Alantolactone induces apoptosis in chronic myelogenous leukemia sensitive or resistant to imatinib through NF-κB inhibition and Bcr/Abl protein deletion
Alantolactone induces apoptosis in chronic myelogenous leukemia sensitive or resistant to imatinib through NF-κB inhibition and Bcr/Abl protein deletion
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Alantolactone 通过 NF-κB 抑制和 Bcr/Abl 蛋白缺失诱导对伊马替尼敏感或耐药的慢性粒细胞白血病细胞凋亡
DOI：
10.1007/s10495-013-0854-2
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发表时间：
2013-09-01
期刊：
影响因子：
7.2
通讯作者：
Yan, Hua
中科院分区：
文献类型：
--
作者：
Wei, Wei;Huang, He;Yan, Hua
Alantolactone是一种致敏倍半萜内酯，最近被发现对恶性肿瘤细胞有显著的抗肿瘤作用。在这里，我们研究了alantolactone对Bcr/Abl+伊马替尼敏感和耐药细胞的潜在影响。Alantolactone处理导致伊马替尼敏感和耐药的K562细胞明显凋亡，表现为Annexin v阳性细胞增加，caspase-3激活，聚（adp -核糖）聚合酶-1 （PARP-1）切割和线粒体膜电位塌陷。Alantolactone显著抑制NF-κ b依赖性报告基因活性，降低NF-ОκB的dna结合活性，阻断TNF-α-诱导的i -κ b α磷酸化。有趣的是，在伊马替尼敏感和耐药的K562细胞中，alantolactone暴露后，致癌的Bcr/Abl融合蛋白（而不是其mRNA水平）迅速降低。Bcr/Abl敲低增强了alantolactone诱导的细胞凋亡。添加蛋白酶体或caspase-3抑制剂不能逆转Bcr/Abl蛋白的减少。p65过表达可抑制alantolactine诱导的细胞凋亡，而p65或Bcr/Abl沉默可增强其诱导凋亡的作用。此外，与K562细胞相比，转染Bcr/Abl的32D细胞对alantolactone的敏感性更高，并且Bcr/Abl蛋白被耗尽。最后，在原代CD34+CML白血病细胞中也观察到阿兰妥内酯诱导的细胞凋亡。综上所述，这些发现表明alantolactone通过抑制NF-κB信号通路和消耗Bcr/Abl蛋白来对抗CML细胞是一种有前途的有效药物。
Alantolactone, an allergenic sesquiterpene lactone, has recently been found to have significant antitumor effects on malignant tumor cells. Here, we investigated the potential effect of alantolactone on Bcr/Abl+imatinib-sensitive and -resistant cells. Alantolactone treatment resulted in obvious apoptosis in both imatinib-sensitive and -resistant K562 cells, as shown by the increase in Annexin V-positive cells, caspase-3 activation, poly(ADP-ribose) polymerase-1 (PARP-1) cleavage and mitochondrial membrane potential collapse. Alantolactone significantly inhibited NF-κB-dependent reporter gene activity, decreased the DNA-binding activity of NF-ОκB, and blocked TNF-α-induced IκBα phosphorylation. Of interest, the oncogenic Bcr/Abl fusion protein but not its mRNA levels were quickly reduced upon alantolactone exposure in imatinib-sensitive and -resistant K562 cells. Bcr/Abl knockdown enhanced the apoptosis driven by alantolactone. Bcr/Abl protein reduction could not be reversed by the addition of proteasome or caspase-3 inhibitors. The overexpression of p65 inhibited alantolactone-induced apoptosis, whereas p65 or Bcr/Abl silencing enhanced its apoptotic-inducing effect. Furthermore, Bcr/Abl-transfected 32D cells showed more sensitivity to alantolactone than vector-transfected control cells, and the Bcr/Abl protein was depleted, as observed in K562 cells. Finally, alantolactone-induced apoptosis was also observed in primary CD34+CML leukemic cells. Collectively, these findings suggest that alantolactone is a promising potent agent to fight against CML cells via the inhibition of the NF-κB signaling pathway and depletion of the Bcr/Abl protein.