Research studies conducted in the laboratory have investigated the properties of silymarin or its isomer silybin using cell lines and animal models. Other substances in milk thistle have not been extensively studied.

Several research studies have investigated the effects of silymarin or silybin in a noncancer context. These studies have tested silymarin or silybin:

• In healthy animal liver and kidney cells.
• As a prophylaxis against toxic chemicals.
• In stimulating detoxification pathways (enzyme concentrations and activity).
• For antioxidant properties.

Silymarin or silybin has also been investigated in cancer models. The effects of silymarin and/or silybin have been investigated in prostate (DU 145, LNCaP, PC-3),[1-5] breast (MDA-MB 468, MCF-7),[6-8] hepatic (HepG2),[9,10] epidermoid (A431),[10] colon (Caco-2),[11] ovarian (OVCA 433, A2780),[12] histiocytic lymphoma (U-937),[13] and leukemia (HL-60) [14,15] cells. In animal tumor models, tongue cancer,[16] skin cancer,[17-22] bladder cancer,[23] and adenocarcinoma of the colon [24,25] and small intestine [25] have been investigated. These studies have tested the ability of silymarin or silibinin to:

• Mitigate the toxicity associated with chemotherapy agents.
• Enhance the efficacy of chemotherapy agents.
• Inhibit the growth of cancer cell lines and inhibit tumor initiation or tumor promotion.

Although many of these studies have produced encouraging results, none of the findings have been replicated in human clinical trials.

Laboratory data suggest that silymarin and silybin protect the liver from damage induced by toxic chemicals. Animal studies have found that liver cells treated with silybin and then exposed to toxins do not incur cell damage or death at the same rate as liver cells that are not treated with silybin. This finding suggests that silybin can prevent toxins from entering the cell or effectively exports toxins out of the cell before damage ensues.[10,26-30] Alternatively, this may be related to the effect of silymarin on detoxification systems. In vitro data have shown silybin to stimulate and/or inhibit phase I detoxification pathways in silybin-treated human liver cells. However, this effect was found to be dose-dependent, and these levels are not physiologically attainable with the current manufacturer dose recommendations.[31,32]

Silymarin has been shown to stimulate phase II detoxification pathways in mice. Administration of silymarin (100 or 200 mg /kg body weight/day) to SENCAR mice for 3 days significantly increased glutathione S-transferase activity in the liver (P < .01–.001), lung (P < .05–.01), stomach (P < .05), small bowel (P < .01), and skin (P < .01). This effect appeared to be dose-dependent.[33] Administration of silymarin to rats challenged with a toxin (50 mg/kg body weight) resulted in higher levels of glutathione in liver cells, decreased levels of oxidative stress (measured by malondialdehyde concentrations), and less elevated liver function tests (measured by levels of aspartate aminotransferase [AST] and alanine aminotransferase [ALT]).[30] Silymarin and silybin have also been found to accelerate cell regeneration in the liver through stimulation of precursors to DNA synthesis and enhancement of production of the cellular enzymes required for synthesis of DNA.[34-39] Laboratory studies have also shown silymarin and silybin to be potent antioxidants.[27,28,40-47] Silymarin has been shown to mitigate oxidative stress in cells treated with pro-oxidant compounds.

A number of laboratory studies have investigated the effect of silymarin or silybin on the efficacy and toxicity of chemotherapy agents or have measured their direct cytotoxic activity. In an investigation of the effect of a variety of flavonoids on the formation of DNA damage, silymarin did not induce DNA damage in colon (Caco-2) cells, hepatoma (HepG2) cells, and human lymphocytes.[11] At higher concentrations of silymarin (400–1,000 μmol/L) DNA damage was induced in an epithelial cell line (HeLa cells). At higher concentrations (1,000 μmol/L) DNA damage was observed in human lymphocytes. Cell growth was inhibited as the flavonoid concentration was increased in human lymphocytes and HeLa cells. Only at very high concentrations was cell viability affected by silymarin in HepG2 cells. Although this study demonstrated that the flavonolignans of Silybum marianum (L.) are capable of inhibiting cellular proliferation and inducing DNA strand breaks, the results were obtained at very high concentrations that may be difficult to achieve in humans. This study also showed that silymarin does not stimulate cell growth in the HeLa, Burkitt lymphoma, and human hepatoma cell lines.

Silymarin has also been investigated as a possible adjunctive agent in mitigating some of the toxicity associated with chemotherapy agents. Silybin and silychristin exerted a protective effect on monkey kidney cells exposed to vincristine and especially cisplatin chemotherapy.[48] Silybin (200 mg/kg body weight) administration with cisplatin in rats resulted in statistically significant reductions in measures of kidney toxicity.[49] Significant decreases in weight loss, faster recovery of urinary osmolality measures, and depressions in the increase in activity of urinary alanine aminopeptidase ([AAP], a marker of kidney toxicity) were observed. Silybin had no effect on magnesium excretion or glomerular function. Silybin (2 g /kg body weight) administration in rats receiving cisplatin prevented reductions in creatinine clearance, increases in urea plasma levels, and large increases in urinary AAP.[50] No effect on magnesium excretion was observed. Silybin did not interfere with the antineoplastic effects of cisplatin or ifosfamide in germ cell tumors. In experiments with ovarian and breast cancer cell lines, silybin potentiated the effect of cisplatin and doxorubicin.[12] IdB 1,016, a form of silybin bound to a phospholipid complex, was found to enhance the activity of cisplatin against A2780 ovarian cancer cells but had no effect on its own.[51] Silybin increased the chemosensitivity of DU 145 prostate cancer cells resistant to chemotherapy.[52]

Studies have also investigated the effect of silymarin on tumor initiation and promotion. Silymarin appears to have a chemopreventive effect through perturbations in the cell cycle, altering cell signaling that induces cellular proliferation, affecting angiogenesis, or through its anti-inflammatory properties.[1,6,12,18,53] These findings have been supported in human prostate, breast, ectocervical, ovarian, hepatic, leukemia, and epidermoid cell lines.[4,6,8,9,14,54] An investigation of the effect of silymarin on ultraviolet B radiation-induced nonmelanoma skin cancer in mice found that silymarin treatment significantly reduced tumor incidence (P < .003), tumor multiplicity (P < .0001), and tumor volume (P < .0001).[18] These findings suggest that silymarin plays a prominent role in the reduction of cancer cells and in preventing the formation of cancer cells. A number of studies have investigated the mechanism through, which silymarin may affect tumor promotion in mouse skin tumor models. Studies have found that silymarin reduces transcription of markers of tumor promotion and activity,[18] inhibits transcription of tumor promoters,[55] stimulates antioxidant activities,[18,22] interferes with cell signaling,[54] inhibits inflammatory actions,[18,21] and modulates cell-cycle regulation.[56]

In prostate cancer cell lines, silybin has been shown to inhibit growth factors and stimulate cell growth,[1-3,5] promote cell cycle arrest,[1,4] and inhibit antiapoptotic activity.[52] 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.[24,25] Dietary silymarin had no effect on small intestinal adenocarcinoma,[25] but exerted a preventive effect in mice with N-butyl-N-(4-hydroxybutyl) nitrosamine –induced bladder cancer [23] and in F344 rats with 4-nitroquinoline 1-oxide –induced cancer of the tongue.[16] 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]

References

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28. 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.  [PUBMED Abstract]
    
    
29. 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.  [PUBMED Abstract]
    
    
30. 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.  [PUBMED Abstract]
    
    
31. 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.  [PUBMED Abstract]
    
    
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37. 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.  [PUBMED Abstract]
    
    
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39. 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.  [PUBMED Abstract]
    
    
40. 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.  [PUBMED Abstract]
    
    
41. 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.  [PUBMED Abstract]
    
    
42. 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.  [PUBMED Abstract]
    
    
43. Mira L, Silva M, Manso CF: Scavenging of reactive oxygen species by silibinin dihemisuccinate. Biochem Pharmacol 48 (4): 753-9, 1994.  [PUBMED Abstract]
    
    
44. 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.  [PUBMED Abstract]
    
    
45. 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.  [PUBMED Abstract]
    
    
46. 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.  [PUBMED Abstract]
    
    
47. 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.  [PUBMED Abstract]
    
    
48. 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.  [PUBMED Abstract]
    
    
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50. 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.  [PUBMED Abstract]
    
    
51. 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.  [PUBMED Abstract]
    
    
52. 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.  [PUBMED Abstract]
    
    
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54. 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.  [PUBMED Abstract]
    
    
55. 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.  [PUBMED Abstract]
    
    
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Glossary Terms

4-NQO. A substance that is used in cancer research to cause tumors in laboratory animals. This is done to test new diets, drugs, and procedures for use in cancer prevention and treatment. Also called 4-NQO.

Cancer that begins in cells that line certain internal organs and that have gland-like (secretory) properties.

In cancer therapy, a drug or substance used in addition to the primary therapy.

AAP. An enzyme that is used as a biomarker to detect damage to the kidneys, and that may be used to help diagnose certain kidney disorders. It is found at high levels in the urine when there are kidney problems. Also called AAP.

Blood vessel formation. Tumor angiogenesis is the growth of new blood vessels needed for tumors to grow. This is caused by the release of chemicals by the tumor.

An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models.

Having to do with reducing inflammation.

A substance that blocks the formation of neoplasms (growths that may become cancerous).

A substance that protects cells from the damage caused by free radicals (unstable molecules made by the process of oxidation during normal metabolism). Free radicals may play a part in cancer, heart disease, stroke, and other diseases of aging. Antioxidants include beta-carotene, lycopene, vitamins A, C, and E, and other natural and manufactured substances.

A substance that is used in cancer research to cause colon tumors in laboratory animals. This is done to test new diets, drugs, and procedures for use in cancer prevention and treatment.

The organ that stores urine.

Glandular organ located on the chest. The breast is made up of connective tissue, fat, and breast tissue that contains the glands that can make milk. Also called mammary gland.

An aggressive (fast-growing) type of B-cell non-Hodgkin lymphoma that occurs most often in children and young adults. The disease may affect the jaw, central nervous system, bowel, kidneys, ovaries, or other organs. There are three main types of Burkitt lymphoma (sporadic, endemic, and immunodeficiency related). Sporadic Burkitt lymphoma occurs throughout the world, and endemic Burkitt lymphoma occurs in Africa. Immunodeficiency-related Burkitt lymphoma is most often seen in AIDS patients.

The individual unit that makes up the tissues of the body. All living things are made up of one or more cells.

An increase in the number of cells as a result of cell growth and cell division.

The use of drugs, vitamins, or other agents to try to reduce the risk of, or delay the development or recurrence of, cancer.

The susceptibility of tumor cells to the cell-killing effects of anticancer drugs.

A drug used to treat cancer.

A drug used to treat many types of cancer. Cisplatin contains the metal platinum. It kills cancer cells by damaging their DNA and stopping them from dividing. Cisplatin is a type of alkylating agent.

A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease. Also called a clinical study.

The longest part of the large intestine, which is a tube-like organ connected to the small intestine at one end and the anus at the other. The colon removes water and some nutrients and electrolytes from partially digested food. The remaining material, solid waste called stool, moves through the colon to the rectum and leaves the body through the anus.

A compound that is excreted from the body in urine. Creatinine levels are measured to monitor kidney function.

Cells of a single type (human, animal, or plant) that have been adapted to grow continuously in the laboratory and are used in research.

Cell-killing.

DNA. The molecules inside cells that carry genetic information and pass it from one generation to the next. Also called DNA.

The amount of medicine taken, or radiation given, at one time.

Refers to the effects of treatment with a drug. If the effects change when the dose of the drug is changed, the effects are said to be dose-dependent.

A drug that is used to treat many types of cancer and is being studied in the treatment of other types of cancer. Doxorubicin comes from the bacterium Streptomyces peucetius. It damages DNA (the molecules inside cells that carry genetic information) and stops cells from growing. Rapidly growing tumor cells that take up doxorubicin may die. It is a type of anthracycline antitumor antibiotic. Also called doxorubicin hydrochloride, Adriamycin PFS, Adriamycin RDF, and Rubex.

Having to do with the part of the cervix that protrudes into the vagina and is lined with epithelial cells.

Effectiveness. In medicine, the ability of an intervention (for example, a drug or surgery) to produce the desired beneficial effect.

A protein that speeds up chemical reactions in the body.

Refers to the cells that line the internal and external surfaces of the body.

A member of a group of substances found in many plants and plant-based foods. Flavonoids have shown antioxidant effects.

A type of tumor that begins in the cells that give rise to sperm or eggs. Germ cell tumors can occur almost anywhere in the body and can be either benign or malignant.

A substance found in plant and animal tissues that has many functions in a cell. These include activating certain enzymes and destroying toxic compounds and chemicals that contain oxygen.

A family of enzymes involved in metabolism and in making toxic compounds less harmful to the body.

A unit of weight in the metric system. One gram is equal to one thousandth of a kilogram and is approximately 30-times less than an ounce.

Refers to the liver.

A liver tumor.

An outdated term referring to non-Hodgkin lymphomas made up of large abnormal lymphoid cells. Histiocytic lymphomas include mature B-cell and T-cell non-Hodgkin lymphomas. Many tumors that were once called histiocytic lymphomas are now considered to be a type of large cell lymphoma.

An anticancer drug that belongs to the family of drugs called alkylating agents.

In the laboratory (outside the body). The opposite of in vivo (in the body).

Redness, swelling, pain, and/or a feeling of heat in an area of the body. This is a protective reaction to injury, disease, or irritation of the tissues.

A hormone made by the islet cells of the pancreas. Insulin controls the amount of sugar in the blood by moving it into the cells, where it can be used by the body for energy.

One of two or more compounds that have the same chemical formula but different arrangements of the atoms within the molecules and that may have different physical/chemical properties.

One of a pair of organs in the abdomen. Kidneys remove waste from the blood (as urine), produce erythropoietin (a substance that stimulates red blood cell production), and play a role in blood pressure regulation.

A measure of weight. A kilogram is equal to 2.2 pounds.

Research done in a laboratory. These studies may use test tubes or animals to find out if a drug, procedure, or treatment is likely to be useful. Laboratory studies take place before any testing is done in humans.

Cancer that starts in blood-forming tissue such as the bone marrow and causes large numbers of blood cells to be produced and enter the bloodstream.

A large organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile.

A type of white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infections and other diseases.

In medicine, a mineral used by the body to help maintain muscles, nerves, and bones. It is also used in energy metabolism and protein synthesis.

A byproduct of lipid (fat) metabolism in the body. It is also found in many foods and can be present in high amounts in rancid food.

A concentration of 1/1,000,000 (one millionth) molecular weight per liter (mol/L).

A plant that has been used in some cultures to treat certain medical problems, including stomach, liver, and gallbladder disorders. The active extract of milk thistle seeds is called silymarin. It is being studied in the prevention of liver damage caused by some cancer treatments. Also called Silybum marianum.

A measure of weight. A milligram is approximately 450,000 times smaller than a pound and 28,000 times smaller than an ounce.

A large number or variety.

A substance that is used in cancer research to cause bladder tumors in laboratory animals. This is done to test new diets, drugs, and procedures for use in cancer prevention and treatment.

Skin cancer that forms in basal cells or squamous cells but not in melanocytes (pigment-producing cells of the skin).

The concentration of particles dissolved in a fluid. The osmolality of serum can help diagnose several medical conditions such as dehydration, diabetes, and shock.

Having to do with the ovaries, the female reproductive glands in which the ova (eggs) are formed. The ovaries are located in the pelvis, one on each side of the uterus.

A condition in which antioxidant levels are lower than normal. Antioxidant levels are usually measured in blood plasma.

The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma.

In medicine, the effect of increasing the potency or effectiveness of a drug or other treatment.

A substance that can produce oxygen byproducts of metabolism that can cause damage to cells.

An attempt to prevent disease.

A gland in the male reproductive system. The prostate surrounds the part of the urethra (the tube that empties the bladder) just below the bladder, and produces a fluid that forms part of the semen.

A tiny, round cluster of blood vessels within the kidneys. It filters the blood to reabsorb useful materials and remove waste as urine.

To make a copy or duplicate of something.

A plant that has been used in some cultures to treat certain medical problems, including stomach, liver, and gallbladder disorders. The active extract of Silybum marianum seeds is called silymarin. It is being studied in the prevention of liver damage caused by some cancer treatments. Also called milk thistle.

A substance obtained from milk thistle seeds that is being studied in the prevention of liver damage caused by certain cancer treatments.

The part of the digestive tract that is located between the stomach and the large intestine.

Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. Also called significant.

Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects.

A poison produced by certain animals, plants, or bacteria.

Cells, tissues, or animals used to study the development and progression of cancer, and to test new treatments before they are given to humans. Animals with transplanted human tumors or other tissues are called xenograft models.

Invisible rays that are part of the energy that comes from the sun. UV radiation also comes from sun lamps and tanning beds. UV radiation can damage the skin and cause melanoma and other types of skin cancer. UV radiation that reaches the Earth's surface is made up of two types of rays, called UVA and UVB rays. UVB rays are more likely than UVA rays to cause sunburn, but UVA rays pass deeper into the skin. Scientists have long thought that UVB radiation can cause melanoma and other types of skin cancer. They now think that UVA radiation also may add to skin damage that can lead to skin cancer and cause premature aging. For this reason, skin specialists recommend that people use sunscreens that reflect, absorb, or scatter both kinds of UV radiation. Also called UV radiation.

Nitrogen in the blood that comes from urea (a substance formed by the breakdown of protein in the liver). The kidneys filter urea out of the blood and into the urine. A high level of urea nitrogen in the blood may be a sign of a kidney problem. Also called blood urea nitrogen and BUN.

Having to do with urine or the organs of the body that produce and get rid of urine.

The active ingredient in a drug used to treat acute leukemia. It is used in combination with other drugs to treat Hodgkin disease, non-Hodgkin lymphoma, rhabdomyosarcoma, neuroblastoma, and Wilms tumor. Vincristine is also being studied in the treatment of other types of cancer. It blocks cell growth by stopping cell division. It is a type of vinca alkaloid and a type of antimitotic agent.