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REVIEW ARTICLE
Year : 2013  |  Volume : 3  |  Issue : 3  |  Page : 206-218

Silibinin: A promising anti-neoplastic agent for the future? A critical reappraisal


1 Clinical Pharmacology, Dr. Naveen's Care and Cure Clinic, Chandigarh, India
2 Gynecology and obstetrics, Dr. Naveen's Care and Cure Clinic, Chandigarh, India
3 Department of Internal Medicine, PGIMER, Chandigarh, India
4 Dentistry Dr. Naveen's Care and Cure Clinic, Chandigarh, India

Date of Submission29-Nov-2012
Date of Acceptance12-Feb-2013
Date of Web Publication10-Jul-2013

Correspondence Address:
Naveen Chhabra
W.S. 334, Basti Sheikh, Jalandhar, Punjab
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2231-0738.114836

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   Abstract 

Silibinin, a flavonolignan, is the major active component of the milk thistle plant (Silybummarianum). Silibinin have been used as medicinal herbs in the treatment of liver cirrhosis, chronic hepatitis, and gallbladder disorders. Numerous studies suggest that silibinin is a powerful antioxidant and has hepatoprotective properties and anti-neoplastic effects against various carcinoma cells. Silibinin had shown promising anti-neoplastic effects against skin, breast, lung, pancreatic, colon, cervical, prostate, bladder, and kidney carcinomas in various in vitro/in vivo and preclinical studies. Treatment claims also include lowering cholesterol levels, reducing insulin resistance, and anti-viral activity. Other reported uses of milk thistle in folk medicine include as a treatment for malarial fever, bronchitis, peritonitis, uterine congestion, varicose veins, and as a milk production stimulant for nursing mothers. The aim of the present article is to review and summarize the pharmacokinetics, physical properties, the mechanism of action, and the effectiveness and safety of silibininin various cancers/neoplasms.

Keywords: Breast cancer, colorectal cancer, pancreatic cancer, prostate cancer, silibinin


How to cite this article:
Chhabra N, Buzarbaruah S, Singh R, Kaur J. Silibinin: A promising anti-neoplastic agent for the future? A critical reappraisal. Int J Nutr Pharmacol Neurol Dis 2013;3:206-18

How to cite this URL:
Chhabra N, Buzarbaruah S, Singh R, Kaur J. Silibinin: A promising anti-neoplastic agent for the future? A critical reappraisal. Int J Nutr Pharmacol Neurol Dis [serial online] 2013 [cited 2019 Dec 13];3:206-18. Available from: http://www.ijnpnd.com/text.asp?2013/3/3/206/114836


   Introduction Top


Silibinin (silybin), a natural occurring flavnone, is the active constituent of silymarin, which consist a number of flavonolignans such assilibinin, isosilibinin, silicristin and silidianin. Silibinin, an effective anti-cancer and chemopreventive agent in various epithelial cancer models, has been reported to inhibit cancer cell growth through mitogenic signaling pathways, however, until date; exact mechanism is not well-elucidated. The International Union of Pure and Applied Chemistry name for silibinin is (2R, 3R)-3, 5, 7-trihydroxy-2-([2R, 3R]-3-[4-hydroxy-3-methoxyphenyl]-2-[hydroxymethyl]-2, 3dihydrobenzo [b] [1],[4] dioxin-6-yl) chroman-4-one. [1],[2],[3],[4],[5],[6],[7]

The roots soaked in water overnight are used in food, and the despised leaves are added to salads had shown hepatoprotective effects in various hepatic diseases (chronic persistent hepatitis, chronic active hepatitis, [1],[2] alcoholic and Child grade 'A' cirrhosis. [3] Silibininhad shown anti-neoplastic effects against human prostate adenocarcinoma cells, estrogen-dependent and-independent human breast carcinoma cells, ectocervical carcinoma cells, colon cancer cells, lung carcinoma (small cell and non-small cell), and pancreactic cancer cells. [4],[5],[6],[7]

Physical and chemical properties

Molecular mass: 482.44 g/mol. Chemical formula: C 25 H 22 O 10 . Stability: >2 years at −20°C. Ultraviolet (UV)/Visibility: χ229 , 288 nM. Water solubility: Poor. Silibinin is soluble in organic solvents (ethanol, di methyl form amide) [Figure 1]. [1],[2],[3],[4],[5],[6],[7]
Figure 1: Chemical structure of silibinin

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Pharmacokinetic properties

Absorption-Bio-availability of silymarin is low, which led to the development of newer formulations: Silipide and phosphatidylcholine (lecithin). These newer formulations are more bioavailable (about 10 times) than silymarin. [8] Silymarin inclusion complex with β-cyclodextrin is much more soluble than silymarin. [9] Silibinin has also been prepared as glycosides of silybin, which showed more water solubility. [10] Chemically, modified silibinin, silibinin dihydrogendisuccinate disodium a solution for injection, is currently being under investigation for treatment of severe intoxications with hepatotoxic substances, such as Amanita phalloides poisoning.

Tissue distribution and protein bindings

Animal studies were conducted by Zhou et al., [11] in SENsitivity to CARcinogenesis (SENCAR) mice models to determine the distribution and conjugate formation of systemically administered silibinin in liver, lungs, stomach, skin, prostate, and pancreas and to evaluate the effect of orally administered silibinin on Phase II enzyme activity in liver, lungs, stomach, skin, and small bowel. For tissue distribution studies, SENCAR mice were starved for 24 h, orally fed with silibinin (50 mg/kg dose) and killed after 0.5, 1, 2, 3, 4, and 8 h. Peak levels of free silibinin were observed at 0.5 h after administration in liver, lung, stomach, and pancreas, accounting for 8.8 ± 1.6, 4.3 ± 0.8, 123 ± 21, and 5.8 ± 1.1(mean ± SD) μgsilibinin/gtissuerespectively. In the case of skin and prostate, the peak levels of silibinin were 1.4 ± 0.5, and 2.5 ± 0.4, respectively and were achieved 1 h after administration. With regard to sulfate and beta-glucuronidate conjugates of silibinin, other than lung and stomach showing peak levels at 0.5 h, all other tissues showed peak levels at 1 h after silibinin administration. The levels of both free and conjugated silibinin declined after 0.5 h or 1 h in an exponential fashion with an elimination half-life of 57-127 min for free and 45-94 min for conjugated silibinin in different tissues. In the studies examining, the effect of silibinin on Phase II enzymes, oral feeding of silibinin at doses of 100 mg/kg/day and 200 mg/kg/day showed a moderate to highly significant (P < 0.1-0.001, Student's t-test) increase in both glutathione S-transferase and quinonereductase activities are in liver, lung, stomach, skin, and small bowel in a dose-and time-dependent manner. This study concluded that the bioavailability of and Phase II enzyme induction by systemically administered silibinin in different tissues, including skin, where silymarin has been shown to be a strong cancer chemopreventive agent.

Metabolism and excretion

Silymarin undergoes Phase I and Phase II metabolism, especially, Phase II conjugationreactions. It undergoes multiple conjugation reactions, and is primarily excreted into bile and urine. Silymarin has limited effect on the pharmacokinetics of several drugs in vivo; despite silymarin decreasing the activity of cytochrome P 450 (CYPs) enzymes, uridinediphosphate (UDP)-glucuronosyltransferase enzyme, and reducing P-glycoprotein (P-gp) transport. Silymarin has been shown to inhibit P-gp-mediated cellular efflux. The modulation of P-gp activity may result in altered absorption and bioavailability of drugs that are P-gp substrates. It has also been reported that silymarin inhibits CYPs enzymes. [11],[12]

Toxicity

The acute toxicity of silymarin and silybin was investigated by oral and intravenous (IV) route in various animal models. No mortality or any signs of adverse effects were observed of silymarin at oral doses of 20 g/kg in mice and 1 g/kg in dogs. The median lethal dose (LD 50 ) after IV infusion values were reported as 400 mg/kg in mice, 385 mg/kg in rats and 140 mg/kg in rabbits and dogs. Its subacute and chronic toxicity doses were reported very high and it was found to be devoid of embryotoxic potential.

Toxicity and genotoxicity studies for Silibinin conducted inmale and female F344/N rat and B6C3F1 mice, which were exposed to an ethanol/water extract of milk thistle fruit (milk thistle extract) containing approximately 65%silymarin in feed for 3 months or 2 years. Genetictoxicology studies were conducted in Salmonella typhimurium and Escherichia coli and mouse peripheral blood erythrocytes. Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of milk thistle extract in male or female F344/N rat or B6C3F1 mice exposed to 12,500, 25,000, or 50,000 ppm. Exposure to milk thistle extract resulted in increased incidences of clear cell and mixed cell foci in the liver of female rats and decreases in body weights of exposed groups of male and female mice. Decreased incidences of mammary gland neoplasms occurred in exposed groups of female rats, and decreased incidences of hepatocellular neoplasms occurred in exposed groups of male mice. [13]

Mechanism of action of silibinin

Ahmed-Belkacem et al. [14] suggested that silymarin components (Silibinin A and silibinin B, a commercially available IV preparation of silibinin) mainly inhibit hepatitis C virus NS5B ribonucleic acid (RNA)-dependent RNA polymerase activity. Dhanalakshmi et al.[15] reported a dual efficacy of silibinin in protecting or enhancing ultraviolet B (UVB)-caused apoptosis in HaCaT cells, which could be of great significance in (i) protecting normal human skin against UVB-caused cell damage and (ii) preventing carcinogenesis by simultaneously deleting initiated cells. Silibinin significantly inhibits proliferation through cell-cycle arrest via inhibition of cyclin-dependent kinase (CDK) promoter activity. Apoptosis does not appear to be greatly increased in human colon cancer cell lines Fet, Geo, and HCT 116. Rather, inhibition of cell cycle regulatory proteins plays a fundamental role in silibinin'smechanism of action, and this may serve as a basis for combined use with conventional chemotherapeutics. [6]

The silibinin treatment of HeLa cells was found to arrest cells in G2 arrest and to induce a decrease in CDKs involved in both G1 and G2 progression in a study conducted by Zhang et al. [16] In addition, silibinin also showed a dose-dependent and a time-dependent apoptotic death in HeLa cells in both the mitochondrial pathway and the death receptor-mediated pathway, providing a strong rationale for future studies evaluating preventive and/or intervention strategies for silibinin in cervical cancer pre-clinical models.

In a study, conducted by Fan et al., [17] to investigate, whether the autophagy- and apoptosis-associated molecules also involved in reactive oxygen species (ROS) generation or not, Silibinin was reported to promote the expression phosphorylated-p53 (p-p53) in a dose-dependent manner. Pifithrin-α (PFT-α), a specific inhibitor of p53, reduced ROS production and reversed silibinin's growth-inhibitory effect. The ROS scavenger N-acetyl cysteine (NAC) attenuated silibinin-induced up-regulation of p-p53 expression, suggesting that p53 might be regulated by ROS and forms a positive feedback loop with ROS. On the other hand, silibinin dose-dependently promoted the expression of phosphorylated-c-Jun N-terminal kinase (p-JNK). Inhibition of JNK by SP600125 decreased ROS generation. NAC down-regulated the expressions of p-JNK indicates that JNK could be activated by ROS. Activation of p53 was suppressed by SP600125 and expression of p-JNK was inhibited by PFT-α, therefore silibinin might activate a ROS-JNK-p53 cycle to induce cell death. Silibinin up-regulates the p53 up-regulated modulator of apoptosis (PUMA) and B - cell lymphoma 2 (BCL 2)-associated X protein (Bax) expressions and down-regulated the mitochondrial membrane potential (MMP) level. PFT-α reduce the expression of PUMA and Bax. These results showed that p53 could interfere with mitochondrial functions such as mitochondrial membrane permeabilization (MMP) via PUMA pathways, thus, resulting in ROS generation. In order to elucidate the functions of p53 in silibinin induced ROS generation, we have chosen the A431 cells (human epithelial carcinoma) because they lack p53 activity (p53His273 mutation). Interestingly, silibinin did not up-regulate the ROS level in A431 cells but lower the ROS level. PFT-α had no influence on ROS level in A431 cells. p53 activation plays a crucial role in silibinin induced ROS generation.

Yu et al. [18] investigated the contribution of silibinin to the induction of apoptosis and autophagy via generation of ROS and nitric oxide (NO) in human epidermoid carcinoma A431 cells. In this study, silibinin inhibited the cell growth in a dose- and time-dependent manner. Obvious autophagy was observed after treatment with different doses of silibinin. At a high dose (400 μM), silibinin induced apoptosis through both the intrinsic and extrinsic apoptotic pathways. Loss of mitochondrial membrane potential by silibinin led to mitochondrial dysfunction and decreased ROS levels, suggesting that silibinin might act as an antioxidant in this process. Furthermore, silibinin induced NO generation in a time-and dose-dependent manner. The NO scavenger 2-(4-carboxy-phenyl)-4, 4, 5, 5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) could effectively clear NO and exerted a minor cell protection effect through partial inhibition of silibinin-in hagy.

The efficacy and safety of silibinin in various malignancies/neoplasm has been studied in various in-vivo/in-vitro studies. A summary of various studies is presented below [Table 1].
Table 1: Summary of various in-vitro/in vivo studies regardingeffi cacy and safety of silibinin in various malignancies/neoplasm

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Silibinin and lung cancer

In vivo study

The effect of oral silibinin (742 mg/kg body weight, 5 days/week for 10 weeks) on the growth and progression of established lung adenocarcinomas in mice models was studied by Tyagi et al. [19] It was concluded that oral silibinin decreased both tumor number and tumors size, and its anti-neoplastic effect was found to be correlated with decreased anti-angiogenic activity. The mechanism of action of silibinin in lung tumor growth inhibition by anti-angiogenic mechanisms thought to be mediated by decreased tumor-associated macrophages and cytokines, inhibition of hypoxia-inducible factor-1 alpha, nuclear factor κB (NF-κB1), and Signal transducer and activator of transcription three activation, and up-regulation of the angiogenic inhibitors, Ang -2 and Tie-2. [19]

In vitro study

In a study conducted by Mateen et al., [20] the effect of silibinin on prime endpoints and key molecular targets (cell number, cell cycle progression and cell cycle regulatory molecules) in three cell lines representing different non-small cell lung cancer subtypes (large cell carcinoma cells [H1299 and H460] and a bronchioalveolar carcinoma cell line [H322] was studied. It was observed that silibinin treatment (10-75μM) inhibited cell growth and targeted cell cycle progressing by causing a prominent G1 cell phase arrest in dose-and time-dependent manner, as well as by reduction in kinase activity of CDK4 and CDK2 in all cell lines except no effect on CDK4 kinase activity in H460 cells, and concomitantly reduced retinoblastoma protein phosphorylation.

Silibinin and breast cancer

In vitro studies

A study conducted by Wang et al., [21] concluded that silibinin promotes the sustained superoxide production that was specifically scavenged by exogenous superoxide dismutase (SOD) in Michigan Cancer Foundation-7 (MCF-7) cells, while the activity of endogenous SOD was not changed by silibinin. It was observed that silibinin-induced superoxide had protective effect, as exogenous SOD markedly enhanced silibinin-induced apoptosis.

In another study conducted by Dastpeyman et al., [22] the effect of silibinin on migration and adhesion capacity of MDA-MB-231 cells, a highly metastatic human breast cancer cell line, was investigated by evaluation of β1-integrin and its important down-stream molecules. The 3- [4,5-dimethylthiazol-2-yl]-2, 5, -diphenyltetrazolium bromide (MTT) migration and adhesion assays were performed to evaluate the silibinin effects on proliferation, migration and adhesion of MDA-MB-231 cells. In addition, the influence of the silibinin on the expression of β1-integrin, Raf-1(proto-oncogenic TKL kinase of the RAF family), cell division cycle 42 (CDC42) and D4 Guanine nucleotide dissociation inhibitors(D4-GDI) messenger RNA (mRNAs) was assessed by reverse transcription polymerase chain reaction (RT-PCR). Results showed significant dose-dependent inhibitory effect of silibinin on proliferation, migration and adhesion of MDA-MB-231 cells. It significantly inhibited the expression of Cdc42 and D4-GDI mRNAs but had no statistically significant effect on the expression of β1-integrin and Raf-1 mRNAs although it indirectly but effectively modulated β1-integrin signaling pathway and Raf-1 function. The results of this study showed the silibinin effects on decreasing the rate of metastasis, migration and adhesion of MDA-MB-231 to distant organs.

Noh et al., [23] investigated the effect of silibinin in MCF-7 human breast cancer cells and determined whether silibinin enhances UV B-induced apoptosis. A dose- and time-dependent reduction in viability was observed in MCF-7 cells treated with silibinin. Silibinin strongly induced apoptotic cell death in MCF-7 cells, and induction of apoptosis was associated with increased p53 expression. Silibinin induced a loss of cell viability and apoptotic cell death in MCF-7 cells. Furthermore, the combination of silibinin and UVB resulted in an additive effect on apoptosis in MCF-7 cells. These results suggested that silibinin might be an important supplemental agent for treating patients with breast cancer.

Silibinin and colorectal carcinoma (CRC)

In vitro studies

A study conducted by Kauntz et al., [24] to investigate the potential of silibinin as a chemopreventive agent in colon carcinogenesis. The rat azoxymethane (AOM)-induced colon carcinogenesis model was used. After 1ne week AOM injection (post-initiation), Wistar rats received daily intragastric feeding of 300 mg silibinin/kgbody weight per day until their sacrifice after 7 weeks of treatment. Silibinin-treated rats exhibited a 2-fold reduction in the number of AOM-induced hyper-proliferative crypts and aberrant crypt foci in the colon compared to AOM-injected control rats receiving the vehicle. The Mechanisms involved in silibinin-induced apoptosis was thought to be the down-regulation of the anti-apoptotic protein Bcl-2 and up-regulation of the pro-apoptotic protein Bax, inverting the Bcl-2/Bax ratio to < 1. This modulation already takes place at the mRNA expression level as shown by real-time RT-PCR. Furthermore, silibinin treatment significantly (P < 0.01) decreased the genetic expression of biomarkers of the inflammatory response such as interleukin 1 beta (IL1β), tumour necrosis factor alfa (TNFα) and their down-stream target matrix metalloproteinase-7 (MMP7), all of them shown to be up-regulated during colon carcinogenesis. The down-regulation of MMP7 protein was confirmed by western blot analysis. The results of this study showed the ability of silibinin to shift the disturbed balance between cell renewal and cell death in colon carcinogenesis in rats previously injected with the carcinogen AOM. Silibin in administered via intragastric feeding exhibited potent pro-apoptotic, anti-inflammatory, and multi-targeted effects at the molecular level. The effective reduction of pre-neoplastic lesions by silibinin supports its use as a natural agent for colon cancer chemoprevention.

Kaur et al., [25] studied the effect of silibinin on the growth of human CRC SW480 cells in culture and xenograft. The in vitro and in vivo studies was conducted to examine whether silibinin targets β-catenin pathway in its efficacy against CRC by using human CRC cell lines harboring mutant (SW 480) versus wild type (HCT116) adenomatous polyposis coli APC gene and alteration in β-catenin pathway. It was concluded that silibinintreatment inhibited cell growth, induced cell death, and decreased nuclear and cytoplasmic levels of β-catenin in SW480 but not in HCT116 cells, suggesting its selective effect on the β-catenin pathway and associated biologic responses. Other studies performed in SW480 cells, showed that silibinin significantly decreased β-catenin-dependent T-cell factor-4 transcriptional activity and protein expression of β-catenin target genes such as c-Myc and cyclinD1.Silibinin has also been shown to decrease CDK8, a CRC oncoprotein that positively regulates β-catenin activity, and cyclin C expression. In a SW480 another tumorxenograft study, 100-mg/kg and 200-mg/kg doses of silibinin feeding for 6 weeks inhibited tumor growth significantly. It was concluded that, silibinin decreases proliferation and expression of β-catenin, cyclin D1, c-Myc, and CDK8 but induces apoptosis in vivo. Silibinin inhibits the growth of SW480 tumors carrying the mutant APCgene by down-regulating CDK8 and β-catenin signaling and therefore, could be an effective agent against CRC.

Sangeetha et al., [26] observed thatsilibinin modulates gut microbial enzymes, colonic oxidative stress and Wnt/β-catenin signaling, to exert its anti-proliferative effect against 1,2 di-methylhydrazine (DMH) induced colon carcinogenesis. Their study was conducted to explore the effect of silibinin on xenobiotic metabolizing enzymes during DMH induced colon carcinogenesis. Male albino rats were randomly divided into six groups. Group 1 served as control and group 2 rats received 50 mg/kg body weight of silibininper oral every day. Groups 3-6 rats were given DMH at a dose of (20 mg/kg body weight subcutaneously) once a week for 15 weeks to induce colonic tumors. In addition to DMH, Group 4 (initiation), Group 5 (post-initiation) and Group 6 (entire period) rats received silibinin (50 mg/kg body weight, p.o., everyday) at different time points during the experimental period of 32 weeks. Rats exposed to DMH alone showed increased activities of Phase I enzymes (cytochrome b5, cytochrome b5 reductase, CYPs, CYP sreductase, cytochromP 450 2E1) and decreased activities of Phase II enzymes (Uridinediphos phoglucuronylt ransferase, Glutathione-S-transferase and DT-Diaphorase) in the liver and colonic mucosa as compared to control rats. Silibinin supplementation modulates the xenobiotic metabolizing enzymes favoring carcinogen detoxification. Evaluation of lipid peroxidation and anti-oxidants status showed that silibinin supplementation counteracts DMH induced hepatic and circulatory oxidative stress. Tumor burden in experimental animals was assessed both macroscopically and microscopically in the colon tissues.

In vitro studies

TNF-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer agent, which selectively induces apoptosis in cancer cells. In a study, the effect of silibinin and TRAIL was investigated in an in vitro model of human colon cancer progression, consisting of primary colon tumor cells (SW480), and their derived TRAIL-resistant metastatic cells (SW620). Up-regulation of death receptor 4 (DR4) and DR5 by silibinin was shown by RT-PCR and by flow cytometry. Human recombinant DR5/Fc chimera protein that has a dominant-negative effect by competing with the endogenous receptors abrogated cell death induced by silibinin and TRAIL, demonstrating the activation of the death receptor pathway. Synergistic activation of caspase-3,-8, and-9 by silibinin and TRAIL was shown by colorimetric assays. When caspase inhibitors were used, cell death was blocked. Furthermore, silibinin and TRAIL potentiated activation of the mitochondrial apoptotic pathway and down-regulated the anti-apoptotic proteins [myeloid leukemia cell differentiation protein (Mcl-1) and X-linked inhibitor of apoptosis (XIAP)]. The involvement of XIAP in sensitization of the two cell lines to TRAIL was demonstrated using the XIAP inhibitor embelin. These findings suggested the synergistic action of silibinin and TRAIL, suggesting chemopreventive and therapeutic potential, which should be further explored. [27]

Silibinin and hepatocellular carcinoma

In vitro study

A study was conducted by Vargesh et al., [28] to evaluate efficacy of silibinin against hepatocellular carcinoma. Silibinin effects were examined on growth, cytotoxicity, apoptosis, and cell cycle progression in two different hepatocellular carcinoma (HCC) cell lines, HepG2 (hepatitis B virus negative; p53 intact) and Hep3B (hepB virus positive; p53 mutated). At molecular level, cell cycle effects of silibinin were assessed by immunoblotting and in-bead kinase assays. Silibinin strongly inhibited growth of both HepG2 and Hep3B cells with a relatively stronger cytotoxicity in Hep3B cells, which was associated with apoptosis induction. Silibinin also caused G 1 arrest in HepG2 and both G 1 and G 2 -M arrests in Hep3B cells. Mechanistic studies revealed that silibinin induces Kip1/p27 but decreases cyclin D1, cyclin D3, cyclin E, cyclin-dependent kinase-2, and CDK4 levels in both cell lines. In Hep3B cells, silibinin also reduced the protein levels of G 2 -M regulators. Furthermore, silibinin strongly inhibited CDK2, CDK4, and CDC2 kinase activity in these HCC cells.

Silibinin and pancreatic cancer

In vitro study

Ge et al. [29] evaluated the inhibitory proliferation effects of silibinin in pancreatic carcinoma growth and examined whether Silibinin modulates cell cycle and apoptosis. The results of this study indicate that Silibinin effectively inhibited the pancreatic carcinoma AsPC-1, BxPC-3 and Panc-1 cells proliferation and caused apoptosis. Silibinin induced a decrease in S phase and cell cycle arrest in G1 phase in AsPC-1 cells, but had no obvious changes in BxPC-3 and Panc-1 cell cycle. Furthermore, these results suggest that silibinin might be a candidate chemopreventive agent for pancreatic carcinoma therapy.

Silibininandbladdercarcinoma

In vitro study

Singh et al. [30] investigated the antitumor efficacy of silibinin (100 mg/kg and 200 mg/kg doses, 5 days/week for 12 weeks) in tumorxenografton the human bladder transitional cell papilloma RT4 cells implanted subcutaneously in athymic nude mice. In this study, in vivo anti-tumor efficacy of oral silibinin against human bladder tumor cells involving down-regulation of survivin and an increase in p53 expression together with enhanced apoptosis was identified.

Silibinin and prostate cancer (PCA)

In vivo and In vitro study

Singh et al., [31] observed the effect ofsilibinin/silymarin on PCA cells. A pleiotropic anti-neoplastic effect of silibinin leading to cell growth inhibition in culture and nude mice was observed. The underlying mechanisms ofsilibinin/silymarin efficacy against PCA was identified in this study as alteration in cell cycle progression, and inhibition of mitogenic and cell survival signaling, such as epidermal growth factor receptor, insulin-like growth factor receptor type I (IGF-1R) and nuclear factor kappa beta 1 (NF-κB1) signaling. It was also concluded that, silibinin synergizes the therapeutic effects of doxorubicin in PCA cells.Silibinin/silymarin was also found to inhibit the secretion of pro-angiogenic factors from tumor cells, and in causing growth inhibition, and apoptotic death of endothelial cells accompanied by disruption of capillary tube formation.

In vitro studies

Matrigel Zi et al. [32] studied the effect of silibinin treatment on prostate specific antigen (PSA) levels in hormone-refractory human prostate carcinoma LNCaP cells. It was observed that silibinin treatment of cells grown in serum resulted in a significant decrease in both intracellular and secreted forms of PSA concomitant with a highly significant to complete inhibition of cell growth via a G 1 arrest in cell cycle progression.Silibinin decreases prostate-specific antigen with cell growth inhibition via G 1 arrest, leading to differentiation of prostate carcinoma cells. Silibinin-induced G 1 arrest was associated with a marked decrease in the kinase activity of CDKs and associated cyclins because of a highly significant decrease in cyclin D1, CDK4, and CDK6 levels and an induction of Cip1/p21 and Kip1/p27 followed by their increased binding with CDK2.

A study was conducted to compare the anti-angiogenic potential of four pure diastereoisomericflavonolignans, namely silybin A, silybin B, isosilybin A, and isosilybin B. Results of this study showed that oral feeding of these flavonolignans (50 mg/kg and 100 mg/kg body weight) effectively inhibit the growth of advanced human PCA DU145 xenografts. Immunohistochemical analyses revealed that these flavonolignans inhibit tumor angiogenesis biomarkers (CD31 and nestin) and signaling molecules regulating angiogenesis (vascular endothelial growth factor [VEGF], VEGFR1, VEGFR2, phospho-Akt, and hypoxia-inducible factor 1-alpha, (HIF-1α) without adversely affecting the vessel-count in normal tissues (liver, lung, and kidney) of tumor bearing mice. These flavonolignans were also found to inhibit the microvessel sprouting from mouse dorsal aortas ex vivo, and the VEGF-induced cell proliferation, capillary-like tube formation and invasiveness of human umbilical vein endothelial cells (HUVEC) in vitro. Further studies in HUVEC showed that these diastereoisomers target cell cycle, apoptosis and VEGF-induced signaling cascade. [33]

An in vitro study was conducted by Zheng et al., [34] to evaluate the antitumor activity of silybin nanosuspension on human prostatic carcinoma PC-3 cell line. Silybin nanosuspension was prepared by the high pressure homogenization method. MTT assay, observation of morphological changes, and apoptotic body showed that silybin nanosuspension could significantly enhance the in vitro cytotoxicity against PC-3 cells compared to the silybin solution. Flow cytometric analysis demonstrated that silybin nanosuspension induced G1 cycle arrest and apoptosis in PC-3 cells. Thereby, the overall results suggested that the silybin nanosuspension could be a promising treatment of human prostate cancer.

Silibinin and skin cancers

In vitro study

Katiyar et al., [35] studied the anti-carcinogenic activity for skin by observing the treatment of JB6 C141 cells (pre-neoplastic epidermal keratinocytes) and p53+/+ fibroblasts with silymarin and silibinin. It was concluded that silibinin, in a dose-dependent manner, caused inhibition of cell viability and induction of apoptosis. Silymarin-induced apoptosis was blocked by the caspaseinhibitor N-Benzyloxycarbonyl-Val-Ala-Asp (O-Me) fluoromethyl ketone (Z-VAD-FMK) in JB6 C141 cells, which suggested the role of caspase activation in the induction of apoptosis. These observations concluded that silymarin-induced apoptosis is primarily p53 dependent and mediated through the activation of caspase-3.

In vivo study

A study conducted by Gu et al., [36] reported strong efficacy of silibinin against photocarcinogenesis. In this study, the researchers assessed the protective effects of its dietary feeding on UVB-induced biomarkers involved in non-melanoma skin cancer. Dietary feeding of silibinin at 1% dose (w/w) toSKH-1 hairless mice for 2 weeks before a single UVB irradiation at 180 mJ/cm 2 dose resulted in a strong and significant (P < 0.001) decrease in UVB-induced thymine dimer-positive cells and proliferating cell nuclear antigen, terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling, and apoptotic sunburn cells together with an increase (P < 0.001) in p53 and p21/cip1-positive cell population in epidermis. These findings suggest that dietary feeding of silibinin affords strong protection against UVB-induced damages in skin epidermis by (a) either preventing DNA damage or enhancing repair, (b) reducing UVB-induced hyper-proliferative response, and (c) inhibiting UVB-caused apoptosis and sunburn cell formation, possibly via silibinin-caused up-regulation of p53 and p21/cip1 as major UVB-damage control sensors.

Silibinin and neural tumours

In vitro studies

An in vitro study was undertaken by Jeong et al., [37] to examine the role of calpain in the silibinin-induced glioma cell death. It was observed that the silibinin induced activation of calpain, which was blocked by ethylene glycol tetraacetic acid (EGTA) and the calpain inhibitor N-[(phenylmethoxy) carbonyl]-L-leucyl-N-[(1S)-1-formyl-3-methylbutyl]-L-leucinamide (Z-Leu-Leu-CHO). Silibinincaused ROS generation and its effect was inhibited by calpain inhibitor, the general protein kindase C (PKC) inhibitor GF 109203X, the specific PKCd inhibitor rottlerin, and catalase. Silibinin-induce cell death was blocked by calpain inhibitor and PKC inhibitors. It was concluded that silibinin induces apoptotic cell death through a calpain-dependent mechanism involving PKC, ROS, and apoptosis induced factor (AIF) nuclear translocation in U87MG human glioma cells.

The silibinin's inhibitory effects on invasive properties of human glioblastoma U87MG cells through suppression of cathepsin B and NF-κB1-mediated induction of matrix metalloproteinase ninewere evaluated by Momeny et al. [38] The microculture tetrazolium test, bromodeoxyuridine cell proliferation assay, cell-based NF-κB1 activation assessment, cathepsin B activity assay, gelatine zymography, and quantitative real-time RT-PCR were performed to evaluate the effects of silibinin on the metabolic activity, DNA synthesis, NF-κB1 phosphorylation, cathepsin B activity, and gelatinolytic activity of U87 cells. It was showed that silibinin inhibit metabolic activity, cell proliferation, NF-κB1 activation, cathepsin B enzymatic levels, and gelatinase B activity in U87 cells. In addition, an expressive decrease in mRNA levels of matrix metalloproteinase-9, cathepsin B, urokinase plasminogen activator receptor, urokinase plasminogen activator, and intercellular adhesion molecule 1 coupled with a significant induction in transcriptional levels of stefin A was observed. These findings showed that silibinin treatment could restrict the invasive features of a highly invasive human glioma cell line, U87, through suppression of NF-κB1-mediated stimulation of matrix metalloproteinase-9. Furthermore, silibinin might cripple the activation of gelatinase B by cramping transcriptional and enzymatic activities of cathepsin B in U87 cells. [38]

A study was carried out to appraise the impeding effects of silibinin on two different neuroblastoma cell lines, stromal SK-N-MC, and neuroblastic SK-N-BE (2) cells. The micro-culture tetrazolium assay, gelatine zymography, colony formation assay, cell cycle distribution survey, apoptosis assay, and quantitative real-time reverse transcription-PCR were applied to evaluate the effects of silibinin on metabolic activity, gelatinolytic activity of MMP-2 and MMP-9, surviving potential, cell cycle, apoptosis, and expression pattern of the genes involved in cell survival and invasion of the two neuroblastoma cell lines. Treatment for 48 h inhibited metabolic activity and clonogenic potential of SK-N-MC cells in a dose-dependent manner. Silibinin also inhibited transcriptional levels of MMP-2, MMP-9, and urokinase-type plasminogen activator receptor (uPAR), as markers of cell invasion, in SK-N-MC cells. Higher concentration of silibinin (75, 100 μM) suppressed enzymatic activity of MMP-2 in this cell line. No change in apoptosis and cell cycle was observed in neither of the cells after treatment with silibinin. On the other hand, silibinin highly decreased mRNA expression of Akt, and NF-κB1 and its regulators, IKK 1 and IKK2 in SK-N-MC cell line. Comparison of transcriptional expression of Akt, and NF-κB1 in untreated stromal and neuroblastic cell lines shows that their basal transcriptional levels are much higher in SK-N-BE (2) cell line than that in SK-N-MC cells. The results of this study suggested that suppression of SK-N-MC cell line by silibinin may be through inhibition of Akt-mediated NF-κB1. [39]

Silibininandosteoblasts

An in vitro study investigated the silibinin's bone-forming and osteoprotectiveeffects in vitro cell systems of murine osteoblastic MC3T3-E1 cells and mouse leukaemic monocyte macrophage cell line (RAW 264.7 murine macrophages) MC3T3-E1 cells were incubated in osteogenic media in the presence of 1-20 μM silibinin up to 15 days. Silibinin accelerated cell proliferation and promoted matrix mineralization by enhancing bone nodule formation by calcium deposits. In addition, silibinin promoted the induction of osteoblastogenic biomarkers of alkaline phosphatase, collagen type 1, connective tissue growth factor, and bone morphogenetic protein-2. Differentiated MC3T3-E1 cells enhanced secretion of receptor activator of nuclear factor-κB ligand (RANKL) essential for osteoclastogenesis, which was reversed by silibinin. It was also found that silibinin retarded tartrate-resistant acid phosphatase and cathepsin K induction and matrix metalloproteinase-9 activity elevated by RANKL through disturbing tumour necrosis factor (TNF) receptor associated factor 6 (TRAF6-c-Src) signaling pathways. These results demonstrate that silibinin was a potential therapeutic agent promoting bone-forming osteoblastogenesis and encumbering osteoclastic bone resorption. [40]

Silibinin's effect on other drugs

An in vivo study was conducted by Singh et al., [41] to evaluate the effect of oral silibinin on the therapeutic response of doxorubicin in athymic BALB/cμ/μ mice in suppression of human non-small-cell lung carcinoma A549 xenograft growth and on prevention of doxorubicin-caused adverse health effects. It was concluded that oral silibinin caused the suppression of human non small cell lung cancer (NSCLC) A549 xenograft growth (P < 0.05) and enhances the therapeutic response (P < 0.05) of doxorubicin in with a strong prevention of doxorubicin-caused adverse health effects. Immuno-histochemical analyses of tumors showed that silibinin and doxorubicin decrease ( P < 0.001) proliferation index and vasculature and increase ( P < 0.001) apoptosis; these effects were further enhanced (P < 0.001) in combination treatment. Doxorubicin increased NF-κB DNA binding activity as one of the possible mechanisms for chemoresistance in A549 cells, which was inhibited by silibinin in combination treatment. Consistent with this, silibinin inhibited doxorubicin-caused increased translocation of p65 and p50 from cytosol to nucleus. Silibinin also inhibited cyclooxygenase-2, an NF-κB target, in doxorubicin combination. These observations suggested that silibinin inhibits in vivo lungtumor growth and reduces systemic toxicity of doxorubicin with an enhanced therapeutic efficacy most likely via an inhibition of doxorubicin-induced chemoresistance involving NF-κ Bsignaling.

The combination treatment with silibinin and 5-fluorouracil, paclitaxel, vinblastine, or everolimus (RAD-001) enhanced the chemosensitivity of 5-fluorouracil and paclitaxel in a study conducted by Chang et al. [42] The silibinin was observed to inhibit the invasion and migration of 786-O cells in vitro, inhibits the growth of xenografts in vivo, and enhances chemosensitivity to 5-fluorouracil and paclitaxel. [42] A study was conducted by Zhou et al. [43] to observe, whether silibinin restores paclitaxel sensitivity in paclitaxel resistance in human ovarian cancer cells. In this study, A 2780 and A 2780/taxol cells were treated with silibinin alone or in combination with paclitaxel. It was observed that silibinin enhanced A 2780/taxol cells to Paclitaxel, increased Paclitaxel induced apoptosis and G2/M arrest consistent with down-regulation of survivin and P-gp. A 2780/taxol cells showed a two-fold increase in invasiveness ability as compared to A 2780 cells. The results of this study suggested that silibinin in combination with Paclitaxel may be beneficial in human ovarian cancer cells refractory to treatment with Paclitaxel.

Jiang et al. [44] conducted a study to evaluate the protective effect against chemotherapeutic reagent mitomycin C-induced cell death in A375-S2 cells in a p53-dependent manner, which contradicted the findings of previous studies investigating the anti-neoplastic activity of silibinin and developing silibinin as a potential anti-neoplastic drug in clinical therapy. Mitomycin C administration triggered a time- and dose-dependent cell death in A375-S2 cells. Apoptotic morphology, DNA fragmentation, and caspase-3 activation demonstrated that the major cause of A375-S2 cell death by mitomycin C was apoptosis. This was associated with a marked increase of p53 level and changes in mitochondria associated proteins. However, preincubation with silibinin prior to mitomycin C treatment substantially suppressed cell apoptosis, attenuated the change of p53 and Bcl-2 expressions, blocked the translocation of Bax to mitochondrial outer membrane, and ameliorated the loss of mitochondrial membrane potential, but mitomycin C stimuli led to few changes in the protein levels of caspase 8, Fas ligand, and Fas-associated death domain protein, indicating that silibinin protected cells from mitomycin C-induced apoptosis mainly via suppressing the mitochondria-mediated intrinsic apoptosis pathway, but not in an extrinsic manner.

A study was conducted by Jiang et al., [45] to investigate the mechanism of ROS generation and the role of ROS in protecting cells against silibinin induced cytotoxicity in A375-S2 cells. It was observed that the silibinin induced the generation of large amount of superoxide anion (O2 ) and small amount of hydrogen peroxide (H 2 O2 ) through down-regulating the activity of mitochondrial complex IV and the protein level of cytochrome c. It was also discovered that O2 − generation activated (IGF-1R) and its down-stream phosphatidylinositol 3-kinases-Akt (PI3K-Akt) and phospholipase C γ-protein kinase C ( PLC γ-PKC) signaling pathways, which were augmented by H 2 O 2 scavenger catalase. Scavenging O2 − by SOD or inhibition of IGF-1R-PI3K-Akt and IGF-1R-PLC γ-PKC signaling pathways increased cell apoptosis. Therefore, O2 − mediated cell resistance to silibinin via activating IGF-1R-PI3K-Akt and IGF-1R-PLC γ-PKC pathways in silibinin treated A375-S2 cells.

Dizaji et al., [46] studied the efficacy of arsenic trioxide (ATO), combined with silibinin in the glioblastomamultiforme (GBM) cell line, U87MG. It was showed that the combination therapy synergically inhibited metabolic activity, cell proliferation, and gelatinase A and B activities; it also increased apoptosis. It was also found to decrease the mRNA level of cathepsin B, uPA, matrix metalloproteinase-2 and 9, membrane type 1-MMP, survivin, BCL2, CA9; and it increased mRNA level of caspase-3. Altogether, these results showed that ATO and silibinin in some cases improved and/or complemented the anticancer effects.


   Conclusion Top


Silibinin, a flavonolignan, the major active component of the milk thistle plant (Silybummarianum) have been used as medicinal herbs in the treatment of liver cirrhosis, chronic hepatitis, and gallbladder disorders. Numerous studies suggest that silibinin is a powerful anti-oxidant and has anti-hepatotoxic properties and anti-cancer effects against various carcinoma cells. Silibinin has shown promising anti-neoplastic effects against skin, breast, lung, pancreatic, colon, cervical, prostate, bladder, and kidney carcinomas. Treatment claims also include lowering cholesterol levels, reducing insulin resistance, and antiviral activity. Silibinin is safe and the adverse effects observed in the reviewed studies appear to be minimal. However, targeted randomized clinical trials on silibinin are necessary to establish its safety and efficacy.

 
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