Int. J. Mol. Sci. 2007, 8(12), 1206-1224; doi:10.3390/i8121206
Review

Mechanism of Growth Inhibition of Human Cancer Cells by Conjugated Eicosapentaenoic Acid, an Inhibitor of DNA Polymerase and Topoisomerase

1email, 1email and 1,* email
Received: 12 November 2007; in revised form: 27 November 2007 / Accepted: 28 November 2007 / Published: 7 December 2007
(This article belongs to the Special Issue Natural Compounds for Cancer Treatment and Prevention)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract: DNA topoisomerases (topos) and DNA polymerases (pols) are involved in manyaspects of DNA metabolism such as replication reactions. We found that long chainunsaturated fatty acids such as polyunsaturated fatty acids (PUFA) (i.e., eicosapentaenoicacid (EPA) and docosahexaenoic acid (DHA)) inhibited the activities of eukaryotic pols andtopos in vitro, and the inhibitory effect of conjugated fatty acids converted from EPA andDHA (cEPA and cDHA) on pols and topos was stronger than that of normal EPA and DHA.cEPA and cDHA did not affect the activities of plant and prokaryotic pols or other DNAmetabolic enzymes tested. cEPA was a stronger inhibitor than cDHA with IC50 values formammalian pols and human topos of 11.0 - 31.8 and 0.5 - 2.5 μM, respectively. cEPAinhibited the proliferation of two human leukemia cell lines, NALM-6, which is a p53-wildtype, and HL-60, which is a p53-null mutant, and the inhibitory effect was stronger than thatof normal EPA. In both cell lines, cEPA arrested in the G1 phase, and increased cyclin Eprotein levels, indicating that it blocks the primary step of in vivo DNA replication byinhibiting the activity of replicative pols rather than topos. DNA replication-relatedproteins, such as RPA70, ATR and phosphorylated-Chk1/2, were increased by cEPAtreatment in the cell lines, suggesting that cEPA led to DNA replication fork stressinhibiting 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 cellapoptosis through both p53-dependent and p53-independent pathways in cell lines NALM-6and HL-60, respectively. These results suggested the therapeutic potential of conjugatedPUFA, such as cEPA, as a leading anti-cancer compound that inhibited pols and toposactivities.
Keywords: conjugated eicosapentaenoic acid (cEPA); DNA polymerase; DNA topoisomerase; enzyme inhibitor; DNA replication; cell proliferation; cell cycle arrest; p53; apoptosis
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MDPI and ACS Style

Yonezawa, Y.; Yoshida, H.; Mizushina, Y. Mechanism of Growth Inhibition of Human Cancer Cells by Conjugated Eicosapentaenoic Acid, an Inhibitor of DNA Polymerase and Topoisomerase. Int. J. Mol. Sci. 2007, 8, 1206-1224.

AMA Style

Yonezawa Y, Yoshida H, Mizushina Y. Mechanism of Growth Inhibition of Human Cancer Cells by Conjugated Eicosapentaenoic Acid, an Inhibitor of DNA Polymerase and Topoisomerase. International Journal of Molecular Sciences. 2007; 8(12):1206-1224.

Chicago/Turabian Style

Yonezawa, Yuko; Yoshida, Hiromi; Mizushina, Yoshiyuki. 2007. "Mechanism of Growth Inhibition of Human Cancer Cells by Conjugated Eicosapentaenoic Acid, an Inhibitor of DNA Polymerase and Topoisomerase." Int. J. Mol. Sci. 8, no. 12: 1206-1224.

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