{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T22:59:09Z","timestamp":1793228349264,"version":"4.5.0"},"reference-count":49,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,3,6]],"date-time":"2020-03-06T00:00:00Z","timestamp":1583452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["IG 17118"],"award-info":[{"award-number":["IG 17118"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["TIGEM- CBDM9"],"award-info":[{"award-number":["TIGEM- CBDM9"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004710","name":"Fondazione Umberto Veronesi","doi-asserted-by":"publisher","award":["Fellowship to Raffaella Petruzzelli"],"award-info":[{"award-number":["Fellowship to Raffaella Petruzzelli"]}],"id":[{"id":"10.13039\/501100004710","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration\/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease. To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA\/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the IGROV-CP20 ovarian carcinoma cells, whose resistance significantly relies on ATP7B. Using a synthetic lethality approach, we identified and validated three hits (Tranilast, Telmisartan, and Amphotericin B) that reduced cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these comprised key Pt-transporting proteins, including ATOX1, whose suppression affected ability of ATP7B to traffic in response to cisplatin. In summary, our findings reveal Tranilast, Telmisartan, and Amphotericin B as effective drugs that selectively promote cisplatin toxicity in Pt-resistant ovarian cancer cells and underscore the efficiency of HTS strategy for identification of biosafe compounds, which might be rapidly repurposed to overcome resistance of tumors to Pt-based chemotherapy.<\/jats:p>","DOI":"10.3390\/cancers12030608","type":"journal-article","created":{"date-parts":[[2020,3,6]],"date-time":"2020-03-06T09:26:41Z","timestamp":1583486801000},"page":"608","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin"],"prefix":"10.3390","volume":"12","author":[{"given":"Marta","family":"Mariniello","sequence":"first","affiliation":[{"name":"Telethon Institute of Genetics and Medicine, Pozzuoli, 80078 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Petruzzelli","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine, Pozzuoli, 80078 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca G.","family":"Wanderlingh","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine, Pozzuoli, 80078 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"La Montagna","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine, Pozzuoli, 80078 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Carissimo","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine, Pozzuoli, 80078 Naples, Italy"},{"name":"Institute for Applied Mathematics \u2018Mauro Picone\u2019, CNR, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Pane","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University Federico II, 80126 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Amoresano","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University Federico II, 80126 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina Y.","family":"Ilyechova","sequence":"additional","affiliation":[{"name":"ITMO University, 197101 Saint Petersburg, Russia"},{"name":"Institute of Experimental Medicine, the Russian Academy of the Sciences, 197376 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael M.","family":"Galagudza","sequence":"additional","affiliation":[{"name":"Institute of Experimental Medicine, Almazov National Medical Research Centre, 197101 Saint Pietersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Catalano","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine, Pozzuoli, 80078 Naples, Italy"},{"name":"Institute of Biosciences and Bioresources, CNR, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Crispino","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine, Pozzuoli, 80078 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0958-2812","authenticated-orcid":false,"given":"Ludmila V.","family":"Puchkova","sequence":"additional","affiliation":[{"name":"ITMO University, 197101 Saint Petersburg, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego L.","family":"Medina","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine, Pozzuoli, 80078 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7698-1955","authenticated-orcid":false,"given":"Roman S.","family":"Polishchuk","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics and Medicine, Pozzuoli, 80078 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Siddik, Z.H. 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