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Title: Anti-tumor effects of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase {alpha}

Abstract

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 IC{sub 50} value of 0.5 {mu}M, 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 LD{sub 50} values of 38.0-44.4 {mu}M. 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.

Authors:
 [1];  [2];  [2];  [3];  [1];  [4];  [5];  [4];  [4];  [1];  [6];  [7];  [8]
  1. Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180 (Japan)
  2. Biomedical Research Center Laboratory of Biomedical Engineering, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo 060-8556 (Japan)
  3. Marine Biomedical Institute, Sapporo Medical University School of Medicine, Oshidomari, Rishirifuji, Hokkaido 097-0101 (Japan)
  4. Department of Applied Biological Science, Tokyo University of Science, Noda, Chiba 278-8510 (Japan)
  5. RIKEN - Institute of Physical and Chemical Research, Wako, Saitama 351-0198 (Japan)
  6. (Japan)
  7. Department of Pathology, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo 060-8556 (Japan)
  8. Laboratory of Food and Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180 (Japan) and Cooperative Research Center of Life Sciences, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180 (Japan). E-mail: mizushin@nutr.kobegakuin.ac.jp
Publication Date:
OSTI Identifier:
20857953
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 352; Journal Issue: 2; Other Information: DOI: 10.1016/j.bbrc.2006.11.021; PII: S0006-291X(06)02491-0; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BROMIDES; DMSO; DNA; DNA POLYMERASES; DNA REPLICATION; DRUGS; EDTA; ENZYME INHIBITORS; FUNGI; HELA CELLS; IN VIVO; LETHAL DOSES; MICE; MITOTIC INDEX; NECROSIS; NEOPLASMS; PHOSPHATES; SCREENING; TETRAZOLIUM; TOXICITY

Citation Formats

Maeda, Naoki, Kokai, Yasuo, Ohtani, Seiji, Sahara, Hiroeki, Kuriyama, Isoko, Kamisuki, Shinji, Takahashi, Shunya, Sakaguchi, Kengo, Sugawara, Fumio, Yoshida, Hiromi, Cooperative Research Center of Life Sciences, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Sato, Noriyuki, and Mizushina, Yoshiyuki. Anti-tumor effects of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase {alpha}. United States: N. p., 2007. Web. doi:10.1016/j.bbrc.2006.11.021.
Maeda, Naoki, Kokai, Yasuo, Ohtani, Seiji, Sahara, Hiroeki, Kuriyama, Isoko, Kamisuki, Shinji, Takahashi, Shunya, Sakaguchi, Kengo, Sugawara, Fumio, Yoshida, Hiromi, Cooperative Research Center of Life Sciences, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Sato, Noriyuki, & Mizushina, Yoshiyuki. Anti-tumor effects of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase {alpha}. United States. doi:10.1016/j.bbrc.2006.11.021.
Maeda, Naoki, Kokai, Yasuo, Ohtani, Seiji, Sahara, Hiroeki, Kuriyama, Isoko, Kamisuki, Shinji, Takahashi, Shunya, Sakaguchi, Kengo, Sugawara, Fumio, Yoshida, Hiromi, Cooperative Research Center of Life Sciences, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Sato, Noriyuki, and Mizushina, Yoshiyuki. 2007. "Anti-tumor effects of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase {alpha}". United States. doi:10.1016/j.bbrc.2006.11.021.
@article{osti_20857953,
title = {Anti-tumor effects of dehydroaltenusin, a specific inhibitor of mammalian DNA polymerase {alpha}},
author = {Maeda, Naoki and Kokai, Yasuo and Ohtani, Seiji and Sahara, Hiroeki and Kuriyama, Isoko and Kamisuki, Shinji and Takahashi, Shunya and Sakaguchi, Kengo and Sugawara, Fumio and Yoshida, Hiromi and Cooperative Research Center of Life Sciences, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180 and Sato, Noriyuki and Mizushina, Yoshiyuki},
abstractNote = {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 IC{sub 50} value of 0.5 {mu}M, 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 LD{sub 50} values of 38.0-44.4 {mu}M. 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.},
doi = {10.1016/j.bbrc.2006.11.021},
journal = {Biochemical and Biophysical Research Communications},
number = 2,
volume = 352,
place = {United States},
year = 2007,
month = 1
}
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