Mechanisms of apoptosis and differentiation induced by arsenic trioxide in leukemic cells and its clinical application

三氧化二砷通过诱导复发的急性早幼粒细胞白血病(APL)患者的细胞凋亡而有效地诱导临床缓解。然而，其诱导细胞凋亡的分子机制尚不清楚。此外，这种新型抗白血病药物被认为是一种毒药，其可能的不良反应是关系到其临床使用的一个非常重要的问题。三氧化二砷可诱导维甲酸敏感的NB4细胞和耐药的UF-1细胞发生凋亡，其作用机制分别是下调Bcl2和上调Bax蛋白。此外，三氧化二砷还能降解急性早幼粒细胞白血病特异性PML/RARα融合蛋白。有趣的是，三氧化二砷和GM-CSF联合应用可诱导APL细胞分化，但不能诱导其凋亡。在NB4和UF-1细胞中，GM-CSF与JAK2激酶的酪氨酸磷酸化增加有关。JAK2的特异性抑制剂AG490可完全阻断GM-CSF对三氧化二砷诱导的APL细胞的诱导分化和抗凋亡作用，提示JAK/STAT信号转导通路在两者诱导的APL细胞中的抗凋亡作用中起重要作用。这些结果也通过使用产生人GM-CSF的转基因SCID小鼠模型在体内观察到。综上所述，三氧化二砷联合GM-CSF可能是一种新的诱导分化治疗方法，还需要进一步的分子研究来确定三氧化二砷的靶分子。

Arsenic trioxide effectively induces clinical remission via apoptosis in relapsed acute promyelocytic leukemia (APL). However, its molecular mechniams od inducing apoptosis is still unclear. In addition, this new anti-leukemic drug is considered to be a poison, its possible adverse effects are a highly important issue related to its clinical use. Arsenic trioxide can induce apoptosis of both retinoic acid-sensitive NB4 and-resistant UF-1 cells with down-regulation of Bcl-2 and up-regulation of Bax proteins, respectively. Also, arsenic trioxide degrades APL-specific PML/RARα fusion protein. Interestingly, a combination of arsenic trioxide and GM-CSF induces differentiation, but not apoptosis of APL cells. GM-CSF was found to be associated with increased tyrosine phosphorylation of Jak2 kinase in both NB4 and UF-1 cells. A specific inhibitor of Jak2, AG490, completely blocked the ability of GM-CSF to prevent apoptosis and induce differentiation of arsenic trioxide-treated APL cells, suggesting that Jak/STAT pathway is dritical for the anti-apoptotic activity of GM-CSF in APL cells treated with both agents. These results are also observed in vivo by using human GM-CSF-producing transgenic SCID mice model. In conclusion, a combination of arsenic trioxide and GM-CSF appears to be a novel differentiation-inducing therapy in patients with APL.Further molecular studies to determine the target molecules of arsenic trioxide will be needed.