TY - JOUR
T1 - Ceramide nanoliposomes augment the efficacy of venetoclax and cytarabine in models of acute myeloid leukemia
AU - Khokhlatchev, Andrei V.
AU - Sharma, Arati
AU - Deering, Tye G.
AU - Shaw, Jeremy J.P.
AU - Costa-Pinheiro, Pedro
AU - Golla, Upendarrao
AU - Annageldiyev, Charyguly
AU - Cabot, Myles C.
AU - Conaway, Mark R.
AU - Tan, Su Fern
AU - Ung, Johnson
AU - Feith, David J.
AU - Loughran, Thomas P.
AU - Claxton, David F.
AU - Fox, Todd E.
AU - Kester, Mark
N1 - Funding Information:
The authors thank Drs. Benjamin Ebert, Didier Trono, and Anthony Futerman for gifts of plasmids, The University of Virginia Flow Cytometry Core, and the Bioluminescence Imaging Core at the Penn State University College of Medicine.
Funding Information:
This work was supported by NCI Award P01‐CA171983 and a Cancer Center Support Grant P30‐CA044579. P.C.P was funded by the National Cancer Institute of the National Institutes of Health (F99‐CA245802). J.U. was supported in part by F31‐CA271809 and by the Robert R. Wagner Fellowship at the University of Virginia.
Publisher Copyright:
© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
PY - 2022/10
Y1 - 2022/10
N2 - 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.
AB - 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.
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U2 - 10.1096/fj.202200765R
DO - 10.1096/fj.202200765R
M3 - Article
C2 - 36106439
AN - SCOPUS:85137894257
SN - 0892-6638
VL - 36
JO - FASEB Journal
JF - FASEB Journal
IS - 10
M1 - e22514
ER -