Ceramide nanoliposomes augment the efficacy of venetoclax and cytarabine in models of acute myeloid leukemia.

Autor:	Khokhlatchev AV; Department of Pharmacology, University of Virginia, Charlottesville, Virginia, USA., Sharma A; Division of Hematology and Oncology, Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.; Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.; Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA., Deering TG; Department of Pharmacology, University of Virginia, Charlottesville, Virginia, USA., Shaw JJP; Department of Experimental Pathology, University of Virginia, Charlottesville, Virginia, USA., Costa-Pinheiro P; Department of Experimental Pathology, University of Virginia, Charlottesville, Virginia, USA., Golla U; Division of Hematology and Oncology, Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.; Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA., Annageldiyev C; Division of Hematology and Oncology, Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.; Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA., Cabot MC; Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA.; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA., Conaway MR; University of Virginia School of Medicine, Public Health Sciences, Charlottesville, Virginia, USA., Tan SF; Division of Hematology and Oncology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA.; University of Virginia Cancer Center, Charlottesville, Virginia, USA., Ung J; Division of Hematology and Oncology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA.; Department of Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia, USA., Feith DJ; Division of Hematology and Oncology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA.; University of Virginia Cancer Center, Charlottesville, Virginia, USA., Loughran TP Jr; Division of Hematology and Oncology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA.; University of Virginia Cancer Center, Charlottesville, Virginia, USA., Claxton DF; Division of Hematology and Oncology, Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.; Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA., Fox TE; Department of Pharmacology, University of Virginia, Charlottesville, Virginia, USA., Kester M; Department of Pharmacology, University of Virginia, Charlottesville, Virginia, USA.; University of Virginia Cancer Center, Charlottesville, Virginia, USA.; NanoSTAR Institute, Charlottesville, Virginia, USA.
Jazyk:	angličtina
Zdroj:	FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2022 Oct; Vol. 36 (10), pp. e22514.
DOI:	10.1096/fj.202200765R
Abstrakt:	Despite several new therapeutic options for acute myeloid leukemia (AML), disease relapse remains a significant challenge. We have previously demonstrated that augmenting ceramides can counter various drug-resistance 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-C) 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-apoptotic cytotoxicity, and augmented cell death induced by Ara-C and venetoclax. Mechanistically, CNL reduced both venetoclax (Mcl-1) and cytarabine (Chk1) drug-resistant signaling pathways. Moreover, venetoclax and Ara-C augmented the generation of endogenous pro-death 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. (© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
Databáze:	MEDLINE
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