The immunomodulator AS101 induces growth arrest and apoptosis in Multiple Myeloma: Association with the Akt/Survivin pathway
The immunomodulator AS101 induces growth arrest and apoptosis in Multiple Myeloma: Association with the Akt/Survivin pathway
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DOI：
10.1016/j.bcp.2006.06.015
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发表时间：
2006-11-30
影响因子：
5.8
通讯作者：
Sredni, Benjamin
中科院分区：
文献类型：
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作者：
Hayun, Michal;Naor, Yaniv;Sredni, Benjamin
多发性骨髓瘤（MM）是一种影响免疫系统和骨骼系统的克隆性b细胞恶性肿瘤，占所有血液系统癌症的10%。免疫调节剂三氯（二氧乙烯-O，O'）碲酸铵（AS101）是一种无毒化合物，在几种肿瘤模型中具有直接抗肿瘤特性。本研究通过靶向Akt/Survivin信号通路检测AS101在MM中的抗肿瘤活性，Akt/Survivin信号通路对生存至关重要。我们发现AS101以剂量依赖的方式抑制MM细胞系的细胞增殖和集落形成。AS101诱导G(2)/M生长停滞，增加细胞周期蛋白依赖性激酶抑制剂p2l（waf1）蛋白水平和Cdk1 (p34(cdc2))-抑制性磷酸化。AS101在MM细胞中孵育较长时间，导致凋亡细胞群的积累和caspase 9、3和7活性的增加。我们还发现AS101下调Akt磷酸化，并降低凋亡抑制剂survivin的表达。由于Akt和survivin是MM治疗的潜在靶点，我们认为目前在临床研究中使用的AS101可能对骨髓瘤和其他造血恶性肿瘤具有治疗意义。(c) 2006爱思唯尔公司版权所有。
Multiple Myeloma (MM) is a clonal B-cell malignancy affecting both the immune and the skeletal systems, and accounts for 10% of all hematological cancers. The immunomodulator ammonium trichloro (dioxoethylene-O,O') tellurate (AS101) is a non-toxic compound which has direct anti-tumoral properties in several tumor models. The present study examined the anti-tumoral activity of AS101 in MM by targeting the Akt/Survivin signaling pathway, crucial for survival. We showed that AS101 inhibites cell proliferation and colonies formation of MM cell lines, in a dose-dependent manner. AS101 induced G(2)/M growth arrest and increased both cyclin-dependent kinase inhibitor p2l(waf1) protein levels and Cdk1 (p34(cdc2))- inhibitory phosphorylation. Longer incubation of MM cells with AS101 resulted in accumulation of apoptotic cell population and in increased caspase 9, 3 and 7 activities. We also showed that AS101 down-regulated Akt phosphorylation and decreased expression of the inhibitor of apoptosis, survivin. Since Akt and survivin are potentials targets for MM therapy, we suggest that AS101, currently being used in clinical studies, may have therapeutic implications in myeloma and other hematopoietic malignancies.. (c) 2006 Elsevier Inc. All rights reserved.