silymarin in the prevention and treatment of liver diseases and primary liver cancer

8/18/2019 Silymarin in the Prevention and Treatment of Liver Diseases and Primary Liver Cancer

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210 Current Pharmaceutical Biotechnology, 2012 , 13, 210-217

1389-2010/12 $58.00+.00 © 2012 Bentham Science Publishers

Silymarin in the Prevention and Treatment of Liver Diseases and PrimaryLiver Cancer

†

János Fehér and Gabriella Lengyel*

2nd Department of Medicine, Semmelweis University, Budapest, Hungary

Abstract: In chronic liver diseases caused by oxidative stress (alcoholic and non-alcoholic fatty liver diseases, drug- and

chemical-induced hepatic toxicity), the antioxidant medicines such as silymarin can have beneficial effect. Liver cirrhosis,

non-alcoholic fatty liver and steatohepatitis are risk factors for hepatocellular carcinoma (HCC). Insulin resistance and

oxidative stress are the major pathogenetic mechanisms leading the hepatic cell injury in these patients. The silymarin ex-

erts membrane-stabilizing and antioxidant activity, it promotes hepatocyte regeneration; furthermore it reduces the in-

flammatory reaction, and inhibits the fibrogenesis in the liver. These results have been established by experimental and

clinical trials. According to open studies the long-term administration of silymarin significantly increased survival time of

patients with alcohol induced liver cirrhosis. Based on the results of studies using methods of molecular biology, sily-

marin can significantly reduce tumor cell proliferation, angiogenesis as well as insulin resistance. Furthermore, it exerts an

anti-atherosclerotic effect, and suppresses tumor necrosis factor-alpha-induced protein production and mRNA expression

due to adhesion molecules. The chemopreventive effect of silymarin on HCC has been established in several studies using

in vitro and in vivo methods; it can exert a beneficial effect on the balance of cell survival and apoptosis by interfering cy-

tokines. In addition to this, anti-inflammatory activity and inhibitory effect of silymarin on the development of metastases

have also been detected. In some neoplastic diseases silymarin can be administered as adjuvant therapy as well.

Keywords: Cancer prevention, chronic liver diseases, hepatitis B virus, hepatitis C virus, hepatocellular carcinoma, silymarinsteatohepatitis.

INTRODUCTION

Silymarin is an extract of the milk thistle (Silybum mari-anum). The tea made of milk thistle was used for the treat-ment of liver diseases already in the ancient world. Dating back to the time of the ancient Greeks (Theophrastus, 4thcentury B.C.) and Romans (Pliny the Elder, 1st centuryA.D.), the seeds of milk thistle (also known as St. Mary’s

thistle and lady’s thistle), have been used to protect liverhealth [1]. In the 1st century A.D., Dioskurides used this plant as an emetic as well as a general medicinal herb. It became a favored medicine for hepatobiliary diseases in 16thcentury and the drug was revived again in 1960 in centralEurope [2,3]. Milk thistle grows up to 6 feet tall, particularlywell on sunny slopes in Mediterranean countries, particularlySpain and Greece. The plant of the milk thistle blooms fromJune through August, and the shiny black seeds are harvestedafter the end of the summer to be used for medicinal pur- poses [1].

Silymarin is a mixture of flavonoids and polyphenols.The commercial silymarin preparations contain several dif-

ferent flavonoids, like silibinin (silybin A and B), isosilibinin(isosilybin A and B), silichristin and silidianin Fig. (1).Silibinin is the major bioactive component of this material.The most prevalent forms are the diastereoisomers silybin Aand silybin B. Silymarin has membrane-stabilizing and

*Address correspondence to this author at the 2nd Department of Medicine,Semmelweis University, H-1088 Budapest, Szentkirályi str. 46, Hungary;Tel: +3630 984 6953; Fax: +361 317 4548; E-mail: [email protected]

†Dedicated to the memory of Professor János Fehér (1932-2010).

antioxidant activity, it promotes hepatocyte regenerationreduces inflammatory reaction, and inhibits fibrogenesisThese results have been established in experimental andclinical trials [4-13].

The pharmacological data [1, 14] show that silymarin possesses fairly specific effects on cell-regulating mechanisms, beyond the well known reactive oxygen species

(ROS) scavenging properties confirmed in new studies, indicating a potential to reduce toxic effects of other drugs (e.gcisplatin, amiodarone). This scavenging effect has been proved by atomic force microscopic examinations [15]. Insome models, silymarin already at low dose was shown toreduce the inducible nitric oxide synthase-mediated production of nitric oxide and to modulate the inflammatory immune response [1, 14].

In liver diseases caused by oxidative stress (alcoholic andnon-alcoholic fatty liver and steatohepatitis, drug- andchemically-induced hepatic toxicity) the antioxidant medicines such as silymarin is the primary therapeutic modalityof choice [4, 16, 17]. This can be realized in part by propercomposition of food, in part by application of free radicascavengers such as the marketed silymarin products [18-21]Recently several reports have dealt with the beneficial effecof silymarin not only in chronic liver diseases caused by oxidative stress, but also in viral-induced chronic hepatitis andin primary liver cancer. Chronic hepatitis and liver cirrhosiare the risk factors of hepatocellular carcinoma (HCC). Inseveral studies the chemopreventive and adjuvant effect osilymarin has been also established in different kind of tumors.


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Silymarin, Liver Diseases and Liver Cancer Current Pharmaceutical Biotechnology, 2012 , Vol. 13, No. 1 21

SILYMARIN AND LIVER DISEASES

Silymarin and Experimental Liver Damage

Hepatoprotective activity of silymarin has been demon-strated by various researchers from all over the world against partial hepatectomy models and toxic models in experimen-tal animals by using acetaminophen [22], carbon tetrachlo-ride [23, 24], ethanol, D-galactosamine and Amanita phal-loides toxin [25]. Silymarin has also been found to protectliver cells from injury caused by ischemia, radiation and vi-ral hepatitis [25]. In these experiments the biochemicalmarkers of hepatocyte damage namely, alanine aminotrans-ferase (ALT), aspartate aminotransferase (AST), and -

glutamyl transpeptidase, caused by the toxic effects weredecreased. The signs of lipid peroxidation (malondialdehydecontent) and the parameters of antioxidant capacity (activi-ties of superoxide dismutase, catalase, and glutathione per-oxidase) beneficially changed after silymarin treatment [25-27]. Additional demonstrations of silimaryn effects includeup regulation of low-density lipoprotein receptor and perox-isome proliferators-activated alpha gene expression [27]. Newer novel findings suggest that silymarin and garlic havea synergistic effect, and could be used as hepatoprotectiveagents [28].

Silymarin and Micronodular Liver Cirrhosis

In our own earlier clinical pharmacological studies [7, 11,

12] we have demonstrated in a prospective multicentre con-trolled trial, treatment with silymarin (Legalon 140, Madaus,Cologne, Germany) for 6 months in 36 human patients (bi-opsy confirmed) with micronodular hepatic cirrhosis (ChildA). The treatment had a beneficial effect on immune re-sponse of the body and on parameters of the antioxidant pro-tective mechanism [11, 12]. Serum procollagen III levelsalso decreased significantly in the therapeutic group duringthe 6 months of treatment, indicating inhibition of fibrogene-sis in the hepatic tissue [7]. Our open studies similarly to thedata of Ferenci et al. [4] showed that the long-term admini-stration of silymarin significantly increased the life expec-

tancy of patients with alcohol induced liver cirrhosis in a period by 5-10 years [17].

Silymarin and Non-Alcoholic Fatty Liver Diseases

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial liver injury, one form a significant risk for HCC. Iincludes a wide spectrum of liver damage characterized byhistological changes of alcoholic origin (ranging from uncomplicated fatty liver to steatohepatitis, fibrosis and cirrhosis) in non-alcoholics (< 20 g/day ethanol consumption). It ideveloped mainly by insulin resistance and oxidative stress but the exact metabolic and cellular mechanisms are not fullyunderstood [29-31].

Researches have identified the factors that can play acausative role: oxidative stress, abnormal cytokine production, fatty-acid metabolic disturbance and insulin resistanceThe combination of these events causes hepatocyte injury viadirect oxidative injury, tumor necrosis factor-alpha (TNF-induced apoptosis, or inflammation [29-35]. This disease is atwo hit alteration in the liver: first phase is the pure steatosisand the second phase is characterized by steatohepatiti(non-alcoholic steatohepatitis, NASH) or fatty liver cirrhosisCurrently, treatment of NAFLD is focused on modifying riskfactors (obesity, diabetes mellitus, and hyperlipidemia)Many therapeutic approaches have been attempted withvarying degrees of success [36, 37].

Mitochondrial dysfunction and oxidative stress are determinant events in the pathogenesis of NASH. Silymarinhas been shown to have antioxidant, anti-inflammatory, andantifibrotic effects in chronic liver disease. In several ex perimental models [38-40] and in clinical trial [31, 41-44different authors have demonstrated the beneficial effect osilymarin silibinin, silybin-phospholipid complex, silybinvitamin E-phospholipids complex. These therapy modalitiewere effective in preventing severe oxidative stress and preserving hepatic mitochondrial bioenergetics in NASH induced in different animal models or in human disease. Themodifications of mitochondrial membrane fatty acid compo

Fig. (1). Molecules of the components of silymarin.

HO

OH

O

O

OH

O

O

CH2OH

OCH3

OH

HO

OH

O

O

OH

O

O CH2OH

OCH3

OH

HO

OH

O

O

OH

O

CH2OH

OCH3

OH

OH

O

OCH3

O

H

H

OH

2'

3'

Silibinin Isosilibinin

Silichristin Silidianin


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sition induced by methionine- and choline-deficient diet are partially prevented by silybin-phospholipid complex, confer-ring anti-inflammatory and antifibrotic effects. The increasedvulnerability of lipid membranes to oxidative damage is lim-ited by silybin-phospholipid complex through preserved mi-tochondrial function [40].

Silymarin and Hepatitis C Virus Infection

Silymarin inhibits hepatitis C virus (HCV) by displayingantioxidant, anti-inflammatory, and immunomodulatory ac-tions that contribute to its hepatoprotective effects. Polyak etal. [45] evaluated the in vitro hepatoprotective actions of theseven major flavonolignans and one flavonoid that comprisesilymarin. Activities tested included inhibition of HCV cellculture infection, NS5B polymerase activity, TNF--inducednuclear factot-kappaB (NF- B) transcription, virus-inducedoxidative stress, and T-cell proliferation. Silymarin sup- pressed TNF- activation of NF- B dependent transcription,which involved partial inhibition of inhibitory B and RelA/ p65 serine phosphorylation, and p50 and p65 nuclear trans-location, without affecting the binding of p50 and p65 toDNA. Flavonolignans blocked JFH-1 virus-induced oxidativestress, including compounds that lacked antiviral activity.

There are several clinical studies on the use of herbalextracts, especially silymarin, for the treatment of patientswith chronic hepatitis C, primarily in the belief that this drugimproves response to antiviral agents and reduces adversereactions [21, 46-54]. In a recent multicentre trial (HALT-C)the efficacy of a silymarin preparation added to pegylatedinterferon and ribavirin was also studied. The trial included atotal of 1,145 individuals. In 10 centers there were also pa-tients whose treatment was completed with silymarin as well.Although patients’ ALT levels and viral load showed nosignificant change as compared to those treated with pegy-lated interferon and ribavirin, the quality of life in patients

receiving silymarin was better as they reported much lesscomplaints relating to liver disease [55]. Recent studies re-vealed that silymarin reduces insulin resistance [56]. Thiseffect has a major impact on chronic hepatitis caused byHCV because the rate of sustained virological response(SVR) to the combined treatment with pegylated interferonand ribavirin in patients with insulin resistance was only ahalf (25-33%) as compared to that in patients with no insulinresistance (60%). Based on the available references of litera-ture a clearly higher rate of SVR can be attained by reducinginsulin resistance prior to the initiation of treatment with pegylated interferon and ribavirin [57]. At the European As-sociation for the Study of Liver (EASL, 2008) congress inMilan, Italy, Ferenci et al. [58] presented their most recent

results which showed that silibinin infusion (10 mg/kg Le-galon Sil; Madaus, Cologne, Germany), administered for 8days in patients with chronic hepatitis caused by HCV, sig-nificantly (P


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Table 2. Sylimarin as Chemopreventive and Therapeutic Agent for Extra-Hepatic Tumors

Organ/System Target/Effects Mechanisms References

Reduces the risk of skin cancers initiated with UV-

radiation Inflammation; oxidative stress; DNA-damage [87]

SkinProtective effect against chemotherapeutic agent

mitomycin C-induced cell death in human melanoma

A 375- S2 cells

Mitochondria mediated apoptosis; p53; Bcl-2 [88]

Prevents TPA-induced

MMP-9 expression in human breast cancer cells MMP-9; COX-2 [89]

BreastPreventive effect of arsenite-induced cytotoxicity in

two human breast adenocarcinoma cell lines Oxidative stress [90]

Inhibits the invasion of human lung cancer cells Urokinase plasminogen activator; MMP-2 [82]Lung

Inhibits tumor growth in athymic nude mice NF- B [91]

Suppresses TNF-- induced MMP-9

expression in gastric cancer cell line

MMP-9

MEK/ERK pathway[92]

Suppresses spontaneous tumorgenesis in

APC min/+) mice

Beta- catenin; cyclin D1; proliferation; apoptosis;

c-Myc; phospho-glycogen synthase kinase 3 beta;

COX-2; NOS

[93, 94]

Suppresses 1,2-dimethyl-hydrazine-induced carcino-

genesis

Modulation of biotransforming activity of microbial

enzymes[95]

Inhibits the growth of LoVo cells Apoptosis; Caspases 3, 9;

poly (ADP-ribose) polymerase[96]

Causes strong cell cycle arrest at G(1), G(2)-M-phase

Cyclins; cyclin-dependent kinases (1, 2, 4, 6);

cyclin dependent kinase inhibitor (p21, p27); phos-

phorilation of retinoblastoma protein

[96]

Gastrointestinal tract

Inhibits proliferation and promotes cell-cycle arrest

Angiogenesis; NOS;

COX; HIF-1; VEGF;

proliferation; apoptosis

[97, 98]

ProstateInhibits cell proliferation in PC3 prostate carcinoma

cell line Proliferation; HIF-1 [99, 100]

BladderInhibits the proliferation of RT4 human bladder papil-

loma cells and of bladder tumor xenograft in mice Survivin protein; p53 [101]

Other systems Inhibits invasive properties of U87MG cells

Cathepsin B; NF- B;

MMP-9; gelatinase B;

urokinase plasminogen

Activator receptor; urokinase plasminogen activator;

intercellular adhesion molecule 1; stefin A

[102]

Abbreviations: COX-2, cyclooxygenase-2; HIF-1, hypoxia-inducible factor-1; MMP-2/9, metalloproteinase-2/9, NF- B, nuclear factor-kappaB; NOS, nitri

oxide synthase; TPA, 12-O-tetradecanoylphorbol-13-acetate; VEGF, vascular endothelial growth factor.

cancer cells via decreased production of urokinase- plasminogen activator and MMP-2 [82]. The alleviating ef-fect of silymarin, particularly silibinin has also been demon-strated in relation to the reduction of cellular injury due tochemotherapeutic agents or radiotherapy [83]. This can ob-viously be explained by the free radical scavenger proprietyof silymarin. Its possible inhibitory effects on neoplastic processes are summarized in Fig. (2) based on the publica-tion of Ramasamy et al. [84].

Li et al. [85] examined the pharmacokinetics, mechanisms, effectiveness and adverse effects of silibinin's anticancer actions reported to date in pre-clinical and clinicatrials. The silibinin as an adjunct cancer treatment is able toinfluence such factors as histological subtype, hormonastatus, stromal interactions and drug metabolizing gene polymorphisms. The results of these studies may help to more precisely target and dose silibinin therapy to optimize clinical outcomes for oncology patients [86].


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Fig. (2). Potential anticarcinogenic effects of silymarin [adapted

from ref. 34].

CONCLUSIONS

Numerous studies as presented here suggest that sily-marin may be useful in the treatment of patients with chronicliver diseases, which are risk factors for cirrhosis and HCC,especially alcoholic and non-alcoholic steatohepatitis in thecurrent clinical practice and, as it can be expected, also in thefuture. In addition it can also be administered as adjuvanttherapy in the chemoprevention of other cancerous diseases.The very marked viral load reducing effect of silibinin at

high doses also deserves special attention. The molecularmechanisms of silibinin-mediated antiproliferative effectsare mainly via receptor tyrosine kinase, androgen receptor,signal transducers and activators of transcription, NF- B,cell cycle regulatory and apoptotic signaling pathways invarious cancer cells. Targeting inhibition of proliferative pathways through silibinin treatment may provide a newapproach for improving chemopreventive and chemotherapeutic effects.

Milk thistle is the dietary supplement taken most fre-quently by patients with chronic liver diseases. This supple-ment is one of the most widely used herbal medicines for along time. Both milk thistle and its active ingredient sily-

marin are pharmacologically safe and well tolerated. Thisreview demonstrates that silymarin is a safe and effectiveantioxidant drug in animal model systems, and further hu-man studies are needed to establish its full potential for thetreatment of chronic liver diseases as well as liver cancer prevention.

ACKNOWLEDGEMENT

The studies conducted by the authors as mentioned in thisreview was supported by the EU Project “COST B35 Action: Lipid Peroxida tion Associated Disorders: LPO”.

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Inhibition of

invasive

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Influence of cell

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Received: May 02, 2010 Revised: August 31, 2010 Accepted: September 01, 2010

silymarin in the prevention and treatment of liver diseases and primary liver cancer

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