{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T01:43:09Z","timestamp":1768441389775,"version":"3.49.0"},"reference-count":40,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,4,2]],"date-time":"2022-04-02T00:00:00Z","timestamp":1648857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Malignant mesothelioma (MM) is a currently incurable, aggressive cancer derived from mesothelial cells, most often resulting from asbestos exposure. The current first-line treatment in unresectable MM is cisplatin\/pemetrexed, which shows very little long-term effectiveness, necessitating research for novel therapeutic interventions. The existing chemotherapies often act on the cytoskeleton, including actin filaments and microtubules, but recent advances indicate the \u2018fourth\u2019 form consisting of the family of septins, representing a novel target. The septin inhibitor forchlorfenuron (FCF) and FCF analogs inhibit MM cell growth in vitro, but at concentrations which are too high for clinical applications. Based on the reported requirement of the chloride group in the 2-position of the pyridine ring of FCF for MM cell growth inhibition and cytotoxicity, we systematically investigated the importance (cell growth-inhibiting capacity) of the halogen atoms fluorine, chlorine, bromine and iodine in the 2- or 3-position of the pyridine ring. The MM cell lines ZL55, MSTO-211H, and SPC212, and\u2014as a control\u2014immortalized Met-5A mesothelial cells were used. The potency of the various halogen substitutions in FCF was mostly correlated with the atom size (covalent radius); the small fluoride analogs showed the least effect, while the largest one (iodide) most strongly decreased the MTT signals, in particular in MM cells derived from epithelioid MM. In the latter, the strongest effects in vitro were exerted by the 2-iodo and, unexpectedly, the 2-trifluoromethyl (2-CF3) FCF analogs, which were further tested in vivo in mice. However, FCF-2-I and, more strongly, FCF-2-CF3 caused rapidly occurring strong symptoms of systemic toxicity at doses lower than those previously obtained with FCF. Thus, we investigated the effectiveness of FCF (and selected analogs) in vitro in MM cells which were first exposed to cisplatin. The slowly appearing population of cisplatin-resistant cells was still susceptible to the growth-inhibiting\/cytotoxic effect of FCF and its analogs, indicating that cisplatin and FCF target non-converging pathways in MM cells. Thus, a combination therapy of cisplatin and FCF (analogs) might represent a new avenue for the treatment of repopulating chemo-resistant MM cells in this currently untreatable cancer.<\/jats:p>","DOI":"10.3390\/ijms23073963","type":"journal-article","created":{"date-parts":[[2022,4,3]],"date-time":"2022-04-03T02:59:52Z","timestamp":1648954792000},"page":"3963","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Forchlorfenuron and Novel Analogs Cause Cytotoxic Effects in Untreated and Cisplatin-Resistant Malignant Mesothelioma-Derived Cells"],"prefix":"10.3390","volume":"23","author":[{"given":"Thomas","family":"Henzi","sequence":"first","affiliation":[{"name":"Anatomy, Section of Medicine, Faculty of Science and Medicine, University of Fribourg, Route Albert-Gockel 1, CH-1700 Fribourg, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim-Long","family":"Diep","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science and Medicine, University of Fribourg, Chemin du Musee 9, CH-1700 Fribourg, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"Oberson","sequence":"additional","affiliation":[{"name":"Anatomy, Section of Medicine, Faculty of Science and Medicine, University of Fribourg, Route Albert-Gockel 1, CH-1700 Fribourg, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerie","family":"Salicio","sequence":"additional","affiliation":[{"name":"Anatomy, Section of Medicine, Faculty of Science and Medicine, University of Fribourg, Route Albert-Gockel 1, CH-1700 Fribourg, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4267-0523","authenticated-orcid":false,"given":"Christian","family":"Bochet","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science and Medicine, University of Fribourg, Chemin du Musee 9, CH-1700 Fribourg, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8277-7555","authenticated-orcid":false,"given":"Beat","family":"Schwaller","sequence":"additional","affiliation":[{"name":"Anatomy, Section of Medicine, Faculty of Science and Medicine, University of Fribourg, Route Albert-Gockel 1, CH-1700 Fribourg, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1136\/thoraxjnl-2013-203744","article-title":"Occupational and non-occupational attributable risk of asbestos exposure for malignant pleural mesothelioma","volume":"69","author":"Lacourt","year":"2014","journal-title":"Thorax"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"402","DOI":"10.3322\/caac.21572","article-title":"Mesothelioma: Scientific clues for prevention, diagnosis, and therapy","volume":"69","author":"Carbone","year":"2019","journal-title":"CA Cancer J. 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