Anti-tumor effects of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase α
Anti-tumor effects of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase α
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DOI：
10.1016/j.bbrc.2006.11.021
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发表时间：
2007-01-12
影响因子：
3.1
通讯作者：
Mizushina, Yoshiyuki
中科院分区：
文献类型：
--
作者：
Maeda, Naoki;Kokai, Yasuo;Mizushina, Yoshiyuki
在筛选真核DNA聚合酶（pols）选择性抑制剂时，发现脱氢altenusin是来自真菌（Alternaria tennuis）的pol α抑制剂。我们成功化学合成了脱氢altenusin，该化合物仅抑制哺乳动物pol α，IC50值为0.5 μM，不影响其他复制pol如pols delta和epsilon的活性，而且对其他脊椎动物、鱼类或植物的pol α活性也没有影响。脱氢阿藤菌素对测试的其他聚合酶和 DNA 代谢酶也没有影响。该化合物还能抑制人类癌细胞的增殖，LD50 值为 38.0 - 44.4 μM。在对携带 HeLa 细胞实体瘤的裸鼠进行的体内抗肿瘤试验中，脱氢阿藤菌素被证明是一种有前景的实体瘤抑制剂。组织病理学检查表明，该化合物在体内明显检测到增加的肿瘤坏死和降低的有丝分裂指数。因此，脱氢altenusin不仅可以作为哺乳动物pol ot特异性抑制剂，而且可以作为抗癌治疗的候选药物。 (c) 2006 Elsevier Inc. 保留所有权利。
In the screening of selective inhibitors of eukaryotic DNA polymerases (pols), dehydroaltenusin was found to be an inhibitor of pol alpha from a fungus (Alternaria tennuis). We succeeded in chemically synthesizing dehydroaltenusin, and the compound inhibited only mammalian pol alpha with IC50 value of 0.5 mu M, and did not influence the activities of other replicative pols such as pols delta and epsilon, but also showed no effect on pol alpha activity from another vertebrate, fish, or from a plant species. Dehydroaltenusin also had no influence on the other pols and DNA metabolic enzymes tested. The compound also inhibited the proliferation of human cancer cells with LD50 values of 38.0 - 44.4 mu M. In an in vivo anti-tumor assay on nude mice bearing solid tumors of HeLa cells, dehydroaltenusin was shown to be a promising suppressor of solid tumors. Histopathological examination revealed that increased tumor necrosis and decreased mitotic index were apparently detected by the compound in vivo. Therefore, dehydroaltenusin could be of interest as not only a mammalian pol ot-specific inhibitor, but also as a candidate drug for anti-cancer treatment. (c) 2006 Elsevier Inc. All rights reserved.