Silymarin


Clinical Studies


Silymarin, or Milk Thistle, is used as a liver protectant to lessen damage from potentially hepatotoxic drugs and chemicals, chronic inflammatory liver disease and chronic hepatitis. It is also used for loss of appetite and gallbladder complaints. There is evidence that suggests that Silymarin might have anti-fibrotic, anti-inflammatory, anti-proliferative and immunomodulating effects that could also be beneficial in cancer. Preliminary evidence indicates that Silymarin constituents might protect against kidney damage. There is some interest in using Silymarin for prostate cancer. In vitro research shows that Silymarin may have anti-proliferative effects on androgen-responsive prostate cancer cells.


Published Clinical Studies
Silymarin


New concepts of the pathogenesis of alcoholic liver disease lead to novel treatments.

Lieber CS.

Section of Liver Disease and Nutrition, Bronx VA Medical Center and Mt. Sinai School of Medicine, (151-2), 130 West Kingsbridge Road, Bronx, NY 10468, USA. liebercs@aol.com

Activation of methionine to S-adenosylmethionine is depressed in alcoholics. Its repletion opposes alcoholic liver cirrhosis in baboons, decreases mortality in cirrhotic patients, and opposes oxidative stress resulting from cytochrome P4502E1 (CYP2E1) induction by alcohol, ketones, and fatty acids. Their excess causes alcoholic and nonalcoholic steatohepatitis. CYP2E1 is also induced in Kupffer cells, promoting their activation and release of inflammatory cytokines, including tumor necrosis factor (TNF)-alpha. The TNF-alpha inhibitor pentoxifylline decreased mortality from alcoholic hepatitis. Polyenylphosphatidylcholine (PPC), an antioxidant phosphatidylcholine mixture extracted from soybeans, 50% of which consists of the highly bioavailable dilinoleoylphosphatidylcholine, restores phospholipids of the damaged membranes and reactivates their enzymes, including phosphatidylethanolamine methyltransferase, needed for phospholipid regeneration. In baboons, PPC prevented cirrhosis by stimulating collagenase and by opposing lipid peroxidation, which produces the fibrogenic hydroxynonenal. PPC was beneficial in patients with alcoholic hepatitis, and it opposed fibrosis in heavy drinkers and decreased aminotransferases in patients with hepatitis C. The antioxidant silymarin also successfully opposed alcoholic cirrhosis in baboons and in some but not all clinical trials; this effect also pertains to a-tocopherol. The anti-inflammatory corticosteroids and colchicine yielded mixed results. Finally, replacing long-chain with medium-chain triglycerides opposed the fatty liver experimentally and clinically.

PMID: 14720455 [PubMed - in process]

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Silymarin increases antioxidant enzymes in alloxan-induced diabetes in rat pancreas.

Soto C, Recoba R, Barron H, Alvarez C, Favari L.

Departamento de Sistemas Biologicos, Universidad Autonoma Metropolitana-Xochimilco. Calzada del Hueso 1100, Col. Villa Quietud, DF CP 04960, Mexico. casoto@cueyatl.uam.mx

The aim of this study was to analyze the effect of the flavonoid silymarin, a free radical scavenger that prevents lipoperoxidation, on the pancreatic activity of superoxide dismutase (SOD), glutathione peroxidase (GSHPx) and catalase (CAT) in rats with alloxan-induced diabetes mellitus. Alloxan intoxicated rats were treated with silymarin in two manners, simultaneously (four or eight doses) or 20 days after alloxan administration for 9 weeks. Alloxan elicited a transient increase in the activity of the three enzymes, which decreased after 5 days of treatment. On its own, silymarin significantly increased the activity of these enzymes. Simultaneous treatment with alloxan and silymarin also induced an increment in the activity of the enzymes followed by a delayed decrease (four doses). However, a longer treatment with silymarin (eight doses) induced a more sustained effect. Interestingly, silymarin treatment recovered to control values for the activity of the three-antioxidant enzymes that were significantly diminished after 20 days of alloxan administration. It is suggested that the protective effect of silymarin on pancreatic damage induced by alloxan may be due to an increase in the activity of antioxidant enzymes that, in addition to the glutathione system, constitute the more important defense mechanisms against damage by free radicals.

PMID: 14659454 [PubMed - in process]

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Suppression of advanced human prostate tumor growth in athymic mice by silibinin feeding is associated with reduced cell proliferation, increased apoptosis, and inhibition of angiogenesis.

Singh RP, Sharma G, Dhanalakshmi S, Agarwal C, Agarwal R.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.

Recently, we observed that dietary feeding of silibinin strongly prevents and inhibits the growth of advanced human prostate tumor xenografts in athymic nude mice without any apparent signs of toxicity together with increased secretion of insulin-like growth factor-binding protein 3 from the tumor in to mouse plasma (R. P. Singh et al., Cancer Res., 62:3063-3069, 2002). In the present study, we investigated the effect of silibinin feeding [0.05% and 0.1% (w/w) in diet for 60 days] on the prognostic biomarkers (namely, proliferation, apoptosis, and angiogenesis) in the prostate tumor xenografts of the above-reported study. Immunohistochemical analysis of the tumors for proliferating cell nuclear antigen and Ki-67 showed that silibinin decreases proliferation index by 28-60% and 30-60% (P<0.001) as compared with their controls, respectively. In situ detection of apoptosis by terminal deoxynucleotidyl transferase dUTP-mediated nick end labeling staining of tumors showed a 7.4-8.1-fold (P<0.001) increase in apoptotic cells in silibinin-fed groups over that of control group. Silibinin also increased activated caspase 3-positive cells by 2.3-3.6-fold (P<0.001). CD31 staining for tumor vasculature showed a significant decrease (21-38%; P<0.001) in tumor microvessel density in silibinin-fed groups of tumors as compared with control group of tumors. Tumor sections were also analyzed for vascular endothelial growth factor and insulin-like growth factor-binding protein 3 protein expression, and a slightly decreased and a moderately increased cytoplasmic immunostaining in silibinin-fed groups were observed as compared with the control group, respectively. Together, these results suggest that inhibition of advanced human prostate tumor xenograft growth in athymic nude mice by silibinin is associated with its in vivo antiproliferative, proapoptotic, and antiangiogenic efficacy in prostate tumor.

PMID: 14504208 [PubMed - indexed for MEDLINE]

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Anti-angiogenic effect of silymarin on colon cancer LoVo cell line.

Yang SH, Lin JK, Chen WS, Chiu JH.

Institute of Clinical, National Yang-Ming University, Taipei, Taiwan, Republic of China.

OBJECTIVE: This study was designed to evaluate the anti-angiogenic effect of silymarin (SM) and its major pure component silibinin (SB), and also thalidomide (TH). MATERIALS AND METHODS: A modified in vitro system using a coculture of endothelial (EA.hy 926) and colon cancer (LoVo) cell lines was adopted in this study. RESULTS: In cytotoxicity assay, SM/SB/TH concentrations causing 20% (IC(20)) inhibition of cellular growth were 41.8 microg/ml/0.22 mM/0.088 mM for EA.hy 926 cells, and 16.1 microg/ml/0.12 mM/0.099 mM for LoVo cells, respectively. All 3 drugs showed concentration dependent inhibition of migration and differentiation assay. The IC(50) inhibiting chemotaxis migration of EA.hy 926 towards LoVo by SM/SB/TH was 1.15 microg/ml/0.66 microM/1.98 microM, respectively. In differentiation assay, SM/SB/TH inhibited in vitro capillary tube formation by 50% at 1.25 microg/ml/2.6 micro/6.3 microM, respectively. In an analysis of vascular endothelial growth factor secreted by LoVo cells, SM/SB/TH decreased 50% secretion at 6.52 microg/ml/6.6 microM/131.7 microM, respectively. CONCLUSION: SM/SB has a strong anti-angiogenesis effect on the colon cancer cell line, and this might provide an alternative treatment option for anti-cancer treatment.

PMID: 12943822 [PubMed - indexed for MEDLINE]

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Silibinin induces growth inhibition and apoptotic cell death in human lung carcinoma cells.

Sharma G, Singh RP, Chan DC, Agarwal R.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Box C238, Denver, CO 80262, USA.

BACKGROUND: The high systemic toxicity of chemotherapeutic agents limits their use to treat clinical lung cancer. These limitations could be minimized/overcome by using non-toxic phytochemicals, like, silibinin. MATERIALS AND METHODS: We used small cell lung carcinoma cells (SCLC) SHP-77 and non-small cell lung carcinoma cells (NSCLC) A-549, analyzing cell growth inhibition and death with Trypan blue exclusion, indices of the cell cycle progression with flow cytometry and apoptosis with propidium iodide and Hoechst 33342. RESULTS: Silibinin (25, 50 and 100 microM) treatment of SHP-77 and A-549 cells resulted in their growth inhibition and cell death. Cell cycle studies showed a small increase in G0-G1 population at all the time intervals in SHP-77 cells, however, in A-549 cells, a slight increase in G0-G1 but strong increase in S-phases was observed at lower treatment times, and a strong increase in G0-G1 population at 72 hours. Quantitative apoptotic studies showed that silibinin causes apoptotic cell death in both a dose- and a time-dependent manner with SHP-77 cells showing more apoptotic effect than A-549 cells. CONCLUSION: Silibinin significantly induces growth inhibition, a moderate cell cycle arrest and a strong apoptotic death in both small cell and non-small cell human lung carcinoma cells, which warrants further studies to assess the efficacy of this non-toxic agent in animal lung tumor models.

PMID: 12894553 [PubMed - indexed for MEDLINE]

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Milk thistle: is there a role for its use as an adjunct therapy in patients with cancer?

Ladas EJ, Kelly KM.

Division of Pediatric Oncology, Columbia University, New York, NY, USA. ejd14@columbia.edu

The use of complementary and alternative medicine (CAM) is common among patients with cancer. Many of these patients use CAM therapies to decrease the risk of late effects that are sometimes associated with cancer therapy. Certain classes of effective anticancer agents can induce short- and long-term toxicity to the liver. Currently, there are no safer alternatives to these medications. Milk thistle (Silybum marianum) is a botanical that may be useful in the prevention or treatment of liver dysfunction in patients undergoing anticancer therapy.

Publication Types:

  • Review
  • Review, Tutorial


PMID: 12816629 [PubMed - indexed for MEDLINE]

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[St. Mary's Thistle: an overview]

Laekeman G, De Coster S, De Meyer K.

K.U.Leuven.

St. Marys Thistle has been approved for registration as a regular medicine in Belgium. The hepatotropic properties of this plant are rather difficult to evaluate objectively. Mortality rate in case of life-threatening hepatic diseases is the most objective parameter. Legalon is the only drug registered in Belgium. It has a prescription only status. The plant Silybum marianum is a thistle and as a consequence belongs to the Compositae. There is a limited production of St.-Marys Thistle in Pajottenland, west of Brussels. The seeds are exported to Italy in order to extract silymarine, a mixture of flavonolignanes with antioxidant properties. Silymarine has been tested in living animals deliberately intoxicated with mushroom toxins, medicines, heavy metals or toxic organic solvents. Preventive as well as curative activity has been confirmed. Silymarine accumulates in the liver, which is also the target organ in therapy. Silymarine improves the prognosis after accidental ingestion of the toxic Amanita phalloides. Patients infected with hepatitis B and C might benefit from Silymarine, but more data have to be generated. Silymarine given to patients with liver damages by alcohol lowers the death toll. The drug has a general safety pattern comparable to placebo.

Publication Types:

 

  • Review
  • Review, Tutorial


PMID: 12722542 [PubMed - indexed for MEDLINE]

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Silymarin protects dopaminergic neurons against lipopolysaccharide-induced neurotoxicity by inhibiting microglia activation.

Wang MJ, Lin WW, Chen HL, Chang YH, Ou HC, Kuo JS, Hong JS, Jeng KC.

Department of Education and Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan.

An inflammatory response in the central nervous system mediated by activation of microglia is a key event in the early stages of the development of neurodegenerative diseases. Silymarin is a polyphenolic flavanoid derived from milk thistle that has anti-inflammatory, cytoprotective and anticarcinogenic effects. In this study, we first investigated the neuroprotective effect of silymarin against lipopolysaccharide (LPS)-induced neurotoxicity in mesencephalic mixed neuron-glia cultures. The results showed that silymarin significantly inhibited the LPS-induced activation of microglia and the production of inflammatory mediators, such as tumour necrosis factor-alpha and nitric oxide (NO), and reduced the damage to dopaminergic neurons. Therefore, the inhibitory mechanisms of silymarin on microglia activation were studied further. The production of inducible nitric oxide synthase (iNOS) was studied in LPS-stimulated BV-2 cells as a model of microglia activation. Silymarin significantly reduced the LPS-induced nitrite, iNOS mRNA and protein levels in a dose-dependent manner. Moreover, LPS could induce the activation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase but not extracellular signal-regulated kinase. The LPS-induced production of NO was inhibited by the selective p38 MAPK inhibitor SB203580. These results indicated that the p38 MAPK signalling pathway was involved in the LPS-induced NO production. However, the activation of p38 MAPK was not inhibited by silymarin. Nevertheless, silymarin could effectively reduce LPS-induced superoxide generation and nuclear factor kappaB (NF-kappaB) activation. It suggests that the inhibitory effect of silymarin on microglia activation is mediated through the inhibition of NF-kappaB activation.

PMID: 12473078 [PubMed - indexed for MEDLINE]

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Impact of in utero exposure to EtOH on corpus callosum development and paw preference in rats: protective effects of silymarin.

Moreland N, La Grange L, Montoya R.

Department of Behavioral Sciences, New Mexico Highlands University, 117 Hewett Hall, Las Vegas, NM 87701, USA. nicolmoreland@hotmail.com

BACKGROUND: Using a rat model we have found that the bioflavonoid silymarin (SY) ameliorates some of the negative consequences of in utero exposure to ethanol (EtOH). In the current study our aim was to determine if laterality preference and corpus callosum development were altered in rat offspring whose mothers were provided with a concomitant administration of SY with EtOH throughout gestation. METHODS: We provided pregnant Fisher/344 rats with liquid diets containing 35% ethanol derived calories (EDC) throughout the gestational period. A silymarin/phospholipid compound containing 29.8% silybin was co administered with EtOH to a separate experimental group. We tested the offspring for laterality preference at age 12 weeks. After testing the rats were sacrificed and their brains perfused for later corpus callosum extraction. RESULTS: We observed incomplete development of the splenium in the EtOH-only offspring. Callosal development was complete in all other treatment groups. Rats from the EtOH-only group displayed a left paw preference; whereas control rats were evenly divided between right and left paw preference. Inexplicably both SY groups were largely right paw preferring. CONCLUSIONS: The addition of SY to the EtOH liquid diet did confer some ameliorative effects upon the developing fetal rat brain.

PMID: 12427259 [PubMed - indexed for MEDLINE]

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[Effects of silybin on production of oxygen free radical, lipoperoxide and leukotrienes in brain following ischemia and reperfusion]

Rui YC, Zhang DZ, Sun DX, Zeng GQ.

Department of Pharmacology, Faculty of Pharmacy, Second Military Medical University, Shanghai, China.

Brain ischemia was produced by occluding bilateral common carotid arteries of Mongolia gerbil with clips for 30-min and reperfusion was established by removing the clips. Superoxide dismutase (SOD) in brain tissue was measured by chemoluminescence, malondialdehyde (MDA) by fluorescence spectrometry and leukotrienes (LT) by bioassay. Decrease of SOD and increase of MDA were significant in the brain after 30-min ischemia followed by 2-min reperfusion; The level of SOD increased from 13.4 +/- 2.7 to 18.8 +/- 3.0, 19.8 +/- 2.5, 22.1 +/- 3.9 x 10(3) units/g brain tissue and MDA decreased from 218 +/- 26 to 169 +/- 41, 167 +/- 36, 167 +/- 44 nmol/g brain tissue respectively by ip silybin 100, 200 and 400 mg/kg 30-min before occlusion. LT decreased from 3.1 +/- 1.0 to 1.5 +/- 0.4 ng/g brain tissue after ip silybin 200 mg/kg. It suggested that the protective effect of silybin on ischemic brain result from the inhibition of 5-lipoxygenase and lipoperoxide and scavenging of oxygen free radical.

PMID: 2130596 [PubMed - indexed for MEDLINE]

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Prevention by a silymarin/phospholipid compound of ethanol-induced social learning deficits in rats.

Reid C, Edwards J, Wang M, Manybeads Y, Mike L, Martinez N, La Grange L, Reyes E.

Department of Behavioral Sciences, New Mexico Highlands University, Las Vegas, USA.

We explored the possibility that silymarin (SY), a fraction from Silybum marianum, might protect against the effects of in utero exposure to ethanol upon subsequent social memory function. Three groups of 8 pregnant female Sprague-Dawley rats each were provided with a liquid diet containing 35% ethanol derived calories (EDC). One experimental group received a daily subcutaneous injection of 400 mg/kg SY, the second, a 400 mg/kg oral dose of SY, a third group was maintained on the 35% EDC diet. A fourth group served as the pair-fed control group. The liquid diet regimen was maintained throughout pregnancy. Rats pups were fostered by dams in a fifth group that had been maintained on rat chow. At 90 days the pups were tested for social memory. Social recognition scores recorded for the ethanol pups were significantly poorer than those observed in both SY/ethanol groups and the chow group.

PMID: 10418328 [PubMed - indexed for MEDLINE]