TY - JOUR
T1 - Mechanism of cell cycle arrest and apoptosis induction by conjugated eicosapentaenoic acid, which is a mammalian DNA polymerase and topoisomerase inhibitor
AU - Yonezawa, Yuko
AU - Hada, Takahiko
AU - Uryu, Keisuke
AU - Tsuzuki, Tsuyoshi
AU - Nakagawa, Kiyotaka
AU - Miyazawa, Teruo
AU - Yoshida, Hiromi
AU - Mizushina, Yoshiyuki
PY - 2007/5
Y1 - 2007/5
N2 - Conjugated eicosapentaenoic acid (cEPA) selectively inhibited the activities of mammalian DNA polymerases (pols) and human DNA topoisomerases (topos). cEPA inhibited the cell growth of two human leukemia cell lines, NALM-6, which is a p53-wild type, and HL-60, which is a p53-null mutant, with LD50 values of 37.5 and 12.5 μM, respectively. In both cell lines, cEPA arrested in the G1 phase, and increased cyclin E protein levels, indicating that it blocks the primary step of in vivo DNA replication by inhibiting the activity of replicative pols rather than topos. DNA replication-related proteins such as RPA70, ATR and phosphorylated-Chk1/2 were increased by cEPA treatment in the cell lines, suggesting that cEPA led to DNA replication fork stress inhibiting the activities of pols and topos, and the ATR-dependent DNA damage response pathway could respond to the inhibitor of DNA replication. The compound induced cell apoptosis through both p53-dependent and p53-independent pathways in cell lines NALM-6 and HL-60, respectively. These results suggested the therapeutic potential of cEPA as a leading anticancer compound that inhibited activities of pols and topos.
AB - Conjugated eicosapentaenoic acid (cEPA) selectively inhibited the activities of mammalian DNA polymerases (pols) and human DNA topoisomerases (topos). cEPA inhibited the cell growth of two human leukemia cell lines, NALM-6, which is a p53-wild type, and HL-60, which is a p53-null mutant, with LD50 values of 37.5 and 12.5 μM, respectively. In both cell lines, cEPA arrested in the G1 phase, and increased cyclin E protein levels, indicating that it blocks the primary step of in vivo DNA replication by inhibiting the activity of replicative pols rather than topos. DNA replication-related proteins such as RPA70, ATR and phosphorylated-Chk1/2 were increased by cEPA treatment in the cell lines, suggesting that cEPA led to DNA replication fork stress inhibiting the activities of pols and topos, and the ATR-dependent DNA damage response pathway could respond to the inhibitor of DNA replication. The compound induced cell apoptosis through both p53-dependent and p53-independent pathways in cell lines NALM-6 and HL-60, respectively. These results suggested the therapeutic potential of cEPA as a leading anticancer compound that inhibited activities of pols and topos.
KW - Apoptosis
KW - Cell cycle arrest
KW - Cell proliferation
KW - Conjugated eicosapentaenoic acid
KW - DNA polymerase
KW - DNA replication
KW - DNA topoisomerase
KW - Enzyme inhibitor
KW - p53
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UR - http://www.scopus.com/inward/citedby.url?scp=34447332293&partnerID=8YFLogxK
U2 - 10.3892/ijo.30.5.1197
DO - 10.3892/ijo.30.5.1197
M3 - Article
C2 - 17390022
AN - SCOPUS:34447332293
VL - 30
SP - 1197
EP - 1204
JO - International Journal of Oncology
JF - International Journal of Oncology
SN - 1019-6439
IS - 5
ER -