{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:27:00Z","timestamp":1790742420254,"version":"4.1.0"},"reference-count":57,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T00:00:00Z","timestamp":1702598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Institute","award":["P01 CA171983"],"award-info":[{"award-number":["P01 CA171983"]}]},{"name":"National Cancer Institute","award":["P30 CA044579"],"award-info":[{"award-number":["P30 CA044579"]}]},{"name":"National Cancer Institute","award":["P30 CA138313"],"award-info":[{"award-number":["P30 CA138313"]}]},{"name":"National Cancer Institute","award":["F31 CA271809"],"award-info":[{"award-number":["F31 CA271809"]}]},{"name":"National Cancer Institute","award":["F99 CA284252"],"award-info":[{"award-number":["F99 CA284252"]}]},{"name":"National Cancer Institute","award":["IK6BX004603"],"award-info":[{"award-number":["IK6BX004603"]}]},{"name":"Veteran\u2019s Administration","award":["P01 CA171983"],"award-info":[{"award-number":["P01 CA171983"]}]},{"name":"Veteran\u2019s Administration","award":["P30 CA044579"],"award-info":[{"award-number":["P30 CA044579"]}]},{"name":"Veteran\u2019s Administration","award":["P30 CA138313"],"award-info":[{"award-number":["P30 CA138313"]}]},{"name":"Veteran\u2019s Administration","award":["F31 CA271809"],"award-info":[{"award-number":["F31 CA271809"]}]},{"name":"Veteran\u2019s Administration","award":["F99 CA284252"],"award-info":[{"award-number":["F99 CA284252"]}]},{"name":"Veteran\u2019s Administration","award":["IK6BX004603"],"award-info":[{"award-number":["IK6BX004603"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell-death-promoting signaling lipid that plays a central role in therapy-induced cell death. We previously determined that acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug LCL-805 across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 \u03bcM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 \u03bcM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I\/II clinical trial for relapsed\/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide.<\/jats:p>","DOI":"10.3390\/cancers15245866","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T10:04:47Z","timestamp":1702893887000},"page":"5866","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3275-0530","authenticated-orcid":false,"given":"Johnson","family":"Ung","sequence":"first","affiliation":[{"name":"Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su-Fern","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology & Oncology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA"},{"name":"University of Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5170-3951","authenticated-orcid":false,"given":"Todd E.","family":"Fox","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology & Oncology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA"},{"name":"Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy J. P.","family":"Shaw","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology & Oncology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maansi","family":"Taori","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology & Oncology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany J.","family":"Horton","sequence":"additional","affiliation":[{"name":"Department of Public Health Sciences, Division of Translational Research and Applied Statistics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0519-7087","authenticated-orcid":false,"given":"Upendarrao","family":"Golla","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology and Oncology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arati","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA"},{"name":"Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zdzislaw M.","family":"Szulc","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina College of Medicine, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Gang","family":"Wang","sequence":"additional","affiliation":[{"name":"Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles E.","family":"Chalfant","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology & Oncology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA"},{"name":"University of Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA"},{"name":"Research Service, Richmond Veterans Administration Medical Center, Richmond, VA 23249, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myles C.","family":"Cabot","sequence":"additional","affiliation":[{"name":"East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27858, USA"},{"name":"Department of Biochemistry & Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9209-2405","authenticated-orcid":false,"given":"David F.","family":"Claxton","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology and Oncology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA"},{"name":"Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Thomas P.","family":"Loughran","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology & Oncology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA"},{"name":"University of Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4981-1691","authenticated-orcid":false,"given":"David J.","family":"Feith","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology & Oncology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA"},{"name":"University of Virginia Cancer Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J. 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