TY - JOUR
T1 - Inhibitory effect of conjugated eicosapentaenoic acid on mammalian DNA polymerase and topoisomerase activities and human cancer cell proliferation
AU - Yonezawa, Yuko
AU - Hada, Takahiko
AU - Uryu, Keisuke
AU - Tsuzuki, Tsuyoshi
AU - Eitsuka, Takahiro
AU - Miyazawa, Teruo
AU - Murakami-Nakai, Chikako
AU - Yoshida, Hiromi
AU - Mizushina, Yoshiyuki
N1 - Funding Information:
We are grateful for the donations of calf pol α, rat pol β and human pol δ, ɛ by Dr. M. Takemura of Mie University (Mie, Japan), Dr. A. Matsukage of Japan Women's University (Tokyo, Japan) and Dr. K. Sakaguchi of Tokyo University of Science (Chiba, Japan), respectively. This work was supported in part by a Grant-in-aid for Kobe Gakuin University Joint Research (B) (H.Y. and Y.M.) and “High-Tech Research Center” Project for Private Universities: matching fund subsidy from MEXT (Ministry of Education, Culture, Sports, Science and Technology), 2001–2005 (H.Y. and Y.M.). Y.M. acknowledges Grants-in-aid from the Uehara Memorial Foundation (Japan), the Takeda Science Foundation (Japan) and The Japan Food Chemical Research Foundation (Japan), and Grant-in-aid 16710161 for Scientific Research, MEXT (Japan).
PY - 2005/8/1
Y1 - 2005/8/1
N2 - Conjugated eicosapentaenoic acid (cEPA) selectively inhibited the activities of mammalian DNA polymerases (pols) and human DNA topoisomerases (topos) [Yonezawa Y, Tsuzuki T, Eitsuka T, Miyazawa T, Hada T, Uryu K, et al. Inhibitory effect of conjugated eicosapentaenoic acid on human DNA topoisomerases I and II. Arch Biochem Biophys 2005;435:197-206]. In this report, we investigated the inhibitory effect of cEPA on a human promyelocytic leukemia cell line, HL-60, to determine which enzymes influence cell proliferation. cEPA inhibited the proliferation of HL-60 cells (LD50 = 20.0 μM), and the inhibitory effect was stronger than that of non-conjugated EPA. cEPA arrested the cells at G1/S-phase, increased cyclin A and E protein levels, and prevented the incorporation of thymidine into the cells, indicating that it blocks the primary step of in vivo DNA replication by inhibiting the activity of replicative pols rather than topos. This compound also induced apoptosis of the cells. These results suggested the therapeutic potential of cEPA as a leading anti-cancer compound that poisons pols.
AB - Conjugated eicosapentaenoic acid (cEPA) selectively inhibited the activities of mammalian DNA polymerases (pols) and human DNA topoisomerases (topos) [Yonezawa Y, Tsuzuki T, Eitsuka T, Miyazawa T, Hada T, Uryu K, et al. Inhibitory effect of conjugated eicosapentaenoic acid on human DNA topoisomerases I and II. Arch Biochem Biophys 2005;435:197-206]. In this report, we investigated the inhibitory effect of cEPA on a human promyelocytic leukemia cell line, HL-60, to determine which enzymes influence cell proliferation. cEPA inhibited the proliferation of HL-60 cells (LD50 = 20.0 μM), and the inhibitory effect was stronger than that of non-conjugated EPA. cEPA arrested the cells at G1/S-phase, increased cyclin A and E protein levels, and prevented the incorporation of thymidine into the cells, indicating that it blocks the primary step of in vivo DNA replication by inhibiting the activity of replicative pols rather than topos. This compound also induced apoptosis of the cells. These results suggested the therapeutic potential of cEPA as a leading anti-cancer compound that poisons pols.
KW - Apoptosis
KW - Cell proliferation
KW - Conjugated eicosapentaenoic acid (cEPA)
KW - Cytotoxicity
KW - DNA polymerase
KW - DNA replication
KW - Enzyme inhibitor
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U2 - 10.1016/j.bcp.2005.05.008
DO - 10.1016/j.bcp.2005.05.008
M3 - Article
C2 - 15963470
AN - SCOPUS:21344432832
SN - 0006-2952
VL - 70
SP - 453
EP - 460
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 3
ER -
