{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T15:51:07Z","timestamp":1779983467843,"version":"3.53.1"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T00:00:00Z","timestamp":1675209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Current cancer research has led to a renewed interest in exploring lysosomal membrane permeabilization and lysosomal cell death as a targeted therapeutic approach for cancer treatment. Evidence suggests that differences in lysosomal biogenesis between cancer and normal cells might open a therapeutic window. Lysosomal membrane stability may be affected by the so-called \u2018<jats:italic>busy lysosomal behaviour\u2019<\/jats:italic> characterized by higher lysosomal abundance and activity and more intensive fusion or interaction with other vacuole compartments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used a panel of multiple myeloid leukemia (ML) cell lines as well as leukemic patient samples and updated methodology to study auto-lysosomal compartment, lysosomal membrane permeabilization and lysosomal cell death.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our analyses demonstrated several-fold higher constitutive autolysosomal activity in ML cells as compared to human CD34<jats:sup>+<\/jats:sup> hematopoietic cells. Importantly, we identified mefloquine as a selective activator of ML cells' lysosomal biogenesis, which induced a sizeable increase in ML lysosomal mass, acidity as well as cathepsin B and L activity. Concomitant mTOR inhibition synergistically increased lysosomal activity and autolysosomal fusion and simultaneously decreased the levels of key lysosomal stabilizing proteins, such as LAMP-1 and 2.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>In conclusion, mefloquine treatment combined with mTOR inhibition synergistically induced targeted ML cell death without additional toxicity. Taken together, these data provide a molecular mechanism and thus a rationale for a therapeutic approach for specific targeting of ML lysosomes.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2023.999738","type":"journal-article","created":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T19:16:27Z","timestamp":1675278987000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Autolysosomal activation combined with lysosomal destabilization efficiently targets myeloid leukemia cells for cell death"],"prefix":"10.3389","volume":"13","author":[{"given":"Harshit","family":"Shah","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Metodi","family":"Stankov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Panayotova-Dimitrova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Yazdi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramachandramouli","family":"Budida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan-Henning","family":"Klusmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg M. 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