Abstract
Silibinin is a flavonolignan extracted from milk thistle with cancer chemopreventive activity in preclinical models of prostate and colorectal cancer. A milk thistle extract, of which silibin is a major component, has recently been shown to exacerbate mammary carcinogenesis in two rodent models. We tested the hypothesis that consumption of silibinin or silipide, a silibinin formulation with pharmaceutical properties superior to the unformulated agent, affect breast cancer development in the C3(1) SV40 T,t antigen transgenic multiple mammary adenocarcinoma mouse model. Mice received silibinin or silipide (0.2% silibinin equivalents) with their diet from weaning, and tumour development was monitored by weekly palpation and the number and weight of neoplasms at the end of the experiment. Intervention neither promoted, nor interfered with, tumour development. The result suggests that promotion of carcinogenesis is not a feature of silibinin consistent across rodent models of mammary carcinogenesis.
This is a preview of subscription content, log in via an institution to check access.
References
Singh RP, Dhanalakshmi S, Tyagi AK, Chan DCF, Agarwal C, Agarwal R (2002) Dietary feeding of silibinin inhibits advance human prostate carcinoma growth in athymic nude mice and increases plasma insulin-like growth factor-binding protein-3 levels. Cancer Res 62:3063–3069
Kohno H, Suzuki R, Sugie S, Tsuda H, Tanaka T (2005) Dietary supplementation with silymarin inhibits 3,2′-dimethyl-4-aminobiphenyl-induced prostate carcinogenesis in male F344 rats. Clin Cancer Res 11:6492–6497
Katiyar SK, Korman NJ, Mukhtar H, Agarwal R (1997) Protective effects of silymarin against photocarcinogenesis in a mouse skin model. J Natl Cancer Inst 89:556–566
Lahiri-Chatterjee M, Katiyar SK, Mohan RR, Agarwal R (1999) A flavonoid antioxidant, silymarin, affords exceptionally high protection against tumor promotion in the SENCAR mouse skin tumorigenesis model. Cancer Res 59:622–632
Vinh PQ, Sugie S, Tanaka T, Hara A, Yamada Y, Katayama M, Deguchi T, Mori H (2002) Chemopreventive effects of a flavonoid antioxidant silymarin on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice. Jpn J Cancer Res 93:42–49
Gershbein LL (1994) Action of dietary trypsin, pressed coffee, silymarin and iron salt on 1,2-dimethylhydrazine tumorigenesis by gavage. Anticancer Res 14:1113–1116
Kohno H, Tanaka T, Kawabata K, Hirose Y, Sugie S, Tsuda H, Mori H (2002) Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats. Int J Cancer 101:461–468
Volate SR, Davenport DM, Muga SJ, Wargovich MJ (2005) Modulation of aberrant crypt foci and apoptosis by dietary herbal supplements (quercetin, curcumin, silymarin, ginseng and rutin). Carcinogenesis 26:1450–1456
Comoglio A, Leonarduzzzi G, Carini R, Busolin D, Basaga H, Albano E, Tomasi A, Poli G, Morazzoni P, Magistretti MJ (1990) Studies on the antioxidant and free radical scavenging properties of IdB 1016: a new flavonolignan complex. Free Radic Res Commun 11:109–115
Hoh C, Boocock D, Marczylo T, Singh R, Berry DP, Dennison AR, Hemingway D, Miller A, West K, Euden S, Garcea G, Farmer PB, Steward WP, Gescher AJ (2006) Pilot study of oral silibinin, a putative chemopreventive agent, in colorectal cancer patients: assessment of silibinin levels in plasma, colorectum and liver and their pharmacodynamic consequences. Clin Cancer Res 12:2944–2950
Barzaghi N, Crema F, Gatti G, Pifferi G, Perucca E (1990) Pharmacokinetic studies on IdB 1016, a sylibin-phosphatidylcholine complex, in healthy human subjects. Eur J Drug Metab Pharmacokin 15:333–338
Flaig TW, Gustafson DL, Su LJ, Zirrolli JA, Crighton F, Harrison GS, Pierson AS, Agarwal R, Glode LM (2007) A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients. Invest New Drugs 25:139–146
Malewicz B, Wang ZS, Jiang C, Guo JM, Cleary MP, Grande JP, Lu JX (2006) Enhancement of mammary carcinogenesis in two rodent models by silymarin dietary supplements. Carcinogenesis 27:1739–1747
Maroulakou IG, Anver M, Garrett L, Green JE (1994) Prostate and mammary adenocarcinoma in transgenic mice carrying a rat C3(1) simian virus 40 large tumor antigen fusion gene. Proc Natl Acad Sci USA 91:11236–11240
Mietz JA, Unger T, Huibregtse JM, Howley PM (1992) The transcriptional transactivation function of wild-type p53 is inhibited by SV40 large T-antigen and by HPV-16 E6 oncoprotein. EMBO J 11:5013–5020
Dyson N, Buchkovich K, Whyte P, Harlow E (1989) The cellular 107 K protein that binds to adenovirus E1A also associates with the large T antigens of SV40 and JC virus. Cell 58:249–255
Workman P, Twentyman P, Balkwill F, Balmain A, Chaplin D, Double J, Embleton J, Newell D, Raymond R, Stables J, Stephens T, Wallace J (1998) United Kingdom co-ordinating committee on cancer research (UKCCCR) guidelines for the welfare of animals in experimental neoplasia (second edition). Br J Cancer 77:1–10
Freireich EJ, Gehan EA, Rall DP, Schmidt LH, Skipper HE (1966) Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother Rep 50:219–244
Kavanaugh C, Green JE (2003) The use of genetically altered mice for breast cancer prevention studies. J Nutr 133:2404S–2409S
Kaur S, Greaves P, Cooke D, Edwards R, Steward WP, Gescher AJ, Marczylo TH (2007) Breast cancer prevention by green tea catechins and black tea theaflavins in the C3(1) SV40 T,t antigen transgenic mouse model is accompanied by increased apoptosis and a decrease in oxidative DNA adducts. J Agric Food Chem 55:3378–3385
Acknowledgments
The work was supported by Cancer Research UK programme grant C325/A6691 and UK Medical Research Council programme grant G0100874. The authors thank Dr Paolo Morazzoni, Indena S.p.a., for generous provision of silipide, and the staff in the Leicester University Biomedical Services facility for animal husbandry.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Verschoyle, R.D., Brown, K., Steward, W.P. et al. Consumption of silibinin, a flavonolignan from milk thistle, and mammary cancer development in the C3(1) SV40 T,t antigen transgenic multiple mammary adenocarcinoma (TAg) mouse. Cancer Chemother Pharmacol 62, 369–372 (2008). https://doi.org/10.1007/s00280-007-0611-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-007-0611-8