Inhibitory effect of novel somatostatin peptide analogues on human cancer cell growth based on the selective inhibition of DNA polymerase β
Inhibitory effect of novel somatostatin peptide analogues on human cancer cell growth based on the selective inhibition of DNA polymerase β
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DOI：
10.1016/j.bmc.2012.11.024
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发表时间：
2013-01-15
影响因子：
3.5
通讯作者：
Mizushina, Yoshiyuki
中科院分区：
文献类型：
--
作者：
Kuriyama, Isoko;Miyazaki, Anna;Mizushina, Yoshiyuki
本研究从生长抑素结构类似物TT-232出发，通过分析其对哺乳动物DNA聚合酶和人癌细胞生长的抑制作用，研究了新的9个小肽(化合物1-9)的抗癌活性。在所研究的化合物中，3[叔丁氧羰基(Boc)-Tyr-Phe-1-萘胺]、4(Boc-Tyr-Ile-1-napthylamy)、5(Boc-Tyr-Leu-1-napthylamy)和6(Boc-Tyr-Val-1-napthylamy)选择性地抑制了与DNA修复相关的POL-β的活性。化合物3-6对人结肠癌HCT116 P53(+/+)细胞生长有较强的抑制作用。化合物1-9对HCT116 P53(+/+)细胞生长的影响与对HCT116 P53(+/+)细胞的影响相似。这些结果提示，这些化合物对癌细胞的生长抑制作用可能与它们对Poll的抑制作用有关。在所测试的9个化合物中，化合物4是对olβ和癌细胞生长抑制作用最强的。该化合物特异性地抑制大鼠POLβ的活性，但对所研究的其他10种哺乳动物的POL没有影响。化合物4与甲基甲烷磺酸(MMS)联合应用对HCT116 P53(+/+)细胞的生长抑制作用明显优于单独应用MMS。该化合物还可诱导有或无P53的HCT116细胞的凋亡。从这些结果中，我们讨论了化合物4，一种特定的polβ抑制剂，对DNA修复和癌细胞生长的关系的影响。(C)2012爱思唯尔有限公司。保留所有权利。
The present study was designed to investigate the anticancer activity of novel nine small peptides (compounds 1-9) derived from TT-232, a somatostatin structural analogue, by analyzing the inhibition of mammalian DNA polymerase (pol) and human cancer cell growth. Among the compounds tested, compounds 3 [tert-butyloxycarbonyl (Boc)-Tyr-Phe-1-naphthylamide], 4 (Boc-Tyr-Ile-1-naphthylamide), 5 (Boc-Tyr-Leu-1-naphthylamide) and 6 (Boc-Tyr-Val-1-naphthylamide) containing tyrosine (Tyr) but no carboxyl groups, selectively inhibited the activity of rat pol beta, which is a DNA repair-related pol. Compounds 3-6 strongly inhibited the growth of human colon carcinoma HCT116 p53(+/+) cells. The influence of compounds 1-9 on HCT116 p53(+/+) cell growth was similar to that observed for HCT116 p53(+/+) cells. These results suggest that the cancer cell growth suppression induced by these compounds might be related to their inhibition of pol. Compound 4 was the strongest inhibitor of pol beta and cancer cell growth among the nine compounds tested. This compound specifically inhibited rat pol beta activity, but had no effect on the other 10 mammalian pols investigated. Compound 4 combined with methyl methane sulfonate (MMS) treatment synergistically suppressed HCT116 p53(+/+) cell growth compared with MMS alone. This compound also induced apoptosis in HCT116 cells with or without p53. From these results, the influence of compound 4, a specific pol beta inhibitor, on the relationship between DNA repair and cancer cell growth is discussed. (C) 2012 Elsevier Ltd. All rights reserved.