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.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Gusman, J., Malonne, H. and Atassi, G. (2001) A reappraisal of the potential chemopreventive and chemotherapeutic properties of resveratrol. Carcinogenesis, 22, 1111–1117.
Pervaiz, S. and Holme, A.L. (2009) Resveratrol: its biologic targets and functional activity. Antioxid. Redox. Signaling, 11, 2851–2897.
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.
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.
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.
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.
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.
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.
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.
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.
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 tumor-derived T cells. Exp. Ther. Med., 3, 592–598.
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.
Nath, J. and Krishna, G. (1998) Safety screening of drugs in cancer therapy. Acta Haematol., 99, 138–147.
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.
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.
Maron, D.M. and Ames, B.N. (1983) Revised methods for the Salmonella mutagenicity test. Mutat. Res., 113, 173–215.
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.
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.
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.
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.
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.
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.
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.
Kirkland, D. (1998) Chromosome aberration testing in genetic toxicology-past, present and future. Mutat. Res., 404, 173–185.
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.
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.
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.
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.
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.
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.
Gülçin, I. (2010) Antioxidant properties of resveratrol: A structure-activity insight. Innovative Food Sci. Emerging Technol., 11, 210–218.
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.
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 137Cs-irradiated CHO-K1 Cells. J. Radiat. Res., 55, 464–475.
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.
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
About this article
Cite this article
Jeong, M.H., Yang, K., Lee, C.G. et al. In Vitro Genotoxicity Assessment of a Novel Resveratrol Analogue, HS-1793. Toxicol Res. 30, 211–220 (2014). https://doi.org/10.5487/TR.2014.30.3.211
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.5487/TR.2014.30.3.211