{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:44:44Z","timestamp":1760150684134,"version":"build-2065373602"},"reference-count":81,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,28]],"date-time":"2023-12-28T00:00:00Z","timestamp":1703721600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"Dutch Cancer Society (KWF)","doi-asserted-by":"publisher","award":["11143","955625"],"award-info":[{"award-number":["11143","955625"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018693","name":"HORIZON Europe Framework Programme","doi-asserted-by":"publisher","award":["11143","955625"],"award-info":[{"award-number":["11143","955625"]}],"id":[{"id":"10.13039\/100018693","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Cure for Cancer","award":["11143","955625"],"award-info":[{"award-number":["11143","955625"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Temporary elevation of tumor temperature, also known as hyperthermia, is a safe and well-tolerated treatment modality. The efficacy of hyperthermia can be improved by efficient thermosensitizers, and various candidate drugs, including inhibitors of the heat stress response, have been explored in vitro and in animal models, but clinically relevant thermosensitizers are lacking. Here, we employ unbiased in silico approaches to uncover new mechanisms and compounds that could be leveraged to increase the thermosensitivity of cancer cells. We then focus on elesclomol, a well-performing compound, which amplifies cell killing by hyperthermia by 5- to 20-fold in cell lines and outperforms clinically applied chemotherapy when combined with hyperthermia in vitro. Surprisingly, our findings suggest that the thermosensitizing effects of elesclomol are independent of its previously reported modes of action but depend on copper shuttling. Importantly, we show that, like elesclomol, multiple other copper shuttlers can thermosensitize, suggesting that disturbing copper homeostasis could be a general strategy for improving the efficacy of hyperthermia.<\/jats:p>","DOI":"10.3390\/ijms25010423","type":"journal-article","created":{"date-parts":[[2023,12,28]],"date-time":"2023-12-28T09:35:21Z","timestamp":1703756121000},"page":"423","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Perturbation of Copper Homeostasis Sensitizes Cancer Cells to Elevated Temperature"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2504-2058","authenticated-orcid":false,"given":"Enzo M.","family":"Scutigliani","sequence":"first","affiliation":[{"name":"Department of Medical Biology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Treatment and Quality of Life, Cancer Biology and Immunology, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0528-9512","authenticated-orcid":false,"given":"Jons","family":"van Hattum","sequence":"additional","affiliation":[{"name":"Cancer Center Amsterdam, Treatment and Quality of Life, Cancer Biology and Immunology, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands"},{"name":"Department of Urology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando","family":"Lobo-Cerna","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Treatment and Quality of Life, Cancer Biology and Immunology, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanne","family":"Kruyswijk","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Treatment and Quality of Life, Cancer Biology and Immunology, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maja","family":"Myrcha","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Treatment and Quality of Life, Cancer Biology and Immunology, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederique E. G. A.","family":"Dekkers","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Treatment and Quality of Life, Cancer Biology and Immunology, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ron A.","family":"Hoebe","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Finn","family":"Edwards","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Treatment and Quality of Life, Cancer Biology and Immunology, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jetta J.","family":"Oppelaar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section of Nephrology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Microcirculation, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4585-7505","authenticated-orcid":false,"given":"Liffert","family":"Vogt","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section of Nephrology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Microcirculation, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanne","family":"Bootsma","sequence":"additional","affiliation":[{"name":"Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Cancer Biology, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands"},{"name":"Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6627-3229","authenticated-orcid":false,"given":"Maarten F.","family":"Bijlsma","sequence":"additional","affiliation":[{"name":"Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Cancer Biology, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands"},{"name":"Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisy I.","family":"Picavet","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7474-0533","authenticated-orcid":false,"given":"Johannes","family":"Crezee","sequence":"additional","affiliation":[{"name":"Cancer Center Amsterdam, Treatment and Quality of Life, Cancer Biology and Immunology, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands"},{"name":"Department of Radiation Oncology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6079-5613","authenticated-orcid":false,"given":"Jorg R.","family":"Oddens","sequence":"additional","affiliation":[{"name":"Cancer Center Amsterdam, Treatment and Quality of Life, Cancer Biology and Immunology, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands"},{"name":"Department of Urology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theo M.","family":"de Reijke","sequence":"additional","affiliation":[{"name":"Cancer Center Amsterdam, Treatment and Quality of Life, Cancer Biology and Immunology, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands"},{"name":"Department of Urology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Przemek M.","family":"Krawczyk","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Treatment and Quality of Life, Cancer Biology and Immunology, De Boelelaan 1118, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.ejca.2018.07.005","article-title":"Cancer Incidence and Mortality Patterns in Europe: Estimates for 40 Countries and 25 Major Cancers in 2018","volume":"103","author":"Ferlay","year":"2018","journal-title":"Eur. 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