Silymarin

Silymarin suppresses the PGE2 -induced cell migration through inhibition of EP2 activation; G protein-dependent PKA-CREB and G protein-independent Src-STAT3 signal pathways.[Pubmed: 24127286]

Mol Carcinog. 2015 Mar;54(3):216-28.

Silymarin has been known as a chemopreventive agent, and possesses multiple anti-cancer activities including induction of apoptosis, inhibition of proliferation and growth, and blockade of migration and invasion. However, whether Silymarin could inhibit prostaglandin (PG) E2 -induced renal cell carcinoma (RCC) migration and what are the underlying mechanisms are not well elucidated.
METHODS AND RESULTS:
Here, we found that Silymarin markedly inhibited PGE2 -stimulated migration. PGE2 induced G protein-dependent CREB phosphorylation via protein kinase A (PKA) signaling, and PKA inhibitor (H89) inhibited PGE2 -mediated migration. Silymarin reduced PGE2 -induced CREB phosphorylation and CRE-promoter activity. PGE2 also activated G protien-independent signaling pathways (Src and STAT3) and Silymarin reduced PGE2 -induced phosphorylation of Src and STAT3. Inhibitor of Src (Saracatinib) markedly reduced PGE2 -mediated migration. We found that EP2, a PGE2 receptor, is involved in PGE2 -mediated cell migration. Down regulation of EP2 by EP2 siRNA and EP2 antagonist (AH6809) reduced PGE2 -inudced migration. In contrast, EP2 agonist (Butaprost) increased cell migration and Silymarin effectively reduced butaprost-mediated cell migration. Moreover, PGE2 increased EP2 expression through activation of positive feedback mechanism, and PGE2 -induced EP2 expression, as well as basal EP2 levels, were reduced in Silymarin-treated cells.
CONCLUSIONS:
Taken together, our study demonstrates that Silymarin inhibited PGE2 -induced cell migration through inhibition of EP2 signaling pathways (G protein dependent PKA-CREB and G protein-independent Src-STAT3).

Silymarin liposomes improves oral bioavailability of silybin besides targeting hepatocytes, and immune cells.[Pubmed: 25149982]

Pharmacol Rep. 2014 Oct;66(5):788-98.

Silymarin, a hepatoprotective agent, has poor oral bioavailability. However, the current dosage form of the drug does not target the liver and inflammatory cells selectively. The aim of the present study was to develop lecithin-based carrier system of Silymarin by incorporating phytosomal-liposomal approach to increase its oral bioavailability and to make it target-specific to the liver for enhanced hepatoprotection.
METHODS AND RESULTS:
The formulation was prepared by film hydration method. Release of drug was assessed at pH 1.2 and 7.4. Formulation was assessed for in vitro hepatoprotection on Chang liver cells, lipopolysaccharide-induced reactive oxygen species (ROS) production by RAW 267.4 (murine macrophages), in vivo efficacy against paracetamol-induced hepatotoxicity and pharmacokinetic study by oral route in Wistar rat. The formulation showed maximum entrapment (55%) for a lecithin-cholesterol ratio of 6:1. Comparative release profile of formulation was better than Silymarin at pH 1.2 and pH 7.4. In vitro studies showed a better hepatoprotection efficacy for formulation (one and half times) and better prevention of ROS production (ten times) compared to Silymarin. In in vivo model, paracetamol showed significant hepatotoxicity in Wistar rats assessed through LFT, antioxidant markers and inflammatory markers. The formulation was found more efficacious than Silymarin suspension in protecting the liver against paracetamol toxicity and the associated inflammatory conditions. The liposomal formulation yielded a three and half fold higher bioavailability of Silymarin as compared with Silymarin suspension.
CONCLUSIONS:
Incorporating the phytosomal form of Silymarin in liposomal carrier system increased the oral bioavailability and showed better hepatoprotection and better anti-inflammatory effects compared with Silymarin suspension.

Silymarin and skin cancer prevention: anti-inflammatory, antioxidant and immunomodulatory effects (Review).[Pubmed: 15586237]

Int J Oncol. 2005 Jan;26(1):169-76.

Several environmental and genetic factors are involved in skin cancer induction, however exposure to chemical carcinogens and solar ultraviolet (UV) radiation are primarily responsible for several skin diseases including skin cancer. Chronic exposure of solar UV radiation to the skin leads to basal cell and squamous cell carcinoma, and melanoma. Chemoprevention of skin cancer by consumption of naturally occurring botanicals appears a practical approach and therefore world-wide interest is considerably increasing to use these botanicals. Sunscreens are useful but their protection is not ideal because of inadequate use, incomplete spectral protection and toxicity.
METHODS AND RESULTS:
Silymarin, a plant flavonoid isolated from the seeds of milk thistle (Silybum marianum), has been shown to have chemopreventive effects against chemical carcinogenesis as well as photocarcinogenesis in various animal tumor models. Topical treatment of Silymarin inhibited 7,12-dimethylbenz(a)anthracene-initiated and several tumor promoters, like 12-O-tetradecanoylphorbol-13-acetate, mezerein, benzoyal peroxide and okadaic acid, induced skin carcinogenesis in mouse models. Similarly, Silymarin also prevented UVB-induced skin carcinogenesis. Wide range of in vivo mechanistic studies indicated that Silymarin possesses antioxidant, anti-inflammatory and immunomodulatory properties which may lead to the prevention of skin cancer in in vivo animal models.
CONCLUSIONS:
The available experimental information suggests that Silymarin is a promising chemopreventive and pharmacologically safe agent which can be exploited or tested against skin cancer in human system. Moreover, Silymarin may favorably supplement sunscreen protection and provide additional anti-photocarcinogenic protection.

Silymarin induces apoptosis primarily through a p53-dependent pathway involving Bcl-2/Bax, cytochrome c release, and caspase activation.[Pubmed: 15713892]

Mol Cancer Ther. 2005 Feb;4(2):207-16.

Silymarin, a plant flavonoid, has been shown to inhibit skin carcinogenesis in mice. However, the mechanism responsible for the anti-skin carcinogenic effects of Silymarin is not clearly understood.
METHODS AND RESULTS:
Here, we report that treatment of JB6 C141 cells (preneoplastic epidermal keratinocytes) and p53+/+ fibroblasts with Silymarin and silibinin (a major constituent of Silymarin) resulted in a dose-dependent inhibition of cell viability and induction of apoptosis in an identical manner. Silymarin-induced apoptosis was determined by fluorescence staining (8-64% apoptosis) and flow cytometry (12-76% apoptosis). The Silymarin-induced apoptosis was primarily p53 dependent because apoptosis occurred to a much greater extent in the cells expressing wild-type p53 (p53+/+, 9-61%) than in p53-deficient cells (p53-/-, 6-20%). The induction of apoptosis in JB6 C141 cells was associated with increased expression of the tumor suppressor protein, p53, and its phosphorylation at Ser15. The constitutive expression of antiapoptotic proteins Bcl-2 and Bcl-xl were decreased after Silymarin treatment, whereas the expression of the proapoptotic protein Bax was increased. There was a shift in Bax/Bcl-2 ratio in favor of apoptotic signal in Silymarin-treated cells, which resulted in increased levels of cytochrome c release, apoptotic protease-activating factor-1, and cleaved caspase-3 and poly(ADP-ribose) polymerase in JB6 C141 cells. The shift in Bax/Bcl-2 ratio was more prominent in p53+/+ fibroblasts than in p53-/- cells. Silymarin-induced apoptosis was blocked by the caspase inhibitor (Z-VAD-FMK) in JB6 C141 cells which suggested the role of caspase activation in the induction of apoptosis.
CONCLUSIONS:
These observations show that Silymarin-induced apoptosis is primarily p53 dependent and mediated through the activation of caspase-3.

Cytoprotective effect of silymarin against diabetes-induced cardiomyocyte apoptosis in diabetic rats.[Pubmed: 25566861]

Biomed Environ Sci. 2015 Jan;28(1):36-43.

The beneficial effects of Silymarin have been extensively studied in the context of inflammation and cancer treatment, yet much less is known about its therapeutic effect on diabetes. The present study was aimed to investigate the cytoprotective activity of Silymarin against diabetes-induced cardiomyocyte apoptosis.
METHODS AND RESULTS:
Rats were randomly divided into: control group, untreated diabetes group and diabetes group treated with Silymarin (120 mg/kg•d) for 10 d. Rats were sacrificed, and the cardiac muscle specimens and blood samples were collected. The immunoreactivity of caspase-3 and Bcl-2 in the cardiomyocytes was measured. Total proteins, glucose, insulin, creatinine, AST, ALT, cholesterol, and triglycerides levels were estimated. Unlike the treated diabetes group, cardiomyocyte apoptosis increased in the untreated rats, as evidenced by enhanced caspase-3 and declined Bcl-2 activities. The levels of glucose, creatinine, AST, ALT, cholesterol, and triglycerides declined in the treated rats. The declined levels of insulin were enhanced again after treatment of diabetic rats with Silymarin, reflecting a restoration of the pancreatic β-cells activity.
CONCLUSIONS:
The findings of this study are of great importance, which confirmed for the first time that treatment of diabetic subjects with Silymarin may protect cardiomyocytes against apoptosis and promote survival-restoration of the pancreatic β-cells.