Chen Yi-Jui, Sheng Wei-Yun, Huang Pei-Rong, Wang Tzu-Chien V
Department of Molecular and Cellular Biology, Chang Gung University, Kwei-San, Tao-Yuan, 333, Taiwan.
J Biomed Sci. 2006 Sep;13(5):667-74. doi: 10.1007/s11373-006-9100-z. Epub 2006 Jul 19.
Telomerase activity is repressed in normal human somatic cells, but is activated in most cancers, suggesting that telomerase may be an important target for cancer therapy. In this study, we report that U-73122, an amphiphilic alkylating agent that is commonly used as an inhibitor for phospholipase C, is also a potent and selective inhibitor of human telomerase. The inhibition of telomerase by U-73122 was attributed primarily to the pyrrole-2,5-dione group, since its structural analog U-73343 did not inhibit telomerase. In confirmation, we observed that telomerase was inhibited by N-ethylmaleimide, but not N-ethylsuccinimide. The IC(50) value of U-73122 for the in vitro inhibition of telomerase activity is 0.2 microM, which is comparable to or slightly more sensitive than that for phospholipase C. The inhibitory action of U-73122 on telomerase appears to be rather selective since the presence of externally added proteins did not protect the inhibition and the IC(50) values for the other enzymes tested in this study were at least an order of magnitude higher than that for telomerase. Furthermore, we demonstrate that U-73122 can inhibit telomerase in hematopoietic cancer cells. The potent and selective inhibition of telomerase by U-73122 raises the potential exploitation of this drug and other alkylating agents as telomerase inhibitor.
端粒酶活性在正常人体体细胞中受到抑制，但在大多数癌症中被激活，这表明端粒酶可能是癌症治疗的一个重要靶点。在本研究中，我们报告U - 73122，一种常用作磷脂酶C抑制剂的两亲性烷基化剂，也是人端粒酶的一种有效且选择性的抑制剂。U - 73122对端粒酶的抑制主要归因于吡咯 - 2,5 - 二酮基团，因为其结构类似物U - 73343不抑制端粒酶。经证实，我们观察到N - 乙基马来酰亚胺可抑制端粒酶，但N - 乙基琥珀酰亚胺则不能。U - 73122在体外抑制端粒酶活性的IC(50)值为0.2 microM，这与对磷脂酶C的抑制作用相当或稍更敏感。U - 73122对端粒酶的抑制作用似乎具有相当的选择性，因为外部添加蛋白质的存在并不能保护其免受抑制，且本研究中测试的其他酶的IC(50)值比对端粒酶的IC(50)值至少高一个数量级。此外，我们证明U - 73122可抑制造血癌细胞中的端粒酶。U - 73122对端粒酶的有效且选择性抑制提高了将该药物及其他烷基化剂开发为端粒酶抑制剂的可能性。
