Inhibitory effects of a major soy isoflavone, genistein, on human DNA topoisomerase II activity and cancer cell proliferation

Mizushina,Yoshiyuki; Shiomi,Kazuaki; Kuriyama,Isoko; Takahashi,Yoshihiro; Yoshida,Hiromi

doi:10.3892/ijo.2013.2032

Inhibitory effects of a major soy isoflavone, genistein, on human DNA topoisomerase II activity and cancer cell proliferation

Authors:
- Yoshiyuki Mizushina
- Kazuaki Shiomi
- Isoko Kuriyama
- Yoshihiro Takahashi
- Hiromi Yoshida
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Affiliations: Laboratory of Food and Nutritional Sciences, Faculty of Nutrition, Kobe Gakuin University, Nishi-ku, Kobe, Hyogo 651-2180, Japan, Laboratory of Research and Development, Oguraya Yanagimoto Co. Ltd., Higashi-Nada-ku, Kobe, Hyogo 658-0044, Japan
Published online on: July 23, 2013 https://doi.org/10.3892/ijo.2013.2032
Pages: 1117-1124

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Abstract

The inhibitory activity of 3 soy isoflavones (daidzein, genistein and glycitein) and their glycosides (daidzin, genistin and glycitin) on mammalian DNA polymerases (pols) and topoisomerases (topos) was investigated. Of the compounds tested, only genistein selectively inhibited human topo II activity and had an IC50 value of 37.5 µM. These isoflavones had no effect on the activity of human topo I; mammalian pols α, β, γ and κ; or on any other DNA metabolic enzyme tested. Thermal transition analysis indicated that genistein did not influence the direct binding to double-stranded DNA. Genistein prevented the proliferation of HCT116 human colon carcinoma cells with an LD50 of 94.0 µM and it halted the cell cycle in G2/M phase. These results suggest that decreases in cell proliferation due to genistein may result from the inhibition of cellular topo II and that genistein, a major soy isoflavone, may be an anticancer food component. The relationship between the structures and these bioactivities of soy isoflavones is discussed.

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1.	Liu RH: Potential synergy of phytochemicals in cancer prevention: mechanism of action. J Nutr. 134:3479S–3485S. 2004.PubMed/NCBI
2.	Surh YJ: Cancer chemoprevention with dietary phytochemicals. Nature Rev Cancer. 3:768–780. 2003. View Article : Google Scholar : PubMed/NCBI
3.	Kornberg A and Baker TA: DNA Replication. 2nd edition. W.D. Freeman and Co; New York, NY: pp. 197–225. 1992
4.	Hubscher U, Maga G and Spadari S: Eukaryotic DNA polymerases. Ann Rev Biochem. 71:133–163. 2002. View Article : Google Scholar
5.	Bebenek K and Kunkel TA: Advances in Protein Chemistry. Yang W: Elsevier; San Diego, CA: pp. 137–165. 2004, View Article : Google Scholar
6.	Lange SS, Takata K and Wood RD: DNA polymerases and cancer. Nat Rev Cancer. 11:96–110. 2011. View Article : Google Scholar : PubMed/NCBI
7.	Loeb LA and Monnat RJ Jr: DNA polymerases and human disease. Nature Rev Genet. 9:594–604. 2008. View Article : Google Scholar : PubMed/NCBI
8.	Wang JC: DNA topoisomerases. Ann Rev Biochem. 65:635–692. 1996. View Article : Google Scholar
9.	Liu LF: DNA topoisomerase poisons as antitumor drugs. Ann Rev Biochem. 58:351–375. 1989. View Article : Google Scholar : PubMed/NCBI
10.	Sakaguchi K, Sugawara F and Mizushina Y: Inhibitors of eukaryotic DNA polymerases. Seikagaku. 74:244–251. 2002.(In Japanese).
11.	Berdis AJ: DNA polymerases as therapeutic targets. Biochemistry (Moscow). 47:8253–8260. 2008. View Article : Google Scholar : PubMed/NCBI
12.	Heber D: Plant Foods and Phytochemicals in human health. Berdanier CD, Dwyer JT and Feldman EB: CRC Press. 176–181. 2008.
13.	Barnes S and Messina M: The role of soy products in reducing cancer risk. J Natl Cancer Inst. 83:541–546. 1991. View Article : Google Scholar
14.	Anderson JM, Johnstone BM and Cook-Newell ME: Metaanalysis of the effects of soy protein intake on serum lipids. N Engl J Med. 333:276–282. 1995. View Article : Google Scholar : PubMed/NCBI
15.	Bahram HA, Alekel L, Hollis BW, Amin D, Stacewicz-Sapuntzakis M, Guo P and Kukreja SC: Dietary soybean proteins prevent bone loss in an ovariectomized rat model of osteoporosis. J Nutr. 126:161–167. 1996.PubMed/NCBI
16.	Tamai K, Kojima K, Hanaichi T, Masaki S, Suzuki M, Umekawa H and Yoshida S: Structural study of immunoaffinity-purified DNA polymerase α-DNA primase complex from calf thymus. Biochim Biophys Acta. 950:263–273. 1988.
17.	Date T, Yamaguchi M, Hirose F, Nishimoto Y, Tanihara K and Matsukage A: Expression of active rat DNA polymerase β in Escherichia coli. Biochemistry. 27:2983–2390. 1988.
18.	Umeda S, Muta T, Ohsato T, Takamatsu C, Hamasaki N and Kang D: The D-loop structure of human mtDNA is destabilized directly by 1-methyl-4-phenylpyridinium ion (MPP⁺), a parkinsonism-causing toxin. Eur J Biochem. 267:200–206. 2000. View Article : Google Scholar : PubMed/NCBI
19.	Oshige M, Takeuchi R, Ruike R, Kuroda K and Sakaguchi K: Subunit protein-affinity isolation of Drosophila DNA polymerase catalytic subunit. Protein Expr Purif. 35:248–256. 2004. View Article : Google Scholar : PubMed/NCBI
20.	Kusumoto R, Masutani C, Shimmyo S, Iwai S and Hanaoka F: DNA binding properties of human DNA polymerase η: implications for fidelity and polymerase switching of translesion synthesis. Genes Cells. 9:1139–1150. 2004.
21.	Ohashi E, Murakumo Y, Kanjo N, Akagi J, Masutani C, Hanaoka F and Ohmori H: Interaction of hREV1 with three human Y-family DNA polymerases. Genes Cells. 9:523–531. 2004. View Article : Google Scholar : PubMed/NCBI
22.	Shimazaki N, Yoshida K, Kobayashi T, Toji S, Tamai T and Koiwai O: Over-expression of human DNA polymerase λ in E. coli and characterization of the recombinant enzyme. Genes Cells. 7:639–651. 2002.
23.	Mizushina Y, Tanaka N, Yagi H, Kurosawa T, Onoue M, Seto H, Horie T, Aoyagi N, Yamaoka M, Matsukage A, Yoshida S and Sakaguchi K: Fatty acids selectively inhibit eukaryotic DNA polymerase activities in vitro. Biochim Biophys Acta. 1308:256–262. 1996. View Article : Google Scholar : PubMed/NCBI
24.	Mizushina Y, Yoshida S, Matsukage A and Sakaguchi K: The inhibitory action of fatty acids on DNA polymerase β. Biochim Biophys Acta. 1336:509–521. 1997.
25.	Ogawa A, Murate T, Suzuki M, Nimura Y and Yoshida S: Lithocholic acid, a putative tumor promoter, inhibits mammalian DNA polymerase β. Jpn J Cancer Res. 89:1154–1159. 1998.PubMed/NCBI
26.	Yonezawa Y, Tsuzuki T, Eitsuka T, Miyazawa T, Hada T, Uryu K, Murakami-Nakai C, Ikawa H, Kuriyama I, Takemura M, Oshige M, Yoshida H, Sakaguchi K and Mizushina Y: Inhibitory effect of conjugated eicosapentaenoic acid on human DNA topoisomerases I and II. Arch Biochem Biophys. 435:197–206. 2005. View Article : Google Scholar
27.	Nakayama C and Saneyoshi M: Inhibitory effects of 9-β-D-xylofuranosyladenine 5′-triphosphate on DNA-dependent RNA polymerase I and II from cherry salmon (Oncorhynchus masou). J Biochem (Tokyo). 97:1385–1389. 1985.
28.	Mizushina Y, Dairaku I, Yanaka N, Takeuchi T, Ishimaru C, Sugawara F, Yoshida H and Kato N: Inhibitory action of polyunsaturated fatty acids on IMP dehydrogenase. Biochimie. 89:581–590. 2007. View Article : Google Scholar : PubMed/NCBI
29.	Soltis DA and Uhlenbeck OC: Isolation and characterization of two mutant forms of T4 polynucleotide kinase. J Biol Chem. 257:11332–11339. 1982.PubMed/NCBI
30.	Lu BC and Sakaguchi K: An endo-exonuclease from meiotic tissues of the basidiomycete Coprinus cinereus: ιts purification and characterization. J Biol Chem. 266:21060–21066. 1991.PubMed/NCBI
31.	Mizushina Y, Murakami C, Ohta K, Takikawa H, Mori K, Yoshida H, Sugawara F and Sakaguchi K: Selective inhibition of the activities of both eukaryotic DNA polymerases and DNA topoisomerases by elenic acid. Biochem Pharmacol. 63:399–407. 2002. View Article : Google Scholar : PubMed/NCBI
32.	Ishiyama M, Tominaga H, Shiga M, Sasamoto K, Ohkura Y and Ueno K: A combined assay of cell viability and in vitro cytotoxicity with a highly water-soluble tetrazolium salt, neutral red and crystal violet. Biol Pharm Bull. 19:1518–1520. 1996. View Article : Google Scholar : PubMed/NCBI
33.	Isoflavones contents of food. http://www.isoflavones.info/isoflavones-content.php. Accessed May 15, 2012.
34.	Coldham NG, Darby C, Hows M, King LJ, Zhang AQ and Sauer MJ: Comparative metabolism of genistin by human and rat gut microflora: detection and identification of the end-products of metabolism. Xenobiotica. 22:45–62. 2001.PubMed/NCBI
35.	Christian B: Topoisomerase I poisons and suppressors as anti-cancer drugs. Curr Med Chem. 7:39–58. 2000. View Article : Google Scholar : PubMed/NCBI
36.	Davis TA, Mungunsukh O, Zins S, Day RM and Landauer MR: Genistein induces radioprotection by hematopoietic stem cell quiescence. Int J Radiat Biol. 84:713–726. 2008. View Article : Google Scholar : PubMed/NCBI
37.	Lee YW and Lee WH: Protective effects of genistein on proinflammatory pathways in human brain microvascular endothelial cells. J Nutr Biochem. 19:819–825. 2008. View Article : Google Scholar : PubMed/NCBI
38.	Okamura S, Sawada Y, Satoh T, Sakamoto H, Saito Y, Sumino H, Takizawa T, Kogure T, Chaichantipyuth C, Higuchi Y, Ishikawa T and Sakamaki T: Pueraria mirifica phytoestrogens improve dyslipidemia in postmenopausal women probably by activating estrogen receptor subtypes. Tohoku J Exp Med. 216:341–351. 2008. View Article : Google Scholar