Advertisement

Archives of Pharmacal Research

, Volume 30, Issue 11, pp 1435–1439 | Cite as

Inhibition of topoisomerase I activity and efflux drug transporters’ expression by xanthohumol from hops

  • Sung Ho Lee
  • Hyun Jung Kim
  • Jung Sun Lee
  • Ik-Soo Lee
  • Bok Yun KangEmail author
Article Drug efficacy and safety

Abstract

Xanthohumol (XN) and its related compounds were evaluated for their cytotoxicity against four different human cancer cell lines, A549 (lung), SK-OV-3 (ovarian), SK-MEL-2 (melanoma), and HCT-15 (colon) using a sulforhodamine B assay. XN showed the most active cytotoxicity against the human cancer cell lines. Isoxanthohumol, 8-prenylnaringenin, and xanthohumol 4’-O-β-D-glucopyranoside showed comparable cytotoxicity and (2S)-5-methoxy-8-prenylnaringe-nin 7-O-β-D-glucopyranoside was the least cytotoxic compound. The anticancer properties of XN, the most active cytotoxic compound, were further investigated. XN showed an inhibitory effect on the activity of DNA topoisomerase I (topo I), which was measured from the relaxation of supercoiled DNA. The inhibition of topo I by XN might explain the cytotoxicity against the human cancer cell lines. Moreover, the expression of the drug efflux genes was investigated to predict the drug resistance. XN clearly decreased the mRNA levels of ABCB1 (MDR1), ABCC1 (MRP1), ABCC2 (MRP2), and ABCC3 (MRP3). These results suggest that XN has anticancer properties by inhibiting the topo I activity and it might be used in conjunction with other anticancer chemotherapeutic agents to reduce the drug resistance inhibiting the efflux drug transporters.

Key words

Xanthohumol Cytotoxicity Topoisomerase I Efflux drug transporter Cancer 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Albini, A., Dell’Eva, R., Vene, R., Ferrari, N., Buhler, D. R., Noonan, D. M., and Fassina, G., Mechanisms of the antiangiogenic activity by the hop flavonoid xanthohumol: NF-kappaB and Akt as targets.FASEB J., 20, 527–529 (2006).PubMedGoogle Scholar
  2. Chen, A. Y. and Liu, L. F., DNA topoisomerase: essential enzymes and lethal targets.Annu. Rev. Pharmacol. Toxicol., 34, 191- 218 (1994).PubMedCrossRefGoogle Scholar
  3. Clark, A. M., McChesney, J. D., and Hufford, C. D., The use of microorganisms for the study of drug metabolism.Med. Res. Rev., 5, 231–253 (1985).PubMedCrossRefGoogle Scholar
  4. D’Arpa, P. and Liu, L. F., Topoisomerase-targeting antitumor drugs.Biochim. Biophys. Acta, 989, 163–177 (1989).PubMedGoogle Scholar
  5. Dietz, B. M., Kang, Y. H., Liu, G., Eggler, A. L., Yao, P., Chadwick, L. R., Pauli, G. F., Farnsworth, N. R., Mesecar, A. D., van Breemen, R. B., and Bolton, J. L., Xanthohumol isolated from Humulus lupulus Inhibits menadione-induced DNA damage through induction of quinone reductase.Chem. Res. Toxicol., 18, 1296–1305 (2005).PubMedCrossRefGoogle Scholar
  6. Fukuda, M., Nishio, K., Kanzawa, F., Ogasawara, H., Ishida, T., Arioka, H., Bojanowski, K., Oka, M., and Saijo, N., Synergism between cisplatin and topoisomerase I inhibitors, NB-506 and SN-38, in human small cell lung cancer cells.Cancer Res., 56, 789–793 (1996).PubMedGoogle Scholar
  7. Gerhauser, C., Alt, A., Heiss, E., Gamal-Eldeen, A., Klimo, K., Knauft, J., Neumann, I., Scherf, H. R., Frank, N., Bartsch, H., and Becker, H., Cancer chemopreventive activity of Xanthohumol a natural product derived from hop.Mol. Cancer Ther., 1, 959–969 (2002).PubMedGoogle Scholar
  8. Gottesman, M. M., Fojo, T., and. Bates, S. E., Multidrug resistance in cancer: role of ATP-dependent transporter.Nat. Rev. Cancer, 2, 48–58 (2002).PubMedCrossRefGoogle Scholar
  9. Henderson, M. C., Miranda, C. L., Stevens, J. F., Deinzer, M. L., and Buhler, D. R., In vitro inhibition of human P450 enzymes by prenylated flavonoids from hops,Humulus lupulus. Xenobiotica, 30, 235–251 (2000).CrossRefGoogle Scholar
  10. Hsiang, Y. H., Hertzberg, R., Hecht, S., and Liu, L. F., Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I.J. Biol. Chem., 260, 14873–14878 (1985).PubMedGoogle Scholar
  11. Huang, R., Murry D. J., Kolwankar, D., Hall, S. D., and Foster, D. R., Vincristine transcriptional regulation of efflux drug transporters in carcinoma cell lines.Biochem Pharmacol., 71, 1695–1704 (2006).PubMedCrossRefGoogle Scholar
  12. Jain, A. C., Gupta, R. C., and Sarpal, P. D., Synthesis of (±) lupinifolin, di-O-methyl xanthohumol and isoxanthohumol and related compounds.Tetrahedron, 34, 3563–3567 (1978).CrossRefGoogle Scholar
  13. Kim, H. J. and Lee, I.-S., Microbial metabolism of the prenylated chalcone xanthohumol.J. Nat. Prod., 69, 1522–1524 (2006).PubMedCrossRefGoogle Scholar
  14. Kool, M., de Haas, M., Scheffer, G. L., Scheper, R. J., van Eijk, M. J., Juijn, J. A., Baas, F., and Borst, P., Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines.Cancer Res., 57, 3537–3547 (1997).PubMedGoogle Scholar
  15. Kweon, M. H., Adhami, V. M., Lee, J. S., and Mukhtar, H., Constitutive overexpression of Nrf2-dependent heme oxygenase-1 in A549 cells contributes to resistance to apoptosis induced by epigallocatechin 3-gallate.J. Biol. Chem., 281, 33761–33772 (2006).PubMedCrossRefGoogle Scholar
  16. Liu, G., Eggler, A. L., Dietz, B. M., Mesecar, A. D., Bolton, J. L., Pezzuto, J. M., and van Breemen, R. B., Screening method for the discovery of potential cancer chemoprevention agents based on mass spectrometric detection of alkylated Keap1.Anal. Chem., 77, 6407–6414 (2005).PubMedCrossRefGoogle Scholar
  17. Minemura, M., Tanimura, H., and Tabor, E., Overexpression of multidrug resistance genes MDR1 and cMOAT in human hepatocellular carcinoma and hepatoblastoma cell lines.Int. J.Oncol., 15, 559–563 (1999).PubMedGoogle Scholar
  18. Miranda, C. L., Aponso, G. L., Stevens, J. F., Deinzer, M. L., and Buhler, D. R., Prenylated chalcones and flavanones as inducers of quinone reductase in mouse Hepa 1c1c7 cells.Cancer Lett., 149, 21–29 (2000).PubMedCrossRefGoogle Scholar
  19. Miranda, C. L., Stevens, J. F., Helmlich, A., Henderson, M. C., Rodriguez, R. J., Yang, Y. H., Deinzer, M. L., Barnes, D. W., and Buhler, D. R., Antiproliferative and cytotoxic effects of prenylated flavonoids from hops (Humulus lupulus) in human cancer cell lines.Food Chem. Toxicol., 37, 271–285 (1999).PubMedCrossRefGoogle Scholar
  20. Miranda, C. L., Yang, Y. H., Henderson, M. C., Stevens, J. F., Santana-Rios, G., Deinzer, M. L., and Buhler, D.R., Prenyl- flavonoids from hops inhibit the metabolic activation of the carcinogenic heterocyclic amine 2-amino-3-methylimidazo[4, 5-f]quinoline, mediated by cDNA-expressed human CYP1A2.Drug Metab. Dispos., 28, 1297–1302 (2000).PubMedGoogle Scholar
  21. Skehan, P., Storeng, R., Scudiero, D., Monks, A., McMahon, J., Vistica, D., Warren, J. T., Bokesch, H., Kenney, S., and Boyd, M. R., New colorimetric cytotoxicity assay for anticancer-drug screening.J. Natl. Cancer Inst., 82, 1107–1112 (1990).PubMedCrossRefGoogle Scholar
  22. Slichenmyer, W. J., Rowinsky, E. K., Donehower, R. C., and Kaufmann, S. H., The current status of camptothecin analogues as antitumor agents.J. Natl. Cancer Inst., 85, 271- 291 (1993).PubMedCrossRefGoogle Scholar
  23. Stevens, J. F. and Page, J. E., Xanthohumol and related prenyl-flavonoids from hops and beer: to your good health!Photochemistry, 65, 1317–1330 (2004).CrossRefGoogle Scholar
  24. Stevens, J. F., Ivancic, M., Hsu, V. L., and Deinzer, M. L., Prenyl- flavonoids fromHumulus lupulus.Phytochemistry, 44, 1574–1585 (1997).CrossRefGoogle Scholar
  25. Venisetty, R. K. and Ciddi, V., Application of microbial biotransformation for the new drug discovery using natural drugs as substrates.Curr. Pharm. Biotechnol., 4, 153–167 (2003).PubMedCrossRefGoogle Scholar
  26. Wang, J. C., DNA topoisomerases.Annu. Rev. Biochem., 65, 635–692 (1996).PubMedCrossRefGoogle Scholar
  27. Young, L. C., Campling, B. G., Cole, S. P. C., Deeley R. G., and Gerlach, J. H., Multidrug resistance proteins MRP3, MRP1, and MRP2 in lung cancer: correlation of protein levels with drug response and messenger RNA levels.Clin. Cancer Res., 7, 1798–1804 (2001).PubMedGoogle Scholar
  28. Zhao, F., Nozawa, H., Daikonnya, A., Kondo, K., and Kitanaka, S. Inhibitors of nitric oxide production from hops(Humulus lupulus L.Biol. Pharm. Bull., 26, 61–65 (2003).PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2007

Authors and Affiliations

  • Sung Ho Lee
    • 1
  • Hyun Jung Kim
    • 1
  • Jung Sun Lee
    • 1
  • Ik-Soo Lee
    • 1
  • Bok Yun Kang
    • 1
    Email author
  1. 1.College of Pharmacy and Research Institute of Drug DevelopmentChonnam National UniversityGwangjuKorea

Personalised recommendations