dehydroaltenusin and Neoplasms

We carried out a screen for small molecule selective inhibitors of eukaryotic DNA polymerases (pols). Dehydroaltenusin, isolated from a fungus (Alternaria tenuis), was found to be a specific inhibitor of pol α.. We succeeded in chemically synthesizing dehydroaltenusin along with five analogs. Of these compounds, dehydroaltenusin was the strongest and most specific inhibitor of mammalian pol α, with an IC(50) value of 0.68 μM. The inhibitory mode of action of dehydroaltenusin against mammalian pol α activity was competitive with respect to the DNA template primer and non-competitive with respect to the 2'-deoxyribonucleoside 5'-triphosphate substrate. Dehydroaltenusin inhibited the cell proliferation of a human cervical cancer cell line, HeLa, by arresting the cells at the S-phase, and preventing the incorporation of thymidine into the cells. These observations indicate that dehydroaltenusin blocks in vivo DNA replication by inhibiting pol α.. Dehydroaltenusin was effective in suppressing the growth of solid tumors and, therefore, is of interest as a candidate drug for anti-cancer treatment.

Topics: Animals; Benzopyrans; Cell Proliferation; DNA Polymerase I; Enzyme Inhibitors; Humans; Mammals; Neoplasms

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.

Topics: Animals; Antineoplastic Agents; Benzopyrans; Cell Line, Tumor; Cell Proliferation; DNA Polymerase I; Dose-Response Relationship, Drug; HeLa Cells; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms