Mechanism of cell cycle arrest and apoptosis induction by conjugated eicosapentaenoic acid, which is a mammalian DNA polymerase and topoisomerase inhibitor.
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 microM, 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 anti-cancer compound that inhibited activities of pols and topos.
Yonezawa
Yuko
Y
Laboratory of Food & Nutritional Sciences, Department of Nutritional Science, Kobe-Gakuin University, Kobe, Hyogo, Japan.
Hada
Takahiko
T
Uryu
Keisuke
K
Tsuzuki
Tsuyoshi
T
Nakagawa
Kiyotaka
K
Miyazawa
Teruo
T
Yoshida
Hiromi
H
Mizushina
Yoshiyuki
Y
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004247:DNA / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D015398:Signal Transduction; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D004247:DNA; D015118:Eicosapentaenoic Acid