Anti-tumor effects of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase alpha.
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 microM, 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 microM. 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 alpha-specific inhibitor, but also as a candidate drug for anti-cancer treatment.
Maeda
Naoki
N
Laboratory of Food & Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Kobe, Hyogo 651-2180, Japan.
Kokai
Yasuo
Y
Ohtani
Seiji
S
Sahara
Hiroeki
H
Kuriyama
Isoko
I
Kamisuki
Shinji
S
Takahashi
Shunya
S
Sakaguchi
Kengo
K
Sugawara
Fumio
F
Yoshida
Hiromi
H
Sato
Noriyuki
N
Mizushina
Yoshiyuki
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001578:Benzopyrans / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology
D000970:Antineoplastic Agents; D001578:Benzopyrans; D004256:DNA Polymerase I; C095645:dehydroaltenusin