Lapatinib induces autophagy, apoptosis and megakaryocytic differentiation in chronic myelogenous leukemia K562 cells.
Lapatinib induces autophagy, apoptosis and megakaryocytic differentiation in chronic myelogenous leukemia K562 cells.
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DOI：
10.1371/journal.pone.0029014
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Chen YJ
中科院分区：
文献类型：
--
作者：
Huang HL;Chen YC;Huang YC;Yang KC;Pan Hy;Shih SP;Chen YJ
拉帕替尼是一种口服小分子双重酪氨酸激酶抑制剂，可抑制实体瘤中的表皮生长因子受体（EGFR或ErbB/Her）。关于拉帕替尼对白血病的影响知之甚少。使用人慢性髓性白血病（CML）K562细胞作为实验模型，我们发现拉帕替尼同时诱导类似凋亡，自噬和巨核细胞分化的形态学变化。拉帕替尼诱导的细胞凋亡伴随着线粒体跨膜电位的降低，并被pancaspase抑制剂z-VAD-favorite减弱，表明这是一种pancaspase介导和caspase依赖性途径。拉帕替尼诱导的自噬性细胞死亡通过LC 3-II转化和Beclin-1的上调来验证。此外，自噬抑制剂3-甲基腺嘌呤以及自噬相关蛋白Beclin-1（ATG 6）、ATG 7和ATG 5 shRNA敲低可使细胞免于拉帕替尼诱导的生长抑制。中等数量的拉帕替尼处理的K562细胞表现出巨核细胞分化的特征。总之，拉帕替尼抑制人CML K562细胞的活力并诱导多种细胞事件，包括细胞凋亡、自噬性细胞死亡和巨核细胞分化。拉帕替尼对CML细胞的这种独特活性表明拉帕替尼作为CML治疗剂的潜力。拉帕替尼体内活性的进一步验证是必要的。
Lapatinib is an oral, small-molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptors (EGFR, or ErbB/Her) in solid tumors. Little is known about the effect of lapatinib on leukemia. Using human chronic myelogenous leukemia (CML) K562 cells as an experimental model, we found that lapatinib simultaneously induced morphological changes resembling apoptosis, autophagy, and megakaryocytic differentiation. Lapatinib-induced apoptosis was accompanied by a decrease in mitochondrial transmembrane potential and was attenuated by the pancaspase inhibitor z-VAD-fmk, indicating a mitochondria-mediated and caspase-dependent pathway. Lapatinib-induced autophagic cell death was verified by LC3-II conversion, and upregulation of Beclin-1. Further, autophagy inhibitor 3-methyladenine as well as autophagy-related proteins Beclin-1 (ATG6), ATG7, and ATG5 shRNA knockdown rescued the cells from lapatinib-induced growth inhibition. A moderate number of lapatinib-treated K562 cells exhibited features of megakaryocytic differentiation. In summary, lapatinib inhibited viability and induced multiple cellular events including apoptosis, autophagic cell death, and megakaryocytic differentiation in human CML K562 cells. This distinct activity of lapatinib against CML cells suggests potential for lapatinib as a therapeutic agent for treatment of CML. Further validation of lapatinib activity in vivo is warranted.
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影响因子：
2.1
作者：
Ennishi, Daisuke;Sezaki, Nobuo;Hino, Norihiko
通讯作者：
Hino, Norihiko
影响因子：
13.3
作者：
Colosetti, Pascal;Puissant, Alexandre;Auberger, Patrick
通讯作者：
Auberger, Patrick
影响因子：
13.3
作者：
Bell, Bryan D.;Walsh, Craig M.
通讯作者：
Walsh, Craig M.
影响因子：
20.3
作者：
BUHRING, HJ;SURES, I;ULLRICH, A
通讯作者：
ULLRICH, A
DOI：
10.2325/jbcs.971
发表时间：
2007-01-01
期刊：
Breast cancer (Tokyo, Japan)
影响因子：
--
作者：
Ito, Yoshinori;Tokudome, Nahomi;Hatake, Kiyohiko
通讯作者：
Hatake, Kiyohiko