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We have previously demonstrated that augmenting ceramides can counter various drug\u2010resistance mechanisms, leading to enhanced cell death in cancer cells and extended survival in animal models. Using a nanoscale delivery system for ceramide (ceramide nanoliposomes, CNL), we investigated the effect of CNL within a standard of care venetoclax\/cytarabine (Ara\u2010C) regimen. We demonstrate that CNL augmented the efficacy of venetoclax\/cytarabine in in vitro, ex vivo, and in vivo models of AML. CNL treatment induced non\u2010apoptotic cytotoxicity, and augmented cell death induced by Ara\u2010C and venetoclax. Mechanistically, CNL reduced both venetoclax (Mcl\u20101) and cytarabine (Chk1) drug\u2010resistant signaling pathways. Moreover, venetoclax and Ara\u2010C augmented the generation of endogenous pro\u2010death ceramide species, which was intensified with CNL. Taken together, CNL has the potential to be utilized as an adjuvant therapy to improve outcomes, potentially extending survival, in patients with AML.<\/jats:p>","DOI":"10.1096\/fj.202200765r","type":"journal-article","created":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T03:43:07Z","timestamp":1663213387000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Ceramide nanoliposomes augment the efficacy of venetoclax and cytarabine in models of acute myeloid leukemia"],"prefix":"10.1096","volume":"36","author":[{"given":"Andrei V.","family":"Khokhlatchev","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of Virginia  Charlottesville Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arati","family":"Sharma","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine Penn State University College of Medicine  Hershey Pennsylvania USA"},{"name":"Department of Pharmacology Pennsylvania State University College of Medicine  Hershey Pennsylvania USA"},{"name":"Penn State Cancer Institute Pennsylvania State University College of Medicine  Hershey Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tye G.","family":"Deering","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of Virginia  Charlottesville Virginia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy J. 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