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

Abstract

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.

• Authors: Andrei V Khokhlatchev, Arati Sharma, Tye G Deering, Jeremy J P Shaw, Pedro Costa-Pinheiro, Upendarrao Golla, Charyguly Annageldiyev, Myles C Cabot, Mark R Conaway, Su-Fern Tan, Johnson Ung, David J Feith, Thomas P Loughran Jr, David F Claxton, Todd E Fox, Mark Kester
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 36 Issue 10 Pg. e22514 (10 2022) ISSN: 1530-6860 [Electronic] United States
• PMID: 36106439 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

Chemical References

• Antineoplastic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• Ceramides
• Sulfonamides
• Cytarabine
• venetoclax

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Ceramides
• Cytarabine (pharmacology)
• Leukemia, Myeloid, Acute (drug therapy, metabolism)
• Sulfonamides