{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:00:33Z","timestamp":1760148033415,"version":"build-2065373602"},"reference-count":48,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T00:00:00Z","timestamp":1679443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AGAUR-Producte","award":["201930-30"],"award-info":[{"award-number":["201930-30"]}]},{"name":"Caixaimpulse Program","award":["201930-30"],"award-info":[{"award-number":["201930-30"]}]},{"name":"Josep Carreras International Leukaemia Foundation","award":["201930-30"],"award-info":[{"award-number":["201930-30"]}]},{"name":"l\u2019Obra Social \u201cLa Caixa\u201d-Fundaci\u00f3 Banc\u00e0ria \u201cLa Caixa\u201d","award":["201930-30"],"award-info":[{"award-number":["201930-30"]}]},{"name":"CERCA Programme\/Generalitat de Catalunya (IJC)","award":["201930-30"],"award-info":[{"award-number":["201930-30"]}]},{"name":"Fundaci\u00f3 Marat\u00f3 TV3","award":["201930-30"],"award-info":[{"award-number":["201930-30"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Acute myeloid leukemia (AML) is a heterogeneous hematological cancer characterized by poor prognosis and frequent relapses. Aside from specific mutation-related changes, in AML, the overall function of lysosomes and mitochondria is drastically altered to fulfill the elevated biomass and bioenergetic demands. On the basis of previous results, in silico drug discovery screening was used to identify a new family of lysosome-\/mitochondria-targeting compounds. These novel tetracyclic hits, with a cationic amphiphilic structure, specifically eradicate leukemic cells by inducing both mitochondrial damage and apoptosis, and simultaneous lysosomal membrane leakiness. Lysosomal leakiness does not only elicit canonical lysosome-dependent cell death, but also activates the terminal differentiation of AML cells through the Ca2+\u2013TFEB\u2013MYC signaling axis. In addition to being an effective monotherapy, its combination with the chemotherapeutic arsenic trioxide (ATO) used in other types of leukemia is highly synergistic in AML cells, widening the therapeutic window of the treatment. Moreover, the compounds are effective in a wide panel of cancer cell lines and possess adequate pharmacological properties rendering them promising drug candidates for the treatment of AML and other neoplasias.<\/jats:p>","DOI":"10.3390\/cancers15061912","type":"journal-article","created":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T02:35:26Z","timestamp":1679538926000},"page":"1912","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Novel Family of Lysosomotropic Tetracyclic Compounds for Treating Leukemia"],"prefix":"10.3390","volume":"15","author":[{"given":"Jos\u00e9 M.","family":"Carb\u00f3","sequence":"first","affiliation":[{"name":"Josep Carreras Leukaemia Research Institute (IJC), 08916 Barcelona, Spain"},{"name":"Leukos Biotech, 08021 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josep M.","family":"Cornet-Masana","sequence":"additional","affiliation":[{"name":"Josep Carreras Leukaemia Research Institute (IJC), 08916 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laia","family":"Cuesta-Casanovas","sequence":"additional","affiliation":[{"name":"Josep Carreras Leukaemia Research Institute (IJC), 08916 Barcelona, Spain"},{"name":"Faculty of Biosciences, Autonomous University of Barcelona, 08193 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5962-3064","authenticated-orcid":false,"given":"Jennifer","family":"Delgado-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Josep Carreras Leukaemia Research Institute (IJC), 08916 Barcelona, Spain"},{"name":"Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ant\u00f2nia","family":"Ban\u00fas-Mulet","sequence":"additional","affiliation":[{"name":"Josep Carreras Leukaemia Research Institute (IJC), 08916 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9360-1344","authenticated-orcid":false,"given":"Lise","family":"Cl\u00e9ment-Demange","sequence":"additional","affiliation":[{"name":"Leukos Biotech, 08021 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6643-3077","authenticated-orcid":false,"given":"Carme","family":"Serra","sequence":"additional","affiliation":[{"name":"MCS, Laboratory of Medicinal Chemistry and Synthesis, Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain"},{"name":"SIMChem, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2423-5926","authenticated-orcid":false,"given":"Juanlo","family":"Catena","sequence":"additional","affiliation":[{"name":"MCS, Laboratory of Medicinal Chemistry and Synthesis, Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain"},{"name":"SIMChem, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8200-4827","authenticated-orcid":false,"given":"Amadeu","family":"Llebaria","sequence":"additional","affiliation":[{"name":"MCS, Laboratory of Medicinal Chemistry and Synthesis, Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordi","family":"Esteve","sequence":"additional","affiliation":[{"name":"Josep Carreras Leukaemia Research Institute (IJC), 08916 Barcelona, Spain"},{"name":"Department of Hematology, Hospital Cl\u00ednic, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4048-9536","authenticated-orcid":false,"given":"Ruth M.","family":"Risue\u00f1o","sequence":"additional","affiliation":[{"name":"Josep Carreras Leukaemia Research Institute (IJC), 08916 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/s41375-019-0704-5","article-title":"Recent Drug Approvals for Newly Diagnosed Acute Myeloid Leukemia: Gifts or a Trojan Horse?","volume":"34","author":"Estey","year":"2020","journal-title":"Leukemia"},{"key":"ref_2","first-page":"569","article-title":"New Drug Approvals in Acute Myeloid Leukemia: An Unprecedented Paradigm Shift","volume":"17","author":"Kopmar","year":"2019","journal-title":"Clin. 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