The effects of dehydroaltenusin, a novel mammalian DNA polymerase alpha inhibitor, on cell proliferation and cell cycle progression
| Autor: | Yoshiyuki Mizushina, Shunya Takahashi, Yuko Yonezawa, Hiromi Yoshida, Kengo Sakaguchi, Isoko Kuriyama, Naoki Maeda, Shinji Kamisuki, Fumio Sugawara, Chikako Murakami-Nakai |
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| Rok vydání: | 2004 |
| Předmět: |
DNA Replication
Cell cycle checkpoint DNA polymerase Cell Survival Cyclin A Lipid Bilayers Biophysics Biochemistry HeLa Animals Humans Benzopyrans Molecular Biology biology Dose-Response Relationship Drug Molecular Structure Cell growth Cell Cycle Cell cycle biology.organism_classification DNA Polymerase I Molecular biology Proliferating cell nuclear antigen Cell biology Cancer cell Liposomes biology.protein Cell Division HeLa Cells |
| Zdroj: | Biochimica et biophysica acta. 1674(2) |
| ISSN: | 0006-3002 |
| Popis: | As described previously, a natural product isolated from fungus ( Acremonium sp.), dehydroaltenusin, is an inhibitor of mammalian DNA polymerase α 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 α 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 LD 50 value of 38 μM, 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. |
| Databáze: | OpenAIRE |
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