Mini-reviewMultitargeted therapy of cancer by silymarin
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.
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