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    Milk Thistle (PDQ®): Complementary and alternative medicine - Health Professional Information [NCI] - Laboratory / Animal / Preclinical Studies


    In prostate cancer cell lines, silybin has been shown to inhibit growth factors and stimulate cell growth,[1,2,3,5] promote cell cycle arrest,[1,4] and inhibit antiapoptotic activity.[53] In rats with azoxymethane -induced colon cancer, dietary silymarin resulted in a reduction in the incidence and multiplicity of adenocarcinoma of the colon in a dose-dependent manner.[25,26] Dietary silymarin had no effect on small intestinal adenocarcinoma,[26] but exerted a preventive effect in mice with N-butyl-N-(4-hydroxybutyl) nitrosamine -induced bladder cancer [24] and in F344 rats with 4-nitroquinoline 1-oxide -induced cancer of the tongue.[17] Dietary silybin administered to nude mice with prostate carcinoma increased production of insulin -like growth factor-binding protein-3 in the plasma of mice and significantly inhibited tumor volume (P < .05).[2] Silibinin administered twice daily reduced the growth of colorectal tumor xenografts in mice for a period of 6 weeks.[58,59]


    1. Zi X, Agarwal R: Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. Proc Natl Acad Sci U S A 96 (13): 7490-5, 1999.
    2. Singh RP, Dhanalakshmi S, Tyagi AK, et al.: 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 (11): 3063-9, 2002.
    3. Zi X, Zhang J, Agarwal R, et al.: Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells. Cancer Res 60 (20): 5617-20, 2000.
    4. Zi X, Grasso AW, Kung HJ, et al.: A flavonoid antioxidant, silymarin, inhibits activation of erbB1 signaling and induces cyclin-dependent kinase inhibitors, G1 arrest, and anticarcinogenic effects in human prostate carcinoma DU145 cells. Cancer Res 58 (9): 1920-9, 1998.
    5. Sharma Y, Agarwal C, Singh AK, et al.: Inhibitory effect of silibinin on ligand binding to erbB1 and associated mitogenic signaling, growth, and DNA synthesis in advanced human prostate carcinoma cells. Mol Carcinog 30 (4): 224-36, 2001.
    6. Flaig TW, Glodé M, Gustafson D, et al.: A study of high-dose oral silybin-phytosome followed by prostatectomy in patients with localized prostate cancer. Prostate 70 (8): 848-55, 2010.
    7. Bhatia N, Zhao J, Wolf DM, et al.: Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an active constituent of milk thistle: comparison with silymarin. Cancer Lett 147 (1-2): 77-84, 1999.
    8. Jiang C, Agarwal R, Lü J: Anti-angiogenic potential of a cancer chemopreventive flavonoid antioxidant, silymarin: inhibition of key attributes of vascular endothelial cells and angiogenic cytokine secretion by cancer epithelial cells. Biochem Biophys Res Commun 276 (1): 371-8, 2000.
    9. Zi X, Feyes DK, Agarwal R: Anticarcinogenic effect of a flavonoid antioxidant, silymarin, in human breast cancer cells MDA-MB 468: induction of G1 arrest through an increase in Cip1/p21 concomitant with a decrease in kinase activity of cyclin-dependent kinases and associated cyclins. Clin Cancer Res 4 (4): 1055-64, 1998.
    10. Saliou C, Rihn B, Cillard J, et al.: Selective inhibition of NF-kappaB activation by the flavonoid hepatoprotector silymarin in HepG2. Evidence for different activating pathways. FEBS Lett 440 (1-2): 8-12, 1998.
    11. Shear NH, Malkiewicz IM, Klein D, et al.: Acetaminophen-induced toxicity to human epidermoid cell line A431 and hepatoblastoma cell line Hep G2, in vitro, is diminished by silymarin. Skin Pharmacol 8 (6): 279-91, 1995.
    12. Duthie SJ, Johnson W, Dobson VL: The effect of dietary flavonoids on DNA damage (strand breaks and oxidised pyrimdines) and growth in human cells. Mutat Res 390 (1-2): 141-51, 1997.
    13. Scambia G, De Vincenzo R, Ranelletti FO, et al.: Antiproliferative effect of silybin on gynaecological malignancies: synergism with cisplatin and doxorubicin. Eur J Cancer 32A (5): 877-82, 1996.
    14. Manna SK, Mukhopadhyay A, Van NT, et al.: Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis. J Immunol 163 (12): 6800-9, 1999.
    15. Kang SN, Lee MH, Kim KM, et al.: Induction of human promyelocytic leukemia HL-60 cell differentiation into monocytes by silibinin: involvement of protein kinase C. Biochem Pharmacol 61 (12): 1487-95, 2001.
    16. Clinton SK: The dietary antioxidant network and prostate carcinoma. Cancer 86 (9): 1629-31, 1999.
    17. Yanaida Y, Kohno H, Yoshida K, et al.: Dietary silymarin suppresses 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male F344 rats. Carcinogenesis 23 (5): 787-94, 2002.
    18. Agarwal R, Katiyar SK, Lundgren DW, et al.: Inhibitory effect of silymarin, an anti-hepatotoxic flavonoid, on 12-O-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity and mRNA in SENCAR mice. Carcinogenesis 15 (6): 1099-103, 1994.
    19. Katiyar SK, Korman NJ, Mukhtar H, et al.: Protective effects of silymarin against photocarcinogenesis in a mouse skin model. J Natl Cancer Inst 89 (8): 556-66, 1997.
    20. Lahiri-Chatterjee M, Katiyar SK, Mohan RR, et al.: A flavonoid antioxidant, silymarin, affords exceptionally high protection against tumor promotion in the SENCAR mouse skin tumorigenesis model. Cancer Res 59 (3): 622-32, 1999.
    21. Singh RP, Tyagi AK, Zhao J, et al.: Silymarin inhibits growth and causes regression of established skin tumors in SENCAR mice via modulation of mitogen-activated protein kinases and induction of apoptosis. Carcinogenesis 23 (3): 499-510, 2002.
    22. Zhao J, Sharma Y, Agarwal R: Significant inhibition by the flavonoid antioxidant silymarin against 12-O-tetradecanoylphorbol 13-acetate-caused modulation of antioxidant and inflammatory enzymes, and cyclooxygenase 2 and interleukin-1alpha expression in SENCAR mouse epidermis: implications in the prevention of stage I tumor promotion. Mol Carcinog 26 (4): 321-33, 1999.
    23. Zhao J, Lahiri-Chatterjee M, Sharma Y, et al.: Inhibitory effect of a flavonoid antioxidant silymarin on benzoyl peroxide-induced tumor promotion, oxidative stress and inflammatory responses in SENCAR mouse skin. Carcinogenesis 21 (4): 811-6, 2000.
    24. Vinh PQ, Sugie S, Tanaka T, et al.: 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 (1): 42-9, 2002.
    25. Kohno H, Tanaka T, Kawabata K, et al.: Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats. Int J Cancer 101 (5): 461-8, 2002.
    26. Gershbein LL: Action of dietary trypsin, pressed coffee oil, silymarin and iron salt on 1,2-dimethylhydrazine tumorigenesis by gavage. Anticancer Res 14 (3A): 1113-6, 1994 May-Jun.
    27. Campos R, Garrido A, Guerra R, et al.: Silybin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver. Planta Med 55 (5): 417-9, 1989.
    28. Farghali H, Kameniková L, Hynie S, et al.: Silymarin effects on intracellular calcuim and cytotoxicity: a study in perfused rat hepatocytes after oxidative stress injury. Pharmacol Res 41 (2): 231-7, 2000.
    29. Lettéron P, Labbe G, Degott C, et al.: Mechanism for the protective effects of silymarin against carbon tetrachloride-induced lipid peroxidation and hepatotoxicity in mice. Evidence that silymarin acts both as an inhibitor of metabolic activation and as a chain-breaking antioxidant. Biochem Pharmacol 39 (12): 2027-34, 1990.
    30. Valenzuela A, Guerra R, Garrido A: Silybin dihemisuccinate protects rat erythrocytes against phenylhydrazine-induced lipid peroxidation and hemolysis. Planta Med 53 (5): 402-5, 1987.
    31. Campos R, Garrido A, Guerra R, et al.: Acetaminophen hepatotoxicity in rats is attenuated by silybin dihemisuccinate. Prog Clin Biol Res 280: 375-8, 1988.
    32. Zuber R, Modrianský M, Dvorák Z, et al.: Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities. Phytother Res 16 (7): 632-8, 2002.
    33. Venkataramanan R, Ramachandran V, Komoroski BJ, et al.: Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures. Drug Metab Dispos 28 (11): 1270-3, 2000.
    34. Zhao J, Agarwal R: Tissue distribution of silibinin, the major active constituent of silymarin, in mice and its association with enhancement of phase II enzymes: implications in cancer chemoprevention. Carcinogenesis 20 (11): 2101-8, 1999.
    35. Sonnenbichler J, Mattersberger J, Rosen H: [Stimulation of RNA synthesis in rat liver and isolated hepatocytes by silybin, an antihepatotoxic agent from Silybum marianum L. Gaertn (author's transl)] Hoppe Seylers Z Physiol Chem 357 (8): 1171-80, 1976.
    36. Sonnenbichler J, Zetl I: [Mechanism of action of silibinin. V. Effect of silibinin on the synthesis of ribosomal RNA, mRNA and tRNA in rat liver in vivo] Hoppe Seylers Z Physiol Chem 365 (5): 555-66, 1984.
    37. Sonnenbichler J, Zetl I: Biochemical effects of the flavonolignane silibinin on RNA, protein and DNA synthesis in rat livers. Prog Clin Biol Res 213: 319-31, 1986.
    38. Sonnenbichler J, Goldberg M, Hane L, et al.: Stimulatory effect of Silibinin on the DNA synthesis in partially hepatectomized rat livers: non-response in hepatoma and other malign cell lines. Biochem Pharmacol 35 (3): 538-41, 1986.
    39. Machicao F, Sonnenbichler J: Mechanism of the stimulation of RNA synthesis in rat liver nuclei by silybin. Hoppe Seylers Z Physiol Chem 358 (2): 141-7, 1977.
    40. Dehmlow C, Erhard J, de Groot H: Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin. Hepatology 23 (4): 749-54, 1996.
    41. Valenzuela A, Guerra R, Videla LA: Antioxidant properties of the flavonoids silybin and (+)-cyanidanol-3: comparison with butylated hydroxyanisole and butylated hydroxytoluene. Planta Med (6): 438-40, 1986.
    42. Valenzuela A, Aspillaga M, Vial S, et al.: Selectivity of silymarin on the increase of the glutathione content in different tissues of the rat. Planta Med 55 (5): 420-2, 1989.
    43. Mira ML, Azevedo MS, Manso C: The neutralization of hydroxyl radical by silibin, sorbinil and bendazac. Free Radic Res Commun 4 (2): 125-9, 1987.
    44. Mira L, Silva M, Manso CF: Scavenging of reactive oxygen species by silibinin dihemisuccinate. Biochem Pharmacol 48 (4): 753-9, 1994.
    45. Koch HP, Löffler E: Influence of silymarin and some flavonoids on lipid peroxidation in human platelets. Methods Find Exp Clin Pharmacol 7 (1): 13-8, 1985.
    46. Garrido A, Arancibia C, Campos R, et al.: Acetaminophen does not induce oxidative stress in isolated rat hepatocytes: its probable antioxidant effect is potentiated by the flavonoid silybin. Pharmacol Toxicol 69 (1): 9-12, 1991.
    47. Bosisio E, Benelli C, Pirola O: Effect of the flavanolignans of Silybum marianum L. on lipid peroxidation in rat liver microsomes and freshly isolated hepatocytes. Pharmacol Res 25 (2): 147-54, 1992 Feb-Mar.
    48. Altorjay I, Dalmi L, Sári B, et al.: The effect of silibinin (Legalon) on the the free radical scavenger mechanisms of human erythrocytes in vitro. Acta Physiol Hung 80 (1-4): 375-80, 1992.
    49. Sonnenbichler J, Scalera F, Sonnenbichler I, et al.: Stimulatory effects of silibinin and silicristin from the milk thistle Silybum marianum on kidney cells. J Pharmacol Exp Ther 290 (3): 1375-83, 1999.
    50. Gaedeke J, Fels LM, Bokemeyer C, et al.: Cisplatin nephrotoxicity and protection by silibinin. Nephrol Dial Transplant 11 (1): 55-62, 1996.
    51. Bokemeyer C, Fels LM, Dunn T, et al.: Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity. Br J Cancer 74 (12): 2036-41, 1996.
    52. Giacomelli S, Gallo D, Apollonio P, et al.: Silybin and its bioavailable phospholipid complex (IdB 1016) potentiate in vitro and in vivo the activity of cisplatin. Life Sci 70 (12): 1447-59, 2002.
    53. Dhanalakshmi S, Singh RP, Agarwal C, et al.: Silibinin inhibits constitutive and TNFalpha-induced activation of NF-kappaB and sensitizes human prostate carcinoma DU145 cells to TNFalpha-induced apoptosis. Oncogene 21 (11): 1759-67, 2002.
    54. Zi X, Agarwal R: Modulation of mitogen-activated protein kinase activation and cell cycle regulators by the potent skin cancer preventive agent silymarin. Biochem Biophys Res Commun 263 (2): 528-36, 1999.
    55. Ahmad N, Gali H, Javed S, et al.: Skin cancer chemopreventive effects of a flavonoid antioxidant silymarin are mediated via impairment of receptor tyrosine kinase signaling and perturbation in cell cycle progression. Biochem Biophys Res Commun 247 (2): 294-301, 1998.
    56. Zi X, Mukhtar H, Agarwal R: Novel cancer chemopreventive effects of a flavonoid antioxidant silymarin: inhibition of mRNA expression of an endogenous tumor promoter TNF alpha. Biochem Biophys Res Commun 239 (1): 334-9, 1997.
    57. Singh RP, Agarwal R: Flavonoid antioxidant silymarin and skin cancer. Antioxid Redox Signal 4 (4): 655-63, 2002.
    58. Kaur M, Velmurugan B, Tyagi A, et al.: Silibinin suppresses growth and induces apoptotic death of human colorectal carcinoma LoVo cells in culture and tumor xenograft. Mol Cancer Ther 8 (8): 2366-74, 2009.
    59. Velmurugan B, Gangar SC, Kaur M, et al.: Silibinin exerts sustained growth suppressive effect against human colon carcinoma SW480 xenograft by targeting multiple signaling molecules. Pharm Res 27 (10): 2085-97, 2010.

    This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http:// cancer .gov or call 1-800-4-CANCER.

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    Last Updated: May 28, 2015
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