Inhibitory effect of conjugated eicosapentaenoic acid on mammalian DNA polymerase and topoisomerase activities and human cancer cell proliferation.
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 (LD(50)=20.0 microM), 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.
Yonezawa
Yuko
Y
Laboratory of Food & Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan.
Hada
Takahiko
T
Uryu
Keisuke
K
Tsuzuki
Tsuyoshi
T
Eitsuka
Takahiro
T
Miyazawa
Teruo
T
Murakami-Nakai
Chikako
C
Yoshida
Hiromi
H
Mizushina
Yoshiyuki
Y
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D026942:DNA Topoisomerases / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D019384:Nucleic Acid Synthesis Inhibitors; D059003:Topoisomerase Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D059003:Topoisomerase Inhibitors; D015118:Eicosapentaenoic Acid; D004259:DNA-Directed DNA Polymerase; D026942:DNA Topoisomerases