Anti-tumor effects of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase alpha

作者：Maeda Naoki; Kokai Yasuo; Ohtani Seiji; Sahara Hiroeki; Kuriyama Soko; Kamisuki Shinji; Takahashi Shunya; Sakaguchi Kengo; Sugawara Fumio; Yoshida Hiromi; Sato Noriyuki; Mizushina Yoshiyuki^*

来源：Biochemical and Biophysical Research Communications, 2007, 352(2): 390-396.

DOI：10.1016/j.bbrc.2006.11.021

• dehydroaltenusin
• enzyme inhibitor
• DNA polymerase alpha
• DNA replication
• cytotoxicity
• anti-tumor activity

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.

• 出版日期2007-1-12