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.
急性髓系白血病（AML）是一种侵袭性血液系统恶性肿瘤，亟需治疗手段的革新。神经酰胺是一种促进细胞死亡的信使脂质分子，在治疗诱导的细胞死亡过程中发挥核心作用。我们先前研究发现，酸性神经酰胺酶（AC）——一种消耗神经酰胺的酶——在AML中过度表达，并促进白血病细胞存活及耐药性。神经酰胺酶抑制剂B-13及其新一代定位于溶酶体的衍生物（称为二甲甘氨酸（DMG）-B-13前体药物）已被开发，但尚未在AML中进行测试。本研究报道了DMG-B-13前体药物LCL-805在AML细胞系及原代患者样本中的体外抗白血病效力及作用机制。LCL-805能抑制AC酶活性，增加总神经酰胺水平，并降低鞘氨醇含量。在32种人AML细胞系的细胞活力实验中，LCL-805的中位EC50值为11.7 μM。在71例原代AML患者样本的测试中，LCL-805单药治疗的中位EC50值为15.8 μM。外源性补充C6-神经酰胺纳米脂质体（该疗法已进入针对复发/难治性AML的I/II期临床试验）可显著增强LCL-805的杀伤作用。机制研究表明，LCL-805能拮抗Akt信号通路，并引发不同于经典铁死亡的新型铁依赖性细胞死亡。这些发现阐明了LCL-805细胞毒性的关键作用因素，并证明了AC抑制与外源性神经酰胺联合治疗的潜在效力。
肿瘤(癌症)患者之家