Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia

• Published in: Cancers Vol. 15; no. 24; p. 5866
• Main Authors: Ung, Johnson, Tan, Su-Fern, Fox, Todd E, Shaw, Jeremy J P, Taori, Maansi, Horton, Bethany J, Golla, Upendarrao, Sharma, Arati, Szulc, Zdzislaw M, Wang, Hong-Gang, Chalfant, Charles E, Cabot, Myles C, Claxton, David F, Loughran, Jr, Thomas P, Feith, David J
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.12.2023
• Subjects: Acute myeloid leukemia; AKT protein; Amino acids; Antibodies; Biochemistry; Biotechnology industry; Blood & organ donations; Bone marrow; Cell culture; Cell death; Cell viability; Ceramidase; Ceramide; Ceramides; Chemotherapy; Cytotoxicity; Dimethylglycine; Drug resistance; Enzymatic activity; Ferroptosis; Health aspects; Leukemia; Lipids; Malignancy; Metabolism; Patients; Phosphatase; Prodrugs; Proteins; Sphingosine; Therapeutic targets; Vincristine; United States; United States > US; ceramide; acute myeloid leukemia; sphingolipids; C6-ceramide nanoliposome; LCL-805; iron chelation; Akt; dimethylglycine-B-13 prodrug; acid ceramidase
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers15245866

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 μM 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 μM 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.