Anti-tumor effects of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase α
- 作者：Naoki Maeda ; Yasuo Kokai ; Seiji Ohtani ; Hiroeki Sahara ; Isoko Kuriyama ; Shinji Kamisuki ; Shunya Takahashi ; Kengo Sakaguchi ; Fumio Sugawara ; Hiromi Yoshida ; et al.
- 关键词：Dehydroaltenusin ; Enzyme inhibitor ; DNA polymerase α ; DNA replication ; Cytotoxicity ; Anti-tumor activity
- 刊名：Biochemical and Biophysical Research Communications
- 出版年：2007
- 期刊代码：159_0006291x
- 类别：bio
- 出版时间：12 January 2007
- 卷：352
- 期：2
- 页码：390-396
- 文件大小：792 K
摘要
In the screening of selective inhibitors of eukaryotic DNA polymerases (pols), dehydroaltenusin was found to be an inhibitor of pol α from a fungus (Alternaria tennuis). We succeeded in chemically synthesizing dehydroaltenusin, and the compound inhibited only mammalian pol α with IC50 value of 0.5 μM, and did not influence the activities of other replicative pols such as pols δ and ε, but also showed no effect on pol α 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 μM. 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 α-specific inhibitor, but also as a candidate drug for anti-cancer treatment.