tumor organoids (PDOs), and the chicken chorioallantoic membrane (CAM) in vivo model. TRB and, more substantially, LUR, significantly inhibited cell growth in iCCA cell lines, spheroids, CAFs, and PDOs at very low nanomolar concentrations. Specifically, the two drugs significantly reduced proliferation, triggered apoptosis, and caused DNA damage in iCCA cells. At the metabolic level, TRB and LUR decreased mitochondrial respiration and glycolysis. At the molecular level, the two compounds effectively downregulated the mammalian target of rapamycin complex 1 (mTORC1) and Hippo\/YAP pathways and suppressed the expression of yes-associated protein 1 (YAP1), cellular myelocytomatosis oncogene (c-Myc), E2F transcription factor 1 (E2F1), Bromodomain-containing protein 4 (BRD4), TEA domain transcription factor 4 (TEAD4), and cluster of differentiation 7 (CD7) proto-oncogenes. Furthermore, LUR significantly restrained the in vivo growth of iCCA cells in the CAM model. Our data indicate that TRB and LUR possess strong anti-proliferative and pro-apoptotic activities and could represent promising therapeutic agents for the treatment of iCCA.<\/jats:p>","DOI":"10.3390\/ijms26189085","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T12:54:26Z","timestamp":1758200066000},"page":"9085","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The DNA Minor Groove Binders Trabectedin and Lurbinectedin Are Potent Antitumor Agents in Human Intrahepatic Cholangiocarcinoma"],"prefix":"10.3390","volume":"26","author":[{"given":"Erwin","family":"G\u00e4bele","sequence":"first","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Regensburg, 93053 Regensburg, Germany"},{"name":"Internisten-Regensburg.de, Internal Medicine Group Practice, 93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3712-4149","authenticated-orcid":false,"given":"Isabella","family":"Gigante","sequence":"additional","affiliation":[{"name":"National Institute of Gastroenterology, IRCCS \u201cSaverio de Bellis\u201d, 70013 Castellana Grotte, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0938-3266","authenticated-orcid":false,"given":"Mirella","family":"Pastore","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Cigliano","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery, and Pharmacy, University of Sassari, 07100 Sassari, 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Institute of Gastroenterology, IRCCS \u201cSaverio de Bellis\u201d, 70013 Castellana Grotte, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8520-4568","authenticated-orcid":false,"given":"Martina","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Regensburg, 93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8629-0878","authenticated-orcid":false,"given":"Fabio","family":"Marra","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heiko","family":"Siegmund","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5140-8060","authenticated-orcid":false,"given":"Gianluigi","family":"Giannelli","sequence":"additional","affiliation":[{"name":"National Institute of Gastroenterology, IRCCS \u201cSaverio de Bellis\u201d, 70013 Castellana Grotte, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Evert","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2473-3535","authenticated-orcid":false,"given":"Chiara","family":"Raggi","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diego F.","family":"Calvisi","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara M.","family":"Steinmann","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41575-020-0310-z","article-title":"Cholangiocarcinoma 2020: The next horizon in mechanisms and management","volume":"17","author":"Banales","year":"2020","journal-title":"Nat. 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