Cancer Letters

Cancer Letters

Volume 269, Issue 2, 8 October 2008, Pages 352-362
Cancer Letters

Mini-review
Multitargeted therapy of cancer by silymarin

https://doi.org/10.1016/j.canlet.2008.03.053Get rights and content

Abstract

Silymarin, a flavonolignan from milk thistle (Silybum marianum) plant, is used for the protection against various liver conditions in both clinical settings and experimental models. In this review, we summarize the recent investigations and mechanistic studies regarding possible molecular targets of silymarin for cancer prevention. Number of studies has established the cancer chemopreventive role of silymarin in both in vivo and in vitro models. Silymarin modulates imbalance between cell survival and apoptosis through interference with the expressions of cell cycle regulators and proteins involved in apoptosis. In addition, silymarin also showed anti-inflammatory as well as anti-metastatic activity. Further, the protective effects of silymarin and its major active constituent, silibinin, studied in various tissues, suggest a clinical application in cancer patients as an adjunct to established therapies, to prevent or reduce chemotherapy as well as radiotherapy-induced toxicity. This review focuses on the chemistry and analogues of silymarin, multiple possible molecular mechanisms, in vitro as well as in vivo anti-cancer activities, and studies on human clinical trials.

Introduction

Research over the last three decades has provided convincing evidence to support that the diets rich in fruits and vegetables may be protective against the risk of different types of cancers. Of late, several medicinal herbs from plant origin have also received great attention due to their wide range of pharmacological effects. All these dietary agents, medicinal plants and herbs have been tested for their cancer chemopreventive activity. The reduced cancer risk and lack of toxicity associated with high intake of natural products suggest that specific concentrations of phytochemicals from these plant sources may produce cancer chemopreventive effects without causing significant levels of toxicity. Natural agents are believed to suppress the inflammatory process that lead to neoplastic transformation, hyperproliferation, promotion and progression of carcinogenic process and angiogenesis. It is estimated that nearly one-third of all cancer deaths in the United States could be prevented through appropriate dietary modification. Accumulating research evidence suggests that many dietary agents/medicinal plants may be used alone or in combination with traditional chemotherapeutic agents to prevent the occurrence of cancer, their metastatic spread, or even to treat cancer [1], [2].

Silymarin has been used for more than 2000 years as a natural remedy for treating hepatitis and cirrhosis and to protect liver from toxic substances. Silymarin acts by anti-oxidative, anti-lipid peroxidative, anti-fibrotic, anti-inflammatory, membrane stabilizing, immunomodulatory and liver regenerating mechanisms in experimental liver diseases. Furthermore, silymarin has been extensively studied, both in vivo and in vitro, for its cancer chemopreventive potential against various cancers [3]. This article reviews the current studies regarding various aspects of silymarin as they relate to its efficacy against cancer and associated molecular mechanisms.

Section snippets

Silymarin – chemistry and analogues

Silymarin is an active extract from the seeds of the plant milk thistle (Silybum marianum (L.) Gaertn. (Asterceae), and contains approximately 65–80% silymarin flavonolignans (silymarin complex) with small amounts of flavonoids and approximately 20–35% fatty acids and other polyphenolic compounds. The major component of the silymarin complex is silybin that is synonymous with silibinin (Fig. 1), together with other flavonolignans namely isosilybin, silychristin, silydianin, and flavonoid

Silymarin – molecular targets for anti-cancer efficacy

Carcinogenesis is a multistep process that is activated by altered expression of transcriptional factors and proteins involved in proliferation, cell cycle regulation, differentiation, apoptosis, angiogenesis, invasion and metastasis. Deregulated cell cycle progression and apoptosis together with increased angiogenic potential, invasion and metastasis have been described as hallmarks of cancer. Accordingly, the agents that could target one or more of these processes should be effective and

Anti-inflammatory effects of silymarin

Anti-inflammatory effects of silymarin are related to inhibition of the transcription factor nuclear factor-κB (NF-κB), which regulates and coordinates the expression of various genes involved in inflammation, cell survival, differentiation and growth. In particular, NF-κB contributes to the production of interleukin (IL)-1 and -6, tumor necrosis factor (TNF)-α, lymphotoxin, granulocyte macrophage colony-stimulating factor (GM-CSF) and interferon (IFN)-γ. In most of the resting cells, NF-κB is

Modulation of cell cycle progression by silymarin

Disruption of the normal regulation of cell cycle progression and division is an important event in malignant transformation. The regulation of the cell cycle is controlled by a family of cyclins, CDKs, and CDK inhibitors (CDKIs). Silymarin has been reported to suppress the proliferation of tumor cells in various cancers including prostate [15], [16], [17], [24], ovarian [25], breast [26], lung [27], skin [18], and bladder [28], [29]. Numerous reports indicate that silymarin inhibits

Induction of apoptosis by silymarin

Apoptosis or programmed cell death that occurs in various physiological and pathological conditions is one of the hallmarks of cancer. Several phytochemicals that are known to inhibit NF-κB and AP-1 activation can suppress cell proliferation and sensitize cells to apoptosis induction. Studies have reported that silymarin exerts its anti-cancer effects by causing cell cycle arrest and inducing apoptosis in different type of cancers. Li et al. [32] have shown that silymarin induces apoptotic cell

Anti-angiogenic activity of silymarin

Anti-angiogenic activity is one of the fundamental ways of the cancer treatment. The anti-angiogenic potential of silymarin has been demonstrated in various cancers. We have demonstrated that silymarin inhibits the growth and survival of human umbilical vein endothelial cells (HUVECs) by inhibiting capillary tube formation, and induction of cell cycle arrest and apoptosis together with a reduction in invasion and migration. The molecular events associated with these effects include an

Anti-metastatic activity of silymarin

Cancer metastasis, a primary cause of cancer death and which may complicate the clinical management, depends on the motility and invasiveness of cancer cells. MMPs play an important role in the invasion and metastasis of cancer cells. Silibinin at 100 μM concentration inhibited invasion and motility of SCC-4 tongue cancer as well as A459 lung cancer cells by down-regulating MMP-2 and urokinase-type plasminogen activator (u-PA) and up-regulating tissue inhibitor of metalloproteinase-2 (TIMP-2)

Anti-oxidant activity of silymarin

Silymarin and silibinin exert anti-oxidant activity and support redox homeostasis in several in vitro and in vivo models. Kiruthiga et al. [46] have shown that administration of silymarin increases the activities of anti-oxidant enzymes like superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST) together with a decrease in the levels of malondialdehyde (MDA), a marker for lipid peroxidation, in erythrocytes exposed to H

Anti-cancer activity of silymarin: in vitro studies

Anti-cancer activity of silymarin has been demonstrated in human breast cancer, skin cancer, androgen-dependent and -independent prostate cancer, cervical cancer, colon cancer, ovarian cancer, hepatocellular carcinoma, bladder cancer, and lung cancer cells [14], [15], [16]. Active compounds of silymarin, isosilybin B, and isosilybin A, treatment has been shown to result in growth inhibition and cell death together with a strong G1 arrest and apoptotic death in human prostate carcinoma LNCaP and

Anti-cancer activity of silymarin: in vivo studies

The efficacy of silymarin has been shown against chemically induced carcinogenesis, growth of tumor xenograft, as well as in various transgenic models. We were the first one to demonstrate the activity of silymarin against 12-O-tetradecanoyl-phorbol-13-acetate (TPA) induced tumor promotion by inhibiting the activity and expression of epidermal ornithine decarboxylase [49]. Further studies suggested the important role of silymarin in inhibiting the chemical- and UV-induced skin carcinogenesis

Silymarin in clinical trials

Human clinical studies have demonstrated that milk thistle extract has significant hepatoprotective, anti-diabetic, and cardioprotective effects. The efficacy of silymarin is being evaluated in cancer patients either alone or in combination with other chemotherapeutic agents. Several doses of silymarin have been tested both alone and in conjunction with other drugs in several populations. Silipide, a silibinin formulation, was given orally to patients with colorectal adenocarcinoma at doses of

Pharmacology and metabolism of silymarin

Preclinical and clinical studies have examined the pharmacokinetics, pharmacodyanamics and metabolism of silymarin. The in vivo effectiveness of silymarin flavonolignans depends on bioavailability and achieving therapeutics concentrations in the organs of interest. The components of the silymarin are poorly soluble in water and studies in both preclinical and clinical have shown only ng/ml in plasma following oral administration of powdered extracts. However, pharmacokinetics studies have shown

Conclusions

This mini review briefly summarizes multi-targeted chemopreventive and interventive targets and mechanisms of silymarin/silibinin in various in vitro and in vivo cancer models. All these results validate pharmacological safety of silymarin, which is needed for effective chemopreventive as well as chemotherapeutic agent. Silymarin exerts its anti-cancer effects by multiple molecular mechanisms that could block all stages of carcinogenesis, initiation, promotion and progression. In particular,

Acknowledgements

Original studies are supported in part by the NCI RO1 Grants CA64514, CA102514, CA104286, CA112304, CA113876, and CA116636.

References (68)

  • S.O. Lee et al.

    Silibinin suppresses PMA-induced MMP-9 expression by blocking the AP-1 activation via MAPK signaling pathways in MCF-7 human breast carcinoma cells

    Biochem. Biophys. Res. Commun.

    (2007)
  • A. Svobodová et al.

    Attenuation of UVA-induced damage to human keratinocytes by silymarin

    J. Dermatol. Sci.

    (2007)
  • S. Giacomelli et al.

    Silybin and its bioavailable phospholipid complex (IdB 1016) potentiate in vitro and in vivo the activity of cisplatin

    Life Sci.

    (2002)
  • W. Wu et al.

    Enhanced bioavailability of silymarin by self-microemulsifying drug delivery system

    Eur. J. Pharm. Biopharm.

    (2006)
  • J.K. Prasain et al.

    Metabolism and bioavailability of flavonoids in chemoprevention: current analytical strategies and future prospectus

    Mol. Pharm.

    (2007)
  • H. Nishino et al.

    Cancer control by phytochemicals

    Curr. Pharm. Des.

    (2007)
  • J. Post-White et al.

    Advances in the use of milk thistle (Silybum marianum)

    Integr. Cancer Ther.

    (2007)
  • D.J. Kroll et al.

    Milk thistle nomenclature: why it matters in cancer research and pharmacokinetic studies

    Integr. Cancer Ther.

    (2007)
  • D.Y. Lee et al.

    Molecular structure and stereochemistry of silybin A, silybin B, isosilybin A, and isosilybin B, Isolated from Silybum marianum (milk thistle)

    J. Nat. Prod.

    (2003)
  • I. Szilági et al.

    Structure of silandrin and silymonin, two new flavanolignans from a white blooming Silybum marianum variety

    Planta Med.

    (1981)
  • S.L. MacKinnon et al.

    Silyamandin, a new flavonolignan isolated from milk thistle tinctures

    Planta Med.

    (2007)
  • B. Ahmed et al.

    Synthesis and antihepatotoxic activity of some heterocyclic compounds containing the 1,4-dioxane ring system

    Pharmazie

    (2003)
  • P.R. Davis-Searles et al.

    Milk thistle and prostate cancer: differential effects of pure flavonolignans from Silybum marianum on antiproliferative end points in human prostate carcinoma cells

    Cancer Res.

    (2005)
  • G. Deep et al.

    Isosilybin B and isosilybin A inhibit growth, induce G1 arrest and cause apoptosis in human prostate cancer LNCaP and 22Rv1 cells

    Carcinogenesis

    (2007)
  • R. Agarwal et al.

    Anticancer potential of silymarin: from bench to bed side

    Anticancer Res.

    (2006)
  • R.P. Singh et al.

    Prostate cancer chemoprevention by silibinin: bench to bedside

    Mol. Carcinogen.

    (2006)
  • X. Zi et al.

    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)
  • G. Deep et al.

    Chemopreventive efficacy of silymarin in skin and prostate cancer

    Integr. Cancer Ther.

    (2007)
  • S.K. Manna et al.

    Silymarin suppresses TNF-induced activation of NF-kappa B, c- Jun N-terminal kinase, and apoptosis

    J. Immunol.

    (1999)
  • Y.C. Hsu et al.

    Antifibrotic effects of tetrandrine on hepatic stellate cells and rats with liver fibrosis

    J. Gastroenterol. Hepatol.

    (2007)
  • J.W. Chang et al.

    Proinflammatory cytokine-induced NF-kappaB activation in human mesangial cells is mediated through intracellular calcium but not ROS: effects of silymarin

    Nephron Exp. Nephrol.

    (2006)
  • T. Matsuda et al.

    Silymarin protects pancreatic beta-cells against cytokine-mediated toxicity: implication of c-Jun NH2-terminal kinase and janus kinase/signal transducer and activator of transcription pathways

    Endocrinology

    (2005)
  • A. Tyagi et al.

    Antiproliferative and apoptotic effects of silibinin in rat prostate cancer cells

    Prostate

    (2002)
  • X. Zi et al.

    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)
  • Cited by (362)

    • Flavonoids nanostructures promising therapeutic efficiencies in colorectal cancer

      2023, International Journal of Biological Macromolecules
    View all citing articles on Scopus
    View full text