Late stage cancer, liver damage. Hepatitis C Liver Cirrhosis Pancreatic malfunction

SILIBININ (From Silybum marianum)


The extract of milk thistle seed is commonly referred to as silymarin. Contained within silymarin are specific flavonoids called silibinin. Silymarin is a collective name for a mixture of flavonoids or, more technically, flavolignans. Both flavonoids and lignans are often loosely grouped together with isoflavonoids (soy), phytosterols and coumestans into a category of compounds known as phytoestrogens. Structural and chemical similarities between flavonoids and human steroid hormones, and thyroid hormone are particularly intriguing. Molecular biologists have begun studying the complex hormone-like actions of flavonoids, including the modulation of various enzyme activities and signalling pathways. Eventually this may lead to a fuller understanding of how diets rich in phytoestrogens help protect against a variety of cancers, including breast cancer, prostate cancer and colon cancer.

Silibinin and cancer
The last decade has brought many additional discoveries about the use of Silibinin to prevent breast cancer and prostate cancer.

A recent in vitro study by Zi and Agarwal (1999) found that silibinin was able to arrest cell growth in prostate cancer lines, probably through inhibiting various kinase enzymes. Silibinin helped arrest cell growth in the early
phase of the cell cycle, known as G1. The researchers found a 20% increase in G1 cell population when the culture was treated with silibinin. It is well known that potent flavonoids have an anti-proliferative effect on tumour tissue.

Another study found that silibinin inhibits proliferation in both drug-sensitive and drug-resistant breast cancer and ovarian cancer lines. The suggested mechanism of action involves silibinin's ability to bind to nuclear type II oestrogen receptors, which are thought to mediate the anti-proliferative effects of flavonoids (Scambia 1996). Comparing the properties of silymarin and silibinin, two investigators, Zhao and Agarwal (1999) state:

"Studies from our laboratory have shown that silibinin, the major active constituent of silymarin, has comparable [to silymarin] inhibitory effects towards human prostate, breast and cervical carcinoma cell growth, DNA synthesis and cell viability, and is as strong an antioxidant as silymarin."

Can silibinin slow aging?
The authors of a recent study (Onat 1999) concluded that silymarin's and silibinin's anti-proliferative mechanism of action is not yet fully known, but it may involve modulating signal transduction pathways. These signalling pathways are involved in aging, atherosclerosis and cancer. Compounds that can inhibit excess proliferation involved in aging-related disorders are of great clinical interest. Onat found that both alpha tocopherol and silibinin had a similar inhibitory action on the proliferation of skin fibroblasts. Insofar as excess fibroblast proliferation is one of the phenomena of aging, silibinin could become one of the agents used to slow the aging of the skin.

Cardiovascular health and the brain
An early German study (Schriewer and Rauen 1977) showed that silibinin dose-dependently inhibits the biosynthesis of cholesterol in vitro. This has been confirmed by more recent studies (reviewed by Skottova 1998). Another interesting effect is faster removal of low-density lipoproteins by the liver in the presence of silymarin. Studies have also shown that silymarin and silibinin inhibit the development of diet-related excess cholesterol levels in rats. Supplementing the diet with silymarin or silibinin resulted in an increase in HDL levels and a decrease in liver cholesterol content.

Silibinin's effect on diabetes
Silibinin is of considerable interest in the treatment of diabetes, since preliminary evidence indicates that it may prove helpful in normalizing the action of insulin. A Chinese study found that rats subjected to heat injury showed elevated blood glucose and high insulin levels due to stress-induced insulin resistance. The function of insulin receptors in the liver was shown to be impaired. Treatment with silibinin significantly enhanced the binding of insulin to the receptors (Tang 1991).

Silibinin was also found to help normalize pancreatic function in the presence of cyclosporine A, an immunosuppressive drug that is damaging to the pancreas This included a lowering of insulin secretion without raising serum glucose, possibly indicating that silibinin improves insulin sensitivity.

Schonfeld and colleagues (Schonfeld 1997) suggest that silibinin should be investigated as a potential treatment for Type II diabetics, who overproduce insulin due to insulin resistance. The authors also suggest that the protective effect of silibinin on the pancreas is non-specific, and is probably due to its antioxidant and membrane-stabilizing properties. Very likely, silibinin protects the pancreas not only against cyclosporine A, but also against alcohol and other toxins, and against free radicals in general.

Growth Inhibition and Regression of Lung Tumors by Silibinin: Modulation of Angiogenesis by Macrophage-Associated Cytokines and Nuclear Factor-κB and Signal Transducers and Activators of Transcription 3

Potential antiangiogenic mechanism of silibinin in advanced lung tumor cells in A/J mice. Silibinin inhibits the production and secretion of cytokines and interleukins via inhibition of TAMs. Furthermore, silibinin inhibits the activation of transcription factors (NF-κB/STAT/HIF-1α) but induces the expression of Ang-2/Tie-2 to inhibit the angiogenesis in urethane-induced advanced lung tumors in A/J mice. Events involved in driving angiogenesis (green) and the effect of silibinin (red).
The latency period for lung tumor progression offers a window of opportunity for therapeutic intervention. Herein, we studied the effect of oral silibinin (742 mg/kg body weight, 5 d/wk for 10 weeks) on the growth and progression of established lung adenocarcinomas in A/J mice. Silibinin strongly decreased both tumor number and tumor size, an antitumor effect that correlates with reduced antiangiogenic activity. Silibinin reduced microvessel size (50%, P < 0.01) with no change in the number of tumor microvessels and reduced (by 30%, P < 0.05) the formation of nestin-positive microvessels in tumors. Analysis of several proteins involved in new blood vessel formation showed that silibinin decreased the tumor expression of interleukin-13 (47%) and tumor necrosis factor-α (47%), and increased tissue inhibitor of metalloproteinase-1 (2-fold) and tissue inhibitor of metalloproteinase-2 (7-fold) expression, without significant changes in vascular endothelial growth factor levels. Hypoxia- inducible factor-1α expression and nuclear localization were also decreased by silibinin treatment. Cytokines secreted by tumor cells and tumor-associated macrophages regulate angiogenesis by activating nuclear factor-κB (NF-κB) and signal transducers and activators of transcription (STAT). Silibinin decreased the phosphorylation of p65NF-κB (ser276, 38%; P < 0.01) and STAT-3 (ser727, 16%; P < 0.01) in tumor cells and decreased the lung macrophage population. Angiopoietin-2 (Ang-2) and Ang-receptor tyrosine kinase (Tie-2) expression were increased by silibinin. Therapeutic efficacy of silibinin in lung tumor growth inhibition and regression by antiangiogenic mechanisms seem to be mediated by decreased tumor-associated macrophages and cytokines, inhibition of hypoxia-inducible factor-1α, NF-κB, and STAT-3 activation, and up-regulation of the angiogenic inhibitors, Ang-2 and Tie-2.
(Cancer Prev Res January 1, 2009 vol.2 no.1 Pp.74-83)

Silibinin modulates TNF-α and IFN-γ mediated signaling to regulate COX2 and iNOS expression in tumorigenic mouse lung epithelial LM2 cells
Silibinin inhibits mouse lung tumorigenesis in part by targeting tumor microenvironment. Tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) can be pro- or anti-tumorigenic, but in lung cancer cell lines they induce pro-inflammatory enzymes cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS). Accordingly, here we examined mechanism of silibinin action on TNF-α + IFN-γ (hereafter referred as cytokine mixture) elicited signaling in tumor-derived mouse lung epithelial LM2 cells. Both signal transducers and activators of the transcription (STAT)3 (tyr705 and ser727) and STAT1 (tyr701) were activated within 15 min of cytokine mixture exposure, while STAT1 (ser727) activated after 3 h. Cytokine mixture also activated Erk1/2 and caused an increase in both COX2 and iNOS levels. Pretreatment of cells with a MEK, NF-κB, and/or epidermal growth factor receptor (EGFR) inhibitor inhibited cytokine mixture-induced activation of Erk1/2, NF-κB, or EGFR, respectively, and strongly decreased phosphorylation of STAT3 and STAT1 and expression of COX2 and iNOS. Also, janus family kinases (JAK)1 and JAK2 inhibitors specifically decreased cytokine-induced iNOS expression, suggesting possible roles of JAK1, JAK2, Erk1/2, NF-κB, and EGFR in cytokine mixture-caused induction of COX2 and iNOS expression via STAT3/STAT1 activation in LM2 cells. Importantly, silibinin pretreatment inhibited cytokine mixture-induced phosphorylation of STAT3, STAT1, and Erk1/2, NF-κB-DNA binding, and expression of COX2, iNOS, matrix metalloproteinases (MMP)2, and MMP9, which was mediated through impairment of STAT3 and STAT1 nuclear localization. Silibinin also inhibited cytokine mixture-induced migration of LM2 cells. Together, we showed that STAT3 and STAT1 could be valuable chemopreventive and therapeutic targets within the lung tumor microenvironment in addition to being targets within tumor itself, and that silibinin inhibits their activation as a plausible mechanism of its efficacy against lung cancer (Molecular Carcinogenesis. 2011. DOI: 10.1002/mc.20851).

Enhancement of cytotoxicity of artemisinins toward cancer cells by ferrous iron
Iron(II) heme-mediated activation of the peroxide bond of artemisinins is thought to generate the radical oxygen species responsible for their antimalarial activity. We analyzed the role of ferrous iron in the cytotoxicity of artemisinins toward tumor cells. Iron(II)–glycine sulfate (Ferrosanol) and transferrin increased the cytotoxicity of free artesunate, artesunate microencapsulated in maltosyl-β-cyclodextrin, and artemisinin toward CCRF-CEM leukemia and U373 astrocytoma cells 1.5- to 10.3-fold compared with that of artemisinins applied without iron. Growth inhibition by artesunate and ferrous iron correlated with induction of apoptosis. Cell cycle perturbations by artesunate and ferrous iron were not observed. Treatment of p53 wild-type TK6 and p53 mutated WTK1 lymphoblastic cells showed that mutational status of the tumor suppressor p53 did not influence sensitivity to artesunate. The effect of ferrous iron and transferrin was reversed by monoclonal antibody RVS10 against the transferrin receptor (TfR), which competes with transferrin for binding to TfR. CCRF-CEM and U373 cells expressed TfR in 95 and 48% of the cell population, respectively, whereas TfR expression in peripheral mononuclear blood cells of four healthy donors was confined to 0.4–1.3%. This indicates that artemisinins plus ferrous iron may affect tumor cells more than normal cells. The IC50 values for a series of eight different artemisinin derivatives in 60 cell lines of the U.S. National Cancer Institute were correlated with the microarray mRNA expression of 12 genes involved in iron uptake and metabolism by Kendall's τ test to identify iron-responsive cellular factors enhancing the activity of artemisinins. This pointed to mitochondrial aconitase and ceruloplasmin (ferroxidase).
Efferth T, et al. Free Radical Biology and Medicine. Volume 37, Issue 7, 1 October 2004, Pages 998–1009

Differential involvement of protein kinase C in human promyelocytic leukemia cell differentiation enhanced by artemisinin
Artemisinin, a sesquiterpene lactone endoperoxide that exists in several medicinal plants, is a well-known anti-malarial agent. In this report, we investigated the effect of artemisinin on cellular differentiation in the human promyelocytic leukemia HL-60 cell culture system. Artemisinin markedly increased the degree of HL-60 leukemia cell differentiation when simultaneously combined with low doses of 1α,25-dihydoxyvitamin D3 [1,25-(OH)2D3] or all-trans retinoic acid (all-trans RA). Artemisinin by itself had very weak effects on the differentiation of HL-60 cells. Cytofluorometric analysis and cell morphologic studies indicated that artemisinin potentiated 1,25-(OH)2D3-induced cell differentiation predominantly into monocytes and all-trans RA-induced cell differentiation into granulocytes, respectively. Extracellular-regulated kinase (ERK) inhibitors markedly inhibited HL-60 cell differentiation induced by artemisinin in combination with 1,25-(OH)2D3 or all-trans RA, whereas phosphatidylinositol 3-kinase (PI3-K) inhibitors did not. Particularly, protein kinase C (PKC) inhibitors inhibited HL-60 cell differentiation induced by artemisinin in combination with 1,25-(OH)2D3 but not with all-trans RA. Artemisinin enhanced PKC activity and protein level of PKCβI isoform in only 1,25-(OH)2D3-treated HL-60 cells. Taken together, these results indicate that artemisinin strongly enhanced 1,25-(OH)2D3- and all-trans RA-induced cell differentiation in which PKC is differentially involved in arteminisin-mediated enhancement of leukemia cell differentiation.
European Journal of Pharmacology <http://www.sciencedirect.com/science/journal/00142999> . Volume 482, Issues 1–3 <http://www.sciencedirect.com/science/journal/00142999/482/1> , 15 December 2003, Pages 67–76

Induction of human promyelocytic leukemia HL-60 cell differentiation into monocytes by silibinin: involvement of protein kinase C
The effect of silibinin, an active component of Silybum marianum, on cellular differentiation was investigated in the human promyelocytic leukemia HL-60 cell culture system. Treatment of HL-60 cells with silibinin inhibited cellular proliferation and induced cellular differentiation in a dose-dependent manner. Cytofluorometric analysis and morphologic studies indicated that silibinin induced differentiation of HL-60 cells predominantly into monocytes. Importantly, strongly synergistic induction of differentiation into monocytes was observed when silibinin was combined with 5 nM 1α,25-dihydroxyvitamin D3 [1,25-(OH)2D3], a well-known differentiation inducer of HL-60 cells into the monocytic lineage. Silibinin enhanced protein kinase C (PKC) activity and increased protein levels of both PKCα and PKCβ in 1,25-(OH)2D3-treated HL-60 cells. PKC and extracellular signal-regulated kinase (ERK) inhibitors significantly inhibited HL-60 cell differentiation induced by silibinin alone or in combination with 1,25-(OH)2D3, indicating that PKC and ERK may be involved in silibinin-induced HL-60 cell differentiation
Biochemical Pharmacology <http://www.sciencedirect.com/science/journal/00062952> . Volume 61, Issue 12 <http://www.sciencedirect.com/science/journal/00062952/61/12> , 15 June 2001, Pages 1487–1495

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