-IBIS-1.7.0-
rx
herb
Silybum marianum (Milk Thistle)
Botanicals
definition
botanical name(s): Silybum marianum, Carduus marianum.
synonyms: milk thistle, holy thistle, Marythistle, St. Mary's thistle.
part(s) used: seeds (botanically - fruit).
qualities: pungent, bitter, warm, dry.
affinities: liver.
actions: bitter, hepatoprotective, antihepatotoxic, hepatorestorative, antioxidant, hypocholesterolemic, anticarcinogenic (epithelial malignancies).
dosage:
» Fluid Extract (1:1):up to 10ml T.I.D
» Standardised Extract (70-80% silymarin) 200mg up to 900mg daily in three divided doses (manufacturer's products may vary).
therapy: acute and chronic hepatitis, fatty liver, cirrhosis, hepatoprotection (incl.amanita poisoning, ethanol, carbon tetrachloride, other hepatotoxic solvents and exotoxins such as pesticides), liver complaints associated with cholangitis, pruritis of pregnancy, psoriasis.
specific indications: liver conditions involving inflammation and toxic insult or overload.
constituents:
» flavonolignan complex "silymarin" (incl. silybin, silydianin, silychristin).
» flavonoids (incl. quercitin, kaempferol).
» fixed oil (incl. linoleic acid, oleic acid).
» other: (betaine, stigmasterol, sitosterol, mucilages, Vitamins C, E and K).
pharmacology:
» Hepatoprotective activity: Originally discovered through protective effect against Amanita phalloides (Deathcap mushroom) toxin poisoning. Mechanisms are multifactorial (Valenzuela, 1994) silymarin flavonolignans act to stabilise hepatocyte membranes and block receptor binding of various toxins and drugs. Antioxidant activity is also hepatoprotective:In vivo and in vitro studies show that silymarin has free radical scavenging activity and enhances superoxide dismutase action in erythrocytes and lymphocytes (Altorjay, 1992; Muzes, 1991). Silymarin also protects against glutathione depletion and increases protein synthesis by hepatocytes when there is damage to parenchymatous tissue. Animal studies suggest silymarin is as effective as colchicine in reversing hepatic fibrosis due to CCl4 induced damage. (Favari, 1997) The antinflammatory effects of silymarin are also based on multiple activities including mast cell stabilisation, inhibition of neutrophil migration, Kuppfer cell inhibition and inhibition of leukotriene and prostaglandin formation (reviewed in Luper, 1998).
» Other activities: Recent research has shown silymarin to be an effective hypocholesterolemic and prevents lipid peroxidation (Krecman 1998; Skottova, 1998). It has significant anticarcinogenic activity against epithelial tumors of the skin (Ahmad, 1998) breast (Zi, 1998) and prostate. (Zi,1998 [2]) It is anti-ulcerogenic (Alarcon de la Lastra, 1992) and immunomodulating. (Luper, 1998)
Clinical Trials:
» Numerous clinical trials have demonstrated the effectiveness of Milk thistle for treatment of chronic alcoholic liver disease (Feher, 1989), cirrhosis (Ferenci, 1989), fatty liver disease and viral hepatitis (Magliulo, 1978) according to metabolic markers (transaminase level reduction) as well as histological and clinical criteria (Salmi, 1982) . A recent study on advanced cirrhosis have found no effects on mortality in serious liver disease (Pares, 1998) suggesting that Milk thistle cannot reverse the progress or inevitable outcome of advanced cirrhosis.
AHPA Botanical Safety Rating: 1
toxicity: 0
» Doses at high end or in excess of therapeutic range may have mild laxative effect due to choleretic action (Luper, 1998). A recent case report attributes an acute adverse reaction to the presence of Milk Thistle in a commercial supplement, but acknowledges that the reaction may have been idiosyncratic, and possibly due to other (unspecified) ingredients in the preparation. (ADRAC, 1999).
drug interactions:
» helps prevent liver damage from hepatotoxic drugs including butyrophenones, phenothiazines (Palasciano et al), acetaminophen, halothane, dilantin, and ethanol. (Brinker, 1998)
» due to increased hepatic clearance, serum levels of drugs such as cyclosporine may be lowered. Transplant patients should be monitored with vigilance for possible reduction in immunosuppressive drug levels during milk thistle therapy.
Therapeutic note: The actions of Milk thistle on hepatic detoxification must be considered in light of the relative balance between Phase I (Cyt P450) and Phase II (conjugation) reactions. Silymarin acts to relatively increase Phase II to Phase I activity - directly by increasing glucoronidation and indirectly by inhibition of some cyt P450 reactions. Adequate Phase II cofactors should be present (ie glutathione and its precursors; pyridoxine; magnesium) to optimise therapeutic effects of Milk thistle. Where the cytochrome system is defective (Phase I compromise), it is appropriate to consider combination with other mild hepatic herbal agents (eg Glycyrrhizza, Taraxacum radix, etc) and focus supplementation on antioxidant support.
footnotes
ADRAC, 1999. An adverse reaction to the herbal medication milk thistle (Silybum marianum). MJA 1999; 170: 218-219
Ahmad N; Gali H; Javed S; Agarwal R ,1998; 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 1998 Jun 18;247(2):294-301.
Abstract: Enhanced tyrosine kinase activity due to aberrant or overexpression of receptor and/or non-receptor tyrosine kinases has been implicated in a variety of human malignancies including cutaneous neoplasms. Epidermal growth factor receptor (EGFR)-mediated tyrosine phosphorylation may be a primary indicator of signal transduction regulating cell growth and proliferation. Recent studies have shown that skin tumor promoters such as phorbol ester and ultraviolet B radiation activate EGFR in mouse skin as well as in cell culture. Similarly, oxidative stress, which is implicated in skin tumor promotion, also activates EGFR-mediated cell signaling. Since this signaling pathway has been suggested to be involved in skin tumor promotion, its impairment by antioxidants may lead to an efficient way for skin cancer prevention and therapy. Recently, we showed that silymarin, a flavonoid antioxidant, affords exceptionally high to complete protection against several skin tumor promoters caused tumor promotion in mouse skin. Employing human epidermoid carcinoma cells A431 that contain overexpressed EGFR, in this study, we assessed whether the anti-skin tumor promoting effects of silymarin are due to its inhibitory effect on EGFR activation and down stream signaling pathway leading to perturbations in cell cycle progression. Treatment of cells with silymarin resulted in a significant inhibition of ligand-induced activation of EGFR with no change in its protein levels. Silymarin treatment also resulted in a significant decrease in tyrosine phosphorylation of Shc, an immediate downstream target of EGFR, but no change in the protein levels of Shc. The inhibition of EGFR activation by silymarin was associated with a highly significant to complete inhibition of EGFR intrinsic kinase activity. Cells treated with silymarin also showed a significant G2-M arrest in cell cycle progression, and a highly significant inhibition of DNA synthesis and cell growth in a dose-dependent manner. Taken together, these results suggest that skin cancer chemopreventive effects of silymarin are mediated via impairment of EGFR signaling which ultimately leads to perturbation in cell cycle progression resulting in the inhibition of proliferation and induction of growth arrest.
Alarcon de la Lastra C; Martin MJ; Marhuenda E; Gastric anti-ulcer activity of silymarin, a lipoxygenase inhibitor, in rats. J Pharm Pharmacol 1992 Nov;44(11):929-931 C
Abstract: Oral treatment with silymarin was found to be effective in the prevention of gastric ulceration induced by cold-restraint stress, in rats. Statistically significant ulcer index values with respect to the control group, were observed. In 6 h pyloric-ligated animals silymarin showed a significant reduction in the number and severity of the ulcers; however, it did not alter the gastric secretion volume or acidity although histamine concentration was significantly decreased. In absolute ethanol-induced ulcers, treatment with silymarin 1 or 2 h before the anti-ulcerogenic agent, did not prevent the formation of gastric lesions. Furthermore, the hexosamine content was decreased significantly, but the total protein output was enhanced, showing similar values to those with the standard drug, carbenoxolone. These results suggest that the anti-ulcerogenic effect of silymarin could be related to its inhibitory mechanism of enzymatic peroxidation by the lipoxygenase pathway, avoiding leukotriene synthesis.
Altorjay I, Dalmi L, Sari B, et al. 1992 The effect of silibinin (Legalon) on the the free radical scavenger mechanisms of human erythrocytes in vitro. Acta Physiol Hung (HUNGARY) 80:375-380; 1992.
Abstract:The effect of Legalon was investigated parallel with that of Adriblastina (doxorubicin) and paracetamol on some parameters characterizing the free radical scavenger mechanisms of human erythrocytes in vitro and on the time of acid hemolysis performed in aggregometer. Observations suggest that Adriblastina enhances the lipid peroxidation of the membrane of red blood cells, while paracetamol causes significant depletion of intracellular glutathione level, thus decreasing the free radical eliminating capacity of the glutathione peroxidase system. Legalon on the other hand, is able to increase the activity of both superoxide dismutase and glutathione peroxidase, which may explain the protective effect of the drug against free radicals and also the stabilizing effect on the red blood cell membrane, shown by the increase of the time of full haemolysis.
Brinker F. 1998. Herb Contraindications and Drug Interactions, rev. 2nd ed., Sandy, Oregon: Eclectic Medical Publications.
Favari L; Perez-Alvarez V 1997. Comparative effects of colchicine and silymarin on CCl4-chronic liver damage in rats. Arch Med Res 1997 Spring;28(1):11-17.
Abstract: The comparative effects of colchicine (10 micrograms day-1, p.o.) and silymarin (50 mg kg-1, p.o.) each given for 5 days a week on the chronic carbon tetrachloride (CCl4) liver damage were studied. Treatment with CCl4 resulted in a marked reduction of Na+, K+, and Ca2(+)-ATPases in plasma liver membranes as compared to vehicles or either silymarin or colchicine alone. Collagen content in livers of animals treated with CCl4 was increased about four-fold as compared to controls and histological examination of liver samples showed that collagen increase distorted the normal liver architecture. Colchicine or silymarin treatment completely prevented all the changes observed in CCl4-cirrhotic rats (namely, lipid peroxidation, Na+, K+ and Ca(2+)- ATPases), except for liver collagen content which was reduced only 55% as compared with CCl4-treated rats and for alkaline phosphatase and glutamic pyruvic transaminase which still remained above controls. In the CCl4 + silymarin group, the loss of glycogen content was completely prevented. However, when rats were treated with CCl4 + colchicine, liver glycogen content could not be restored. The hepatoprotective effects of colchicine or silymarin were very similar in regard to the prevention of chronic liver damage.
Feher J,Deak G, Muzes G, et al. Liver-protective action of silymarin therapy in chronic alcoholic liver diseases. Orv Hetil (Hungary) 130:2723-2727;1989.
Abstract: The effects of silymarin (Legalon) therapy on liver function tests, serum procollagen III peptide level and liver histology were studied in36 patients with chronic alcoholic liver disease in a six month double blind clinical trial. During silymarin treatment serum bilirubin, aspartate aminotransferase and alanin-aminotransferase values have been normalized, while gamma-glutamyl transferase activity and procollagen III peptid level decreased. The changes were significant, and there was a significant difference between post-treatment values of the two groups, as well. In the placebo group only gamma-glutamyl transferase values decreased significantly but to a lesser extent than that in the silymarin group. The histological alterations showed an improvement in the silymarin group, while remained unchanged in the placebo group. These results indicate that silymarin exerts hepatoprotective activity and is able to improve liver functions in alcoholic patients.
Ferenci P; Dragosics B; Dittrich H; et al.; 1989. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 1989 Jul;9(1):
Abstract: Silymarin, the active principle of the milk thistle Silybum marianum, protects experimental animals against various hepatotoxic substances. To determine the effect of silymarin on the outcome of patients with cirrhosis, a double blind, prospective, randomized study was performed in 170 patients with cirrhosis. 87 patients (alcoholic 46, non- alcoholic 41; 61 male, 26 female; Child A, 47; B, 37; C, 3; mean age 57) received 140 mg silymarin three times daily. 83 patients (alcoholic 45, non-alcoholic 38; 62 male, 21 female; Child A, 42; B, 32; C, 9: mean age 58) received a placebo. Non-compliant patients and patients who failed to come to a control were considered as 'drop outs' and were withdrawn from the study. All patients received the same treatment until the last patient entered had finished 2-years of treatment. The mean observation period was 41 months. There were 10 drop outs in the placebo group and 14 in the treatment group. In the placebo group, 37 (+2 drop outs) patients had died, and in 31 of these, death was related to liver disease. In the treatment group, 24 (+4 drop outs) had died, and in 18 of these, death was related to liver disease. The 4-year survival rate was 58 +/- 9% (S.E.) in silymarin-treated patients and 39 +/- 9% in the placebo group (P = 0.036). Analysis of subgroups indicated that treatment was effective in patients with alcoholic cirrhosis (P = 0.01) and in patients initially rated 'Child A' (P = 0.03). No side effects of drug treatment were observed. The results of this study suggest that mortality of patients with cirrhosis was reduced by treatment with silymarin. However, as this effect was more pronounced in alcoholic cirrhosis, the interrelation of patterns of alcohol consumption and of drug treatment affecting survival must be addressed by future studies.
Krecman V; Skottova N; Walterova D;et al. 1998 Silymarin inhibits the development of diet-induced hypercholesterolemia in rats. Planta Med 1998 Mar;64(2):138-142.
Abstract: To study the ability of silymarin, a standardized mixture of antioxidant flavonolignans from the medicinal plant Silybum marianum, and of silybin, the main flavonolignan of silymarin, to inhibit the development of diet-induced hypercholesterolemia the rats were fed high cholesterol diet (HCD). Silymarin or silybin were given as dietary supplements, and their influences on serum cholesterol levels were compared to those of probucol, an antioxidant hypocholesterolemic drug. Anticholesterolemic effect of silymarin was parallel to that of probucol, and dose-dependent at dietary drug concentrations of 0.1-0.5- 1.0% (w/w). However, in contradistinction to probucol, silymarin caused an increase in high density lipoprotein (HDL)-cholesterol and a decrease in liver cholesterol content, changes considered to be of benefit. In addition to its anticholesterolemic effect silymarin partially prevented the HCD-induced decrease in liver reduced glutathione, an endogenous antioxidant. Silybin was not so effective as silymarin suggesting that either other constituent(s) of silymarin may be responsible for its anticholesterolemic effect or the bioavailability of silybin alone might be lower than that of silybin as a compound of silymarin.
Kropacova K, Misurova E, Hakova H. Protective and therapeutic effect of silymarin on the development of latent liver damage. Radiats Biol Radioecol 1998 May-Jun;38(3):411-415.
Abstract: Radioprotective and therapeutical effect of silymarin (Flavobion) on development and repair of latent injury in rat liver was examined by its application during the continual gamma irradiation (dose rates 0.2 and 0.6 Gy/day) or after acute gamma irradiation (dose 6 Gy). Silymarin influence was evaluated on the basis of mitotic index and chromosomal aberration frequency in the liver regenerating after partial hepatectomy. We have found that silymarin application stimulates the process of liver regeneration in non-irradiated rats as well as in irradiated ones. Positive effect of silymarin (100 mg per kg p.o. ones per day) was manifested at both dose rates of continual irradiation with increase in mitotic activity and mitigation of chromosomal erration frequency in the regenerating liver in comparison with non-protected irradiated animals. Curative effect of silymarin (70 mg/kg p.o., twice per day) was shown especially after 14 days of its postradiation application.
Luper S, 1998 A review of plants used in the treatment of liver disease: Part 1. Altern Med Rev 1998 Dec;3(6):410-421.
Abstract: Botanicals have been used traditionally by herbalists and indigenous healers worldwide for the prevention and treatment of liver disease. Clinical research in this century has confirmed the efficacy of several plants in the treatment of liver disease. Basic scientific research has uncovered the mechanisms by which some plants afford their therapeutic effects. Silybum marianum (milk thistle) has been shown to have clinical applications in the treatment of toxic hepatitis, fatty liver, cirrhosis, ischemic injury, radiation toxicity, and viral hepatitis via its antioxidative, anti-lipid peroxidative, antifibrotic, anti- inflammatory, immunomodulating, and liver regenerating effects. Picrorhiza kurroa, though less well researched than Silybum, appears to have similar applications and mechanisms of action. When compared with Silybum, the hepatoprotective effect of Picrorhiza was found to be similar, or in many cases, superior to the effect of Silybum.
Magliulo E, Gagliardi B,Fiori GP. 1978, Results of a double blind study on the effect of silymarin in the treatment of acute viral hepatitis, carried out at two medical centres. Med Klin (Germany) 73:1060-1065; 1978.
In a double blind study carried out under standard conditions at two treatment centers silymarin, 2 sugar-coated tablets 70 mg three times daily, showed a definite therapeutic influence on the characteristic increased serum levels of bilirubin, GOT and GPT associated with acute viral hepatitis. The above mentioned values in 28 patients treated with silymarin were compared with those in 29 patients treated with placebo. The laboratory parameters in the silymarin group regressed more than in the placebo group after the 5th day of treatment. The number of patients having attained normal values after 3 weeks' treatment was higher in the silymarin group than in the placebo group. A statistical comparison revealed a difference between bilirubin and GOT values in the placebo and silymarin groups and a definite trend in the regression of GPT values in favour of silymarin. The course of the immune reaction in HBS Ag patients was not influenced by silymarin. As already proved by other investigators, the use of silymarin in acute viral hepatitis can lead to an accelerated regression in pathological values, thus indicating its use in the treatment of this liver disease.
Muzes G; Deak G; Lang I et al.; 1991 Effect of the bioflavonoid silymarin on the in vitro activity and expression of superoxide dismutase (SOD) enzyme. Acta Physiol Hung 1991;78(1):3-9.
Abstract: Superoxide dismutase activity and expression of the erythrocytes and lymphocytes of patients suffering from chronic alcoholic liver disease and those of healthy controls were investigated after in vitro incubation with silymarin. It was concluded that silymarin treatment in a concentration achievable by in vivo treatment (10 micrograms/ml) significantly increased the SOD activity of both the erythrocytes and lymphocytes of patients with liver disease, whereas the SOD expression of the lymphocytes enhanced to a considerable extent. These results indirectly indicate that the scavenger silymarin is able to increase the antioxidant protection of the cells by ameliorating the deleterious effects of free radical reactions.
Palasciano G, Portincasa P, Palmieri V, et al. 1994. The Effect of Silymarin on Plasma Levels of Malon Dialdehyde in Patients Receiving Long-Term Treatment with Psychotropic Drugs. Curr Ther Res, 55:537-545.
Pares A, Planas R, Torres M,et al. 1998 Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial. J Hepatol 1998 Apr;28(4):615-621.
Abstract: BACKGROUND/AIMS: Silymarin has protective effects in different experimental conditions, but its efficacy in human liver cirrhosis has not been completely established. Therefore, this study was carried out to determine the effect of silymarin in alcoholics with liver cirrhosis with respect to survival and clinical and laboratory changes. METHODS: From February 1986 to June 1989, we enrolled 200 alcoholics with histologically or laparoscopically proven liver cirrhosis in a randomized, double-blind multicenter trial comparing 450 mg of silymarin (150 mg/ three times per day) with placebo. The primary outcome was time to death, and the secondary outcome was the progression of liver failure. Additional analyses were also performed in 75 patients in whom anti-hepatitis C virus antibodies were measured after completion of the trial. RESULTS: One hundred and three patients were assigned to receive silymarin and 97 to receive placebo. The two groups were well matched for demographic and baseline clinical and laboratory features. A 2-year study period was completed in 125 patients (57 receiving silymarin and 68 receiving placebo). Twenty-nine patients (15 receiving silymarin, and 14 receiving placebo) died during the trial. Survival was similar in patients receiving silymarin or placebo. The effect of silymarin on survival was not influenced by sex, the persistence of alcohol intake, the severity of liver dysfunction or by the presence of alcoholic hepatitis in the liver biopsy. Silymarin did not have any significant effect on the course of the disease. No relevant side-effects were observed in any group. CONCLUSIONS: The results of this study indicate that silymarin has no effect on survival and the clinical course in alcoholics with liver cirrhosis.
Salmi HA, Sarna S. 1982. Effect of silymarin on chemical, functional, and morphological alterations of the liver. A double-blind controlled study. Scand J Gastroenterol 17:517-521; 1982.
Abstract: One hundred and six consecutive patients with liver disease were selected on the basis of elevated serum transaminase levels. The patients were randomly allocated into a group treated with silymarin (treated) and a group receiving placebo (controls). Ninety-seven patients complete the 4-week trial-47 treated and 50 controls. In general, the series represented a relatively slight acute and subacute liver disease, mostly induced by alcohol abuse. There was a statistically highly significantly greater decrease of S-SGPT (S-ALAT) and S-SGOT (S-ASAT) in the treated group than in controls. Serum total and conjugated bilirubin decreased more in the treated than in controls, but the differences were not statistically significant. BSP retention returned to normal significantly more often in the treated group. The mean percentage decrease of BSP was also markedly higher in the treated. Normalization of histological changes occurred significantly more often in the treated than in controls.
Skottova N, Krecman V. Silymarin as a potential hypocholesterolaemic drug. Physiol Res 1998;47(1):1-7. (Review)
Abstract: Silymarin, a mixture of flavonolignans from medicinal plant Silybum marianum, is used in supportive treatment of liver diseases of different etiology due to its hepatoprotective activity, which is considered to involve antioxidative and the membrane stabilizing effects. The liver plays an important role in regulation of metabolism of plasma lipoproteins, and liver injury is often reflected as a secondary dyslipoproteinaemia, which may lead to the development of atherosclerosis, particularly when associated with hypercholesterolaemia. This review summarizes the experimental evidence indicating that silymarin-induced protection of liver functions may be of benefit with regard to liver lipid metabolism related to the regulation of plasma lipoproteins. Moreover, some data suggest that silymarin could have a direct effect on liver cholesterol metabolism by inhibiting cholesterol biosynthesis. It is proposed that silymarin deserves to be studied as a potential hypocholesterolaemic agent.
Valenzuela A,Garrido A, 1994. Biochemical bases of the pharmacological action of the flavonoid silymarin and of its structural isomer silibinin. Biol Res 1994;27(2):105-112.
Abstract: The flavonoid silymarin and one its structural components, silibinin, have been well characterized as hepato-protective substances. However, little is known about the biochemical mechanisms of action of these substances. This review deals with recent investigations to elucidate the molecular action of the flavonoid. Three levels of action have been proposed for silymarin in experimental animals: a) as an antioxidant, by scavenging prooxidant free radicals and by increasing the intracellular concentration of the tripeptide glutathione; b) regulatory action of the cellular membrane permeability and increase of its stability against xenobiotic injury; c) at the nuclear expression, by increasing the synthesis of ribosomal RNA by stimulating DNA polymerase I and by exerting a steroid-like regulatory action on DNA transcription. The specific hepatoprotective action of silibinin against the toxicity of ethanol, phenylhydrazine and acetaminophen is also discussed. It is suggested that the biochemical effects observed for the flavonoid in experimental models may settle the basis for understanding the pharmacological action of silymarin and silibinin.
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 1998 Apr;4(4):1055-1064.
Abstract: There is an increasing interest in identifying potent cancer preventive and therapeutic agents against breast cancer. Silymarin, a flavonoid antioxidant isolated from milk thistle, exerts exceptionally high to complete anticarcinogenic effects in tumorigenesis models of epithelial origin. In this study, we investigated the anticarcinogenic effect of silymarin and associated molecular mechanisms, using human breast carcinoma cells MDA-MB 468. Silymarin treatment resulted in a significantly high to complete inhibition of both anchorage-dependent and anchorage-independent cell growth in a dose- and time-dependent manner. The inhibitory effects of silymarin on cell growth and proliferation were associated with a G1 arrest in cell cycle progression concomitant with an induction of up to 19-fold in the protein expression of cyclin-dependent kinase (CDK) inhibitor Cip1/p21. Following silymarin treatment of cells, an incremental binding of Cip1/p21 with CDK2 and CDK6 paralleled a significant decrease in CDK2-, CDK6-, cyclin D1-, and cyclin E-associated kinase activity with no change in CDK2 and CDK6 expression but a decrease in G1 cyclins D1 and E. Taken together, these results suggest that silymarin may exert a strong anticarcinogenic effect against breast cancer and that this effect possibly involves an induction of Cip1/p21 by silymarin, which inhibits the threshold kinase activities of CDKs and associated cyclins, leading to a G1 arrest in cell cycle progression.
Zi X; Grasso AW; Kung HJ; Agarwal R,1998; [2] 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 1998.
Abstract: Prostate cancer (PCA) is the most common nonskin malignancy and the second leading cause of cancer deaths in United States males. One practical and translational approach to control PCA is to define a mechanism-based anticarcinogenic agent(s). Recently, we showed that silymarin, a flavonoid antioxidant isolated from milk thistle, possesses exceptionally high to complete protective effects against experimentally induced tumorigenesis. Because the epidermal growth factor receptor (erbB1) and other members of the erbB family have been shown to play important roles in human PCA, efforts should be directed to identify inhibitors of this pathway for PCA intervention. In this study, we assessed whether silymarin inhibits erbB1 activation and associated downstream events and modulates cell cycle regulatory proteins and progression, leading to growth inhibition of human prostate carcinoma DU145 cells. Treatment of serum-starved cells with silymarin resulted in a significant inhibition of transforming growth factor alpha-mediated activation of erbB1 but no change in its protein levels. Silymarin treatment of cells also resulted in a significant decrease in tyrosine phosphorylation of an immediate downstream target of erbB1, the adapter protein SHC, together with a decrease in its binding to erbB1. In the studies analyzing cell cycle regulatory molecules, silymarin treatment of cells also resulted in a significant induction of cyclin-dependent kinase inhibitors (CDKIs) Cip1/p21 and Kip1/p27, concomitant with a significant decrease in CDK4 expression, but no change in the levels of CDK2 and CDK6 and their associated cyclins E and D1, respectively. Cells treated with silymarin also showed an increased binding of CDKIs with CDKs, together with a marked decrease in the kinase activity of CDKs and associated cyclins. In additional studies, treatment of cells grown in 10% serum with anti- epidermal growth factor receptor monoclonal antibody clone 225 or different doses of silymarin also resulted in significant inhibition of constitutive tyrosine phosphorylation of both erbB1 and SHC but no change in their protein levels. Furthermore, whereas silymarin treatment resulted in a significant increase in the protein levels of both Cip1/p21 and Kip1/p27, monoclonal antibody 225 showed an increase only in Kip1/p27. These findings suggest that silymarin also inhibits constitutive activation of erbB1 and that the observed effect of silymarin on an increase in CDKI protein levels is mediated via inhibition of erbB1 activation only in the case of Kip1/p27; however, additional pathways independent of inhibition of erbB1 activation are possibly responsible for the silymarin-caused increase in Cip1/p21 in DU145 cells. In other studies, silymarin treatment also induced a G1 arrest in the cell cycle progression of DU145 cells and resulted in a highly significant to complete inhibition of both anchorage-dependent and anchorage-independent growth of DU145 cells in a dose- and time- dependent manner. Taken together, these results suggest that silymarin may exert a strong anticarcinogenic effect against PCA and that this effect is likely to involve impairment of erbB1-SHC-mediated signaling pathway, induction of CDKIs, and a resultant G1 arrest.