The effects of dehydroaltenusin, a novel mammalian DNA polymerase alpha inhibitor, on cell proliferation and cell cycle progression.
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.
Murakami-Nakai
Chikako
C
Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe 651-2180, Hyogo, Japan.
Maeda
Naoki
N
Yonezawa
Yuko
Y
Kuriyama
Isoko
I
Kamisuki
Shinji
S
Takahashi
Shunya
S
Sugawara
Fumio
F
Yoshida
Hiromi
H
Sakaguchi
Kengo
K
Mizushina
Yoshiyuki
Y
D000818:Animals; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004261:DNA Replication; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure
D001578:Benzopyrans; D008051:Lipid Bilayers; D008081:Liposomes; D004256:DNA Polymerase I; C095645:dehydroaltenusin