1. Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia.
- Author
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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., and Feith, David J.
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THERAPEUTIC use of antineoplastic agents , *IN vitro studies , *CHELATION therapy , *IRON , *ACID ceramidase , *APOPTOSIS , *IRON in the body , *CELL survival , *TREATMENT effectiveness , *TRANSFERASES , *DESCRIPTIVE statistics , *CELL lines , *SPHINGOLIPIDS , *CHEMICAL inhibitors - Abstract
Simple Summary: The lysosomal lipid hydrolase acid ceramidase is upregulated in acute myeloid leukemia and promotes leukemic blast survival, underscoring its potential for therapeutic targeting. B-13 is an established ceramidase inhibitor with demonstrated efficacy in multiple solid cancers. Next-generation lysosome-localizing prodrugs of B-13 have been developed but have not been evaluated in AML. This study characterizes the in vitro anti-leukemic efficacy and cell death mechanisms of the B-13 analog and acid ceramidase inhibitor LCL-805 in acute myeloid leukemia. 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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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