Autophagy contributes to dasatinib-induced myeloid differentiation of human acute myeloid leukemia cells
Autophagy contributes to dasatinib-induced myeloid differentiation of human acute myeloid leukemia cells
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自噬有助于达沙替尼诱导的人急性髓系白血病细胞的骨髓分化
DOI：
10.1016/j.bcp.2014.02.019
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发表时间：
2014-05-01
影响因子：
5.8
通讯作者：
Ying, Meidan
中科院分区：
文献类型：
--
作者：
Xie, Nan;Zhong, Like;Ying, Meidan
全反式维甲酸（ATRA）引发了深入的分化治疗研究，从而实现了临床肿瘤学的突破。然而，分化治疗是有限的，因为ATRA是唯一有效的药物。据报道，达沙替尼在体外诱导急性髓性白血病（AML）细胞向髓样分化，但其机制尚不清楚。此外，达沙替尼引起AML细胞分化的能力尚未得到证实。我们评估了自噬对达沙替尼诱导的AML细胞分化的贡献。我们发现，达沙替尼诱导AML细胞的髓样分化伴随自噬诱导。3-MA、渥曼青霉素、LY 294002和氯喹对自噬的药理学抑制阻断了达沙替尼诱导的AML细胞分化，而雷帕霉素对自噬的诱导增强了AML细胞分化。我们的研究结果表明，视黄酸受体α（RAR α）可能不参与达沙替尼诱导的分化。此外，我们进一步说明，即使是低浓度的达沙替尼也可以通过启动自噬来增强ATRA诱导的分化能力。综上所述，我们得出结论，自噬增强了达沙替尼诱导的分化，这可能为开发达沙替尼作为AML患者未来分化治疗的有前途的策略提供理论支持。(C)2014 Elsevier Inc. All rights reserved.
A breakthrough in clinical oncology was achieved as All-trans-retinoic acid (ATRA) sparked intensive differentiation therapy research. However, differentiation therapy is limited because ATRA is the sole efficient agent. Dasatinib is reported to induce myeloid differentiation of acute myeloid leukemia (AML) cells in vitro, but its mechanism remains unclear. Furthermore, the ability of dasatinib to cause differentiation of AML cells has not yet been proven. We assessed the contribution of autophagy to dasatinib-induced differentiation of AML cells. We found that dasatinib induces myeloid differentiation of AML cells accompanied with autophagy induction. Pharmacological inhibition of autophagy by 3-MA, Wortmannin, LY294002 and chloroquine block dasatinib-induced AML cell differentiation, whereas the induction of autophagy by rapamycin enhances AML cell differentiation. Our results suggest that retinoic acid receptors alpha (RAR alpha) may not be involved in dasatinib-induced differentiation. In addition, we further illustrated that even low concentration of dasatinib can enhance ATRA-induced differentiation capability through initiation of autophagy. Taken together, we conclude that autophagy enhances the dasatinib-induced differentiation, which may provide theoretical support for developing dasatinib as a promising strategy for future differentiation therapy in AML patients. (C) 2014 Elsevier Inc. All rights reserved.