The mechanism of synergistic effects of arsenic trioxide and rapamycin in acute myeloid leukemia cell lines lacking typical t(15;17) translocation
The mechanism of synergistic effects of arsenic trioxide and rapamycin in acute myeloid leukemia cell lines lacking typical t(15;17) translocation
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DOI：
10.1007/s12185-015-1776-2
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发表时间：
2015-07-01
影响因子：
2.1
通讯作者：
Visnjic, Dora
中科院分区：
文献类型：
--
作者：
Dembitz, Vilma;Lalic, Hrvoje;Visnjic, Dora
三氧化二砷（ATO）在治疗急性早幼粒细胞白血病（APL）患者中具有有效的临床活性，但对缺乏t（15;17）易位的急性髓细胞白血病（AML）的疗效要差得多。最近的研究表明，加入哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂可能会增加恶性肿瘤细胞对ATO的敏感性。本研究的目的是测试ATO和雷帕霉素在非APL AML细胞中在治疗可达到的剂量下可能的协同作用。在HL-60和U937细胞系中，低浓度ATO和雷帕霉素的抑制作用是协同的，并且在U937细胞中更明显。联合用药可增加HL-60细胞凋亡率，并使两种细胞系中处于G（0）/G（1）期的细胞比例增加。在U937细胞中，单独的雷帕霉素增加了丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）的活性，ATO的加入降低了磷酸化ERK、Ser 473磷酸化Akt和抗凋亡蛋白Mcl-1的水平。原代AML细胞对雷帕霉素单独或与ATO组合的生长抑制作用显示出高敏感性。本研究的结果揭示了两种药物在非APL AML细胞中在治疗可达到的剂量下的协同作用的机制。
Arsenic trioxide (ATO) has potent clinical activity in the treatment of patients with acute promyelocytic leukemia (APL), but is much less efficacious in acute myeloid leukemia (AML) lacking t(15;17) translocation. Recent studies have indicated that the addition of mammalian target of rapamycin (mTOR) inhibitors may increase the sensitivity of malignant cells to ATO. The aim of the present study was to test for possible synergistic effects of ATO and rapamycin at therapeutically achievable doses in non-APL AML cells. In HL-60 and U937 cell lines, the inhibitory effects of low concentrations of ATO and rapamycin were synergistic and more pronounced in U937 cells. The combination of drugs increased apoptosis in HL-60 cells and increased the percentage of cells in G(0)/G(1) phase in both cell lines. In U937 cells, rapamycin alone increased the activity of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and the addition of ATO decreased the level of phosphorylated ERK, Ser473 phosphorylated Akt and anti-apoptotic Mcl-1 protein. Primary AML cells show high sensitivity to growth-inhibitory effects of rapamycin alone or in combination with ATO. The results of the present study reveal the mechanism of the synergistic effects of two drugs at therapeutically achievable doses in non-APL AML cells.