Fujian Institute of Hematology, Fujian Provincial Key Laboratory of Hematology, The Union Hospital of Fujian Medical University, Fuzhou, China.
Central Laboratory, The Union Hospital of Fujian Medical University, Fuzhou, China.
Exp Cell Res. 2019 Mar 15;376(2):114-123. doi: 10.1016/j.yexcr.2019.02.008. Epub 2019 Feb 11.
Relapse of minimal residual disease (MRD) is a major problem after conventional chemotherapy in patients with acute myeloid leukemia (AML). The bone marrow stroma can protect AML cells from insults of chemotherapy, partly contributing to AML relapse. Arsenic trioxide (ATO) is the main component of arsenical traditional Chinese medicines and has been widely used for the treatment of hematologic malignancies particularly acute promyelocytic leukemia over the past three decades. ATO acts through a direct arsenic binding to cysteine residues in zinc fingers located in promyelocytic leukemia protein (PML), thus killing the leukemia stem cells (LSCs). Our prior study has demonstrated that adhesion to stroma cells could render AML cells resistant to ATO but the detailed mechanism remains to be explored. Here, we report that the adhesion-induced resistance to ATO is related to the up-regulation of myeloid cell leukemia-1 (Mcl-1). Homoharringtonine (HHT) can potentiate the anti-leukemia effects of ATO on adhered AML cells by suppressing Mcl-1 through glycogen synthase kinase-3β (GSK3β). Furthermore, a potentiating effect of HHT on ATO was also observed in primary AML cells and AML xenografted tumors. Thus, these data indicate that HHT could enhance ATO anti-leukemia activity both in vitro and in vivo.
微小残留病（MRD）的复发是急性髓系白血病（AML）患者常规化疗后一个主要问题。骨髓基质可以保护 AML 细胞免受化疗的侵害，这在一定程度上促成了 AML 的复发。三氧化二砷（ATO）是含砷中药的主要成分，在过去三十年中，已广泛用于治疗血液系统恶性肿瘤，特别是急性早幼粒细胞白血病。ATO 通过直接与锌指中位于早幼粒细胞白血病蛋白（PML）的半胱氨酸残基结合而发挥作用，从而杀死白血病干细胞（LSCs）。我们之前的研究表明，与基质细胞的黏附可使 AML 细胞对 ATO 产生耐药性，但详细的机制仍有待探索。在这里，我们报告说，黏附诱导的 ATO 耐药性与髓样细胞白血病-1（Mcl-1）的上调有关。高三尖杉酯碱（HHT）可通过糖原合酶激酶-3β（GSK3β）抑制 Mcl-1，从而增强黏附的 AML 细胞中 ATO 的抗白血病作用。此外，在原代 AML 细胞和 AML 异种移植瘤中也观察到 HHT 对 ATO 的增效作用。因此，这些数据表明 HHT 可以增强 ATO 在体外和体内的抗白血病活性。
