Ethacrynic acid exhibits selective toxicity to chronic lymphocytic leukemia cells by inhibition of the Wnt/beta-catenin pathway.
Ethacrynic acid exhibits selective toxicity to chronic lymphocytic leukemia cells by inhibition of the Wnt/beta-catenin pathway.
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乙酸通过抑制Wnt/β-catenin途径对慢性淋巴细胞性白血病细胞表现出选择性毒性。
DOI：
10.1371/journal.pone.0008294
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发表时间：
2009-12-14
期刊：
影响因子：
3.7
通讯作者：
Carson DA
中科院分区：
文献类型：
--
作者：
Lu D;Liu JX;Endo T;Zhou H;Yao S;Willert K;Schmidt-Wolf IG;Kipps TJ;Carson DA
Wnt/β-catenin信号传导的异常激活促进了几种癌症的发展。已经证明，Wnt信号传导途径在慢性淋巴细胞白血病（CLL）细胞中被激活，并且不受控制的Wnt/β-连环蛋白信号传导可能导致以这种恶性肿瘤为特征的细胞凋亡缺陷。因此，Wnt信号通路是开发CLL靶向治疗的有吸引力的候选者。利尿剂依他尼酸（EA）被确定为Wnt抑制剂使用基于细胞的Wnt报告基因测定。体外实验进一步证实了EA对Wnt/β-catenin信号通路的抑制作用。细胞活力测定表明，EA选择性地诱导原代CLL细胞的细胞死亡。CLL细胞经EA处理后，Wnt/β-catenin靶基因LEF-1、cyclin D1和fibronectin的表达均降低。免疫共沉淀实验表明，EA可直接与LEF-1蛋白结合，破坏LEF-1/β-catenin复合物的稳定性。N-乙酰-L-半胱氨酸（NAC）可与EA中的α，β-不饱和酮反应，而不是其他抗氧化剂，阻止了药物对Wnt/β-catenin活化的抑制及其诱导CLL细胞凋亡的能力。我们的研究表明，由于抑制Wnt/β-catenin信号传导，EA选择性地抑制CLL存活。用EA或相关药物拮抗CLL中的Wnt信号传导可能代表这种疾病的有效治疗。
Aberrant activation of Wnt/β-catenin signaling promotes the development of several cancers. It has been demonstrated that the Wnt signaling pathway is activated in chronic lymphocytic leukemia (CLL) cells, and that uncontrolled Wnt/β-catenin signaling may contribute to the defect in apoptosis that characterizes this malignancy. Thus, the Wnt signaling pathway is an attractive candidate for developing targeted therapies for CLL. The diuretic agent ethacrynic acid (EA) was identified as a Wnt inhibitor using a cell-based Wnt reporter assay. In vitro assays further confirmed the inhibitory effect of EA on Wnt/β-catenin signaling. Cell viability assays showed that EA selectively induced cell death in primary CLL cells. Exposure of CLL cells to EA decreased the expression of Wnt/β-catenin target genes, including LEF-1, cyclin D1 and fibronectin. Immune co-precipitation experiments demonstrated that EA could directly bind to LEF-1 protein and destabilize the LEF-1/β-catenin complex. N-acetyl-L-cysteine (NAC), which can react with the α, β-unsaturated ketone in EA, but not other anti-oxidants, prevented the drug's inhibition of Wnt/β-catenin activation and its ability to induce apoptosis in CLL cells. Our studies indicate that EA selectively suppresses CLL survival due to inhibition of Wnt/β-catenin signaling. Antagonizing Wnt signaling in CLL with EA or related drugs may represent an effective treatment of this disease.
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DOI：
10.1182/asheducation-2002.1.193
发表时间：
2002-01-01
期刊：
Hematology. American Society of Hematology. Education Program
影响因子：
--
作者：
Kay, Neil E;Hamblin, Terry J;Lin, Thomas
通讯作者：
Lin, Thomas
影响因子：
4.8
作者：
Filali, M;Cheng, NL;Engelhardt, JF
通讯作者：
Engelhardt, JF
影响因子：
11.4
作者：
Horie, R;Watanabe, M;Umezawa, K
通讯作者：
Umezawa, K
影响因子：
16.2
作者：
Cavodeassi F;Carreira-Barbosa F;Young RM;Concha ML;Allende ML;Houart C;Tada M;Wilson SW
通讯作者：
Wilson SW
DOI：
10.1073/pnas.0712148105
发表时间：
2008-02-26
影响因子：
11.1
作者：
Fukuda, Tetsuya;Chen, Liguang;Kipps, Thomas J.
通讯作者：
Kipps, Thomas J.