Mechanism of cell cycle arrest and apoptosis induction by conjugated eicosapentaenoic acid, which is a mammalian DNA polymerase and topoisomerase inhibitor

Yuko Yonezawa, Takahiko Hada, Keisuke Uryu, Tsuyoshi Tsuzuki, Kiyotaka Nakagawa, Teruo Miyazawa, Hiromi Yoshida, Yoshiyuki Mizushina

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1197-1204
Number of pages8
JournalInternational journal of oncology
Volume30
Issue number5
DOIs
Publication statusPublished - 2007 May

Keywords

  • Apoptosis
  • Cell cycle arrest
  • Cell proliferation
  • Conjugated eicosapentaenoic acid
  • DNA polymerase
  • DNA replication
  • DNA topoisomerase
  • Enzyme inhibitor
  • p53

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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