Liaoning Key Lab of Targeting Drugs for Hematological Malignancies, Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, 110016, P. R. China.
Department of Medicinal Chemistry, Shenyang Pharmaceutical University, Shenyang, 110016, P. R. China.
Cell Death Dis. 2022 Apr 20;13(4):379. doi: 10.1038/s41419-022-04810-z.
Venetoclax plus cytarabine therapy is approved for elderly acute myeloid leukemia (AML) patients and needs further improvement. We studied the mechanisms of venetoclax plus cytarabine treatment and searched for a third agent to enhance their effects. Cytarabine induces S phase arrest-mediated DNA damage with activation of DNA replication checkpoint kinase 1 (Chk1) through phosphorylation, while venetoclax induces B cell lymphoma 2 (Bcl-2)-interacting mediator of cell death (Bim)-mediated apoptotic DNA damage. Myeloid cell leukemia-1 (Mcl-1) plays negative roles in both events by sequestering Bim and accelerating Chk1 phosphorylation. Venetoclax releases Bim from Bcl-2 with increased Bim binding to Mcl-1. Artesunate, an antimalaria drug, induces Noxa to replace Bim from Mcl-1 and induces synergistic apoptosis with venetoclax accompanied with Mcl-1 reduction. Silencing Mcl-1 or adding venetoclax/artesunate diminishes the cytarabine resistance pathway p-Chk1. The triple combination exhibits S phase arrest with enhanced DNA damage, improves AML colony formation inhibition, and prolongs survival of two mice xenograft models compared to the venetoclax/cytarabine dual combination. Artesunate serves as a bridge for venetoclax and cytarabine combination by Noxa and Bim-mediated apoptosis and Mcl-1 reduction. We provide a new triple combination for AML treatment by targeting the Noxa/Mcl-1/Bim axis to reverse Mcl-1/p-Chk1 resistance of cytarabine therapy.
维奈托克联合阿糖胞苷疗法已被批准用于老年急性髓系白血病（AML）患者，但仍需进一步改善。我们研究了维奈托克联合阿糖胞苷治疗的机制，并寻找第三种药物来增强它们的疗效。阿糖胞苷通过磷酸化激活 DNA 复制检查点激酶 1（Chk1）诱导 S 期阻滞介导的 DNA 损伤，而维奈托克诱导 B 细胞淋巴瘤 2（Bcl-2）相互作用的细胞死亡介体（Bim）介导的凋亡 DNA 损伤。髓样细胞白血病-1（Mcl-1）通过隔离 Bim 和加速 Chk1 磷酸化，在这两个事件中起负作用。维奈托克增加了 Bim 与 Mcl-1 的结合，从而将 Bim 从 Bcl-2 中释放出来。青蒿琥酯，一种抗疟疾药物，诱导 Noxa 取代 Bim 从 Mcl-1 中，并与维奈托克诱导协同凋亡，同时伴有 Mcl-1 减少。沉默 Mcl-1 或添加维奈托克/青蒿琥酯可减弱阿糖胞苷耐药途径 p-Chk1。与维奈托克/阿糖胞苷双重组合相比，三联组合表现出 S 期阻滞，增强了 DNA 损伤，抑制 AML 集落形成的效果更好，并延长了两种小鼠异种移植模型的存活时间。青蒿琥酯通过 Noxa 和 Bim 介导的凋亡和 Mcl-1 减少，为维奈托克和阿糖胞苷联合提供了桥梁。我们通过靶向 Noxa/Mcl-1/Bim 轴提供了一种新的 AML 治疗三联组合，以逆转阿糖胞苷治疗的 Mcl-1/p-Chk1 耐药性。
