As described previously, a
natural product isolated from fungus (Acremonium sp.),
dehydroaltenusin, is an inhibitor of mammalian
DNA polymerase alpha in vitro [Y. Mizushina, S. Kamisuki, T. Mizuno, M. Takemura, H. Asahara, S. Linn, T. Yamaguchi, A. Matsukage, F. Hanaoka, S. Yoshida, M. Saneyoshi, F. Sugawara, K. Sakaguchi,
Dehydroaltenusin, a mammalian
DNA polymerase alpha inhibitor, J. Biol. Chem. 275 (2000) 33957_33961]. In this study, we investigated the interaction of
dehydroaltenusin with
lipid bilayers using an in vitro
liposome system, which is a model of the cell membrane, and found that approximately 4% of
dehydroaltenusin was incorporated into
liposomes. We also investigated the influence of
dehydroaltenusin on cultured
cancer cells.
Dehydroaltenusin inhibited the growth of HeLa cells with an LD50 value of 38 microM, and as expected, S phase accumulation in the cell cycle. The total
DNA polymerase activity of the extract of incubated cells with
dehydroaltenusin was 23% lower than that of nontreated cells.
Dehydroaltenusin increased
cyclin E and
cyclin A levels. In the analysis of the cell cycle using G1/S synchronized cells by employing
hydroxyurea, the compound delayed both entry into the S phase and S phase progression. In a similar analysis using G2/M synchronized cells by employing
nocodazole, the compound accumulated the cells at G1/S and inhibited entry into the S phase. Thus, the pharmacological abrogation of cell proliferation by
dehydroaltenusin may prove to be an effective chemotherapeutic agent against
tumors.