Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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In Vitro Genotoxicity Assessment of a Novel Resveratrol Analogue, HS-1793

  • Jeong, Min Ho (Department of Microbiology, Dong-A University College of Medicine) ;
  • Yang, Kwangmo (Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences) ;
  • Lee, Chang Geun (Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences) ;
  • Jeong, Dong Hyeok (Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences) ;
  • Park, You Soo (Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences) ;
  • Choi, Yoo Jin (Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences) ;
  • Kim, Joong Sun (Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences) ;
  • Oh, Su Jung (Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences) ;
  • Jeong, Soo Kyung (Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences) ;
  • Jo, Wol Soon (Department of Research Center, Dong Nam Institute of Radiological and Medical Sciences)
  • Received : 2014.05.27
  • Accepted : 2014.09.19
  • Published : 2014.09.30
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Abstract

Resveratrol has received considerable attention as a polyphenol with various biological effects such as anti-inflammatory, anti-oxidant, anti-mutagenic, anti-carcinogenic, and cardioprotective properties. As part of the overall safety assessment of HS-1793, a novel resveratrol analogue free from the restriction of metabolic instability and the high dose requirement of resveratrol, we assessed genotoxicity in three in vitro assays: a bacterial mutation assay, a comet assay, and a chromosomal aberration assay. In the bacterial reverse mutation assay, HS-1793 did not increase revertant colony numbers in S. typhimurium strains (TA98, TA100, TA1535 and TA1537) or an E. coli strain (WP2 uvrA) regardless of metabolic activation. HS-1793 showed no evidence of genotoxic activity such as DNA damage on L5178Y $Tk^{+/-}$ mouse lymphoma cells with or without the S9 mix in the in vitro comet assay. No statistically significant differences in the incidence of chromosomal aberrations following HS-1793 treatment was observed on Chinese hamster lung cells exposed with or without the S9 mix. These results provide additional evidence that HS-1793 is non-genotoxic at the dose tested in three standard tests and further supports the generally recognized as safe determination of HS-1793 during early drug development.

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References

  1. Gusman, J., Malonne, H. and Atassi, G. (2001) A reappraisal of the potential chemopreventive and chemotherapeutic properties of resveratrol. Carcinogenesis, 22, 1111-1117. https://doi.org/10.1093/carcin/22.8.1111
  2. Pervaiz, S. and Holme, A.L. (2009) Resveratrol: its biologic targets and functional activity. Antioxid. Redox. Signaling, 11, 2851-2897. https://doi.org/10.1089/ars.2008.2412
  3. Aggarwal, B.B., Bhardwaj, A., Aggarwal, R.S., Seeram, N.P., Shishodia, S. and Takada, Y. (2004) Role of resveratrol in prevention and therapy of cancer: Preclinical and clinical studies. Anticancer Res., 24, 2783-2840.
  4. Park, J.W., Choi, Y.J., Suh, S.I., Baek, W.K., Suh, M.H., Jin, I.N., Min, D.S., Woo, J.H., Chang, J.S., Passaniti, A., Lee, Y.H. and Kwon, T.K. (2001) Bcl-2 overexpression attenuates resveratrol-induced apoptosis in U937 cells by inhibition of caspase-3 activity. Carcinogenesis, 22, 1633-1639. https://doi.org/10.1093/carcin/22.10.1633
  5. Saiko, P., Szakmary, A., Jaeger, W. and Szekeres, T. (2008) Resveratrol and its analogs: defense against cancer, coronary disease and neurodegenerative maladies or just a fad? Mutat. Res., 658, 68-94. https://doi.org/10.1016/j.mrrev.2007.08.004
  6. Jeong, S.H., Lee, J.S., Jeong, N.Y., Kim, T.H., Yoo, K.S., Song, S., Suh, H., Kwon, T.K., Park, B.S. and Yoo, Y.H. (2009) A novel resveratrol analogue HS-1793 treatment overcomes the resistance conferred by Bcl-2 and is associated with the formation of mature PML nuclear bodies in renal clear cell carcinoma Caki-1 cells. Int. J. Oncol., 35, 1353-1360.
  7. Jeong, S.H., Jo, W.S., Song, S., Suh, H., Seo, S.Y., Lee, S.H., Kwon, T.K. and Yoo, Y.H. (2009) A novel resveratrol derivative, HS1793, overcomes the resistance conferred by Bcl-2 in human leukemic U937 cells. Biochem. Pharmacol., 77, 1337-1347. https://doi.org/10.1016/j.bcp.2009.01.002
  8. Kim, H.J., Yang, K.M., Park, Y.S., Choi, Y.J., Yun, J.H., Son, C.H., Suh, H.S., Jeong, M.H. and Jo, W.S. (2012) The novel resveratrol analogue HS-1793 induces apoptosis via the mitochondrial pathway in murine breast cancer cells. Int. J. Oncol., 41, 1628-1634. https://doi.org/10.3892/ijo.2012.1615
  9. Jeong, S.H., Song, I.S., Kim, H.K., Lee, S.R., Song, S., Suh, H., Yoon, Y.G., Yoo, Y.H., Kim, N., Rhee, B.D., Ko, K.S. and Han, J. (2012) An alogue of resveratrol HS-1793 exhibits anticancer activity against MCF-7 Cells via Inhibition of mitochondrial biogenesis bene expression. Mol. Cells, 34, 357-365. https://doi.org/10.1007/s10059-012-0081-7
  10. Jeong, N.Y., Yoon, Y.G., Rho, J.H., Lee, J.S., Lee, S.Y., Yoo, K.S., Song, S., Suh, H., Choi, Y.H. and Yoo, Y.H. (2011) The novel resveratrol analog HS-1793-induced polyploid LNCaP prostate cancer cells are vulnerable to downregulation of BclxL. Int. J. Oncol., 38, 1597-1604.
  11. Choi, Y.J., Yang, K.M., Kim, S.D., Yoo, Y.H., Lee, S.W., Seo, S.Y., Suh, H., Yee, S.T., Jeong, M.H. and Jo, W.S. (2012) Resveratrol analogue HS-1793 induces the modulation of tumorderived T cells. Exp. Ther. Med., 3, 592-598. https://doi.org/10.3892/etm.2012.472
  12. Jeong, M.H., Yang, K.M., Choi, Y.J., Kim, S.D., Yoo, Y.H., Seo, S.Y., Lee, S.H., Ryu, S.R., Lee, C.M., Suh, H.S. and Jo, W.S. (2012) Resveratrol analog, HS-1793 enhance anti-tumor immunity by reducing the CD4+ CD25+ regulatory T cells in FM3A tumor bearing mice. Int. Immunopharmacol., 14, 328-333. https://doi.org/10.1016/j.intimp.2012.07.018
  13. Nath, J. and Krishna, G. (1998) Safety screening of drugs in cancer therapy. Acta Haematol., 99, 138-147. https://doi.org/10.1159/000040828
  14. Madle, S., Korte, A. and Ball, R. (1987) Experience with mutagenicity testing of new drugs: view point of a regulatory agency. Mutat. Res., 182, 187-192. https://doi.org/10.1016/0165-1161(87)90060-4
  15. Tennant, R.W., Spalding, J., Stasiewicz, S. and Ashby, J. (1990) Prediction of the outcome of rodent carcinogenicity bioassays currently being conducted on 44 chemicals by the national toxicology program. Mutagenesis, 5, 3-14. https://doi.org/10.1093/mutage/5.1.3
  16. Maron, D.M. and Ames, B.N. (1983) Revised methods for the Salmonella mutagenicity test. Mutat. Res., 113, 173-215. https://doi.org/10.1016/0165-1161(83)90010-9
  17. Organization for Economic Co-operation and Development (OECD). (1997) OECD guideline for testing of chemicals, no. 471,Genetic Toxicology: Bacterial Reverse Mutation Test. pp. 1-11.
  18. Singh, N.P., McCoy, M.T., Tice, R.R. and Schneider, E.L. (1988) A simple technique for quantitation of low levels of DNA damage in individual cells. Exp. Cell Res., 175, 184-191. https://doi.org/10.1016/0014-4827(88)90265-0
  19. Kim, Y.J., Kim, M.S., Jeong, H.K. and Ryu, J.C. (2006) Genotoxicity study on Khal, a halocidin derivative, in bacterial and mammalian cells. Mol. Cell. Toxicol., 2, 151-158.
  20. Organization for Economic Co-operation and Development (OECD). (1997) OECD guideline for testing of chemicals, no. 473, Genetic Toxicology: In vitro mammalian chromosome aberration test. pp. 1-16.
  21. Matsuoka, A., Sofuni, T., Miyata, N. and Ishidate, M. Jr. (1991) Clastogenicity of 1-nitropyrene, dinitropyrenes, fluorine and mononitrofluorenes in cultured Chinease Hamster cells. Mutat. Res., 259, 103-110. https://doi.org/10.1016/0165-1218(91)90114-2
  22. Ames, B.N., Lee, F.D. and Durston, W.E. (1973) An improved bacterial test system for the detection and classification of mutagens and carcinogens. Proc. Natl. Acad. Sci. USA, 70, 782-786. https://doi.org/10.1073/pnas.70.3.782
  23. Williams, L.D., Burdock, G.A., Edwards, J.A., Beck, M. and Bausch, J. (2009) Safety studies conducted on high-purity trans-resveratrol in experimental animals. Food Chem. Toxicol., 47, 2170-2182. https://doi.org/10.1016/j.fct.2009.06.002
  24. Kirkland, D. (1998) Chromosome aberration testing in genetic toxicology-past, present and future. Mutat. Res., 404, 173-185. https://doi.org/10.1016/S0027-5107(98)00111-0
  25. Buschini, A., Carboni, P., Frigerio, S., Furlini, M., Marabini, L., Monarca, S., Poli, P., Radice, S. and Rossi, C. (2004) Genotoxicity and cytotoxicity assessment in lake drinking water produced in a treatment plant. Mutagenesis, 19, 341-347. https://doi.org/10.1093/mutage/geh040
  26. Lee, M., Kwon, J. and Chung, M.K. (2003) Enhanced prediction of potential rodent carcinogenicity by utilizing comet assay and apoptotic assay in combination. Mutat. Res., 541, 9-19. https://doi.org/10.1016/S1383-5718(03)00175-X
  27. Hartmann, A., Agurell, E., Beevers, C., Brendler-Schwaab, S., Burlinson, B., Clay, P., Collins, A., Smith, A., Speit, G., Thybaud, V. and Tice, R.R. (2003) Recommendation for conducting the in vivo alkaline comet assay. Mutagenesis, 18, 45-51. https://doi.org/10.1093/mutage/18.1.45
  28. Henderson, L., Wolfreys, A., Fedyk, J., Bourner, C. and Windebank, S. (1998) The ability of the comet assay to discriminate between genotoxins and cytotoxins. Mutagenesis, 13, 89-94. https://doi.org/10.1093/mutage/13.1.89
  29. Jang, M., Cai, L., Udeani, G.O., Slowing, K.V., Thomas, C.F., Beecher, C.W., Fong, H.H., Farnsworth, N.R., Kinghorn, A.D., Mehta, R.G., Moon, R.C. and Pezzuto, J.M. (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science, 275, 218-220. https://doi.org/10.1126/science.275.5297.218
  30. Wang, D., Kreutzer D.A. and Essigmann J.M. (1998) Mutagenicity and repair of oxidative DNA damage: insights from studies using defined lesions. Mutat. Res., 400, 99-115. https://doi.org/10.1016/S0027-5107(98)00066-9
  31. Gulcin, I. (2010) Antioxidant properties of resveratrol: A structure-activity insight. Innovative Food Sci. Emerging Technol., 11, 210-218. https://doi.org/10.1016/j.ifset.2009.07.002
  32. Leonard, S.S., Xia, C., Jiang, B.H., Stinefelt, B., Klandorf, H., Harris, G.K. and Shi, X. (2003) Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses. Biochem. Biophys. Res. Commun., 309, 1017-1026. https://doi.org/10.1016/j.bbrc.2003.08.105
  33. Jeong, M.H., Yang, K.M., Jeong, D.H., Lee, C.G., Oh, S.J., Jeong, S.K., Lee, K.W., Jo, Y.R. and Jo, W.S. (2014) Protective activity of a novel resveratrol analogue, HS-1793, against DNA damage in $^{137}Cs-irradiated$ CHO-K1 Cells. J. Radiat. Res., 55, 464-475. https://doi.org/10.1093/jrr/rrt140
  34. Matsuoka, A., Furuta, A., Ozaki, M., Fukuhara, K. and Miyata, N. (2001) Resveratrol, a naturally occurring polyphenol, induces sister chromatid exchanges in a Chinese hamster lung (CHL) cell line. Mutat. Res., 494, 107-113. https://doi.org/10.1016/S1383-5718(01)00184-X
  35. Matsuoka, A., Takeshita , K., Furuta, A., Ozaki, M., Fukuhara, K. and Miyata, N. (2002) The 4-hydroxy group is responsible for the in vitro cytogenetic activity of resveratrol. Mutat. Res., 521, 29-35. https://doi.org/10.1016/S1383-5718(02)00211-5

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