Inhibitory effect of conjugated eicosapentaenoic acid on mammalian DNA polymerase and topoisomerase activities and human cancer cell proliferation

Biochem Pharmacol. 2005 Aug 1;70(3):453-60. doi: 10.1016/j.bcp.2005.05.008.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA Topoisomerases / metabolism
  • DNA-Directed DNA Polymerase / metabolism
  • Eicosapentaenoic Acid / chemistry
  • Eicosapentaenoic Acid / pharmacology*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Growth Inhibitors / chemistry
  • Growth Inhibitors / pharmacology*
  • HL-60 Cells
  • Humans
  • Leukemia, Promyelocytic, Acute / drug therapy*
  • Leukemia, Promyelocytic, Acute / enzymology*
  • Leukemia, Promyelocytic, Acute / pathology
  • Nucleic Acid Synthesis Inhibitors*
  • Topoisomerase Inhibitors*

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Growth Inhibitors
  • Nucleic Acid Synthesis Inhibitors
  • Topoisomerase Inhibitors
  • Eicosapentaenoic Acid
  • DNA-Directed DNA Polymerase
  • DNA Topoisomerases