Disease relevance of SILYMARIN

• CONCLUSIONS: Oral administration of silybin protects against iron-induced hepatic toxicity in vivo [1].
• Antioxidant activity of silybin in vivo during long-term iron overload in rats [1].
• Together, these results suggest that silibinin could be a useful agent for the intervention of hormone-refractory human prostate cancer [2].
• Together, these findings suggest that silibinin preferentially activates the DNA-PK-p53 pathway for apoptosis in response to UVB-induced DNA damage, and that this could be a predominant mechanism of silibinin efficacy against UVB-induced skin cancer [3].
• Additional studies conducted in mice showed that silibinin doses found effective in HT-29 cells are achievable in plasma, which increases the significance of the present findings and their possible translation in in vivo anticancer efficacy of silibinin against colon cancer [4].

Psychiatry related information on SILYMARIN

• Silibinin also moderately inhibited tumor incidence (5-15%; P < 0.01) and delayed tumor latency period (up to 4 weeks; P < 0.01-0.001) [5].

High impact information on SILYMARIN

• METHODS: Rats were fed a 2.5% carbonyl-iron diet and 100 mg.kg body wt-1.day-1 silybin for 4 months and were assayed for accumulation of hepatic lipid peroxidation by-products by immunocytochemistry, mitochondrial energy-dependent functions, and mitochondrial malondialdehyde content [1].
• The same beneficial effect of silybin was found on the iron-induced accumulation of malondialdehyde in mitochondria [1].
• Conversely, silibinin treatment resulted in a significant neuroendocrine differentiation of LNCaP cells as an alternative pathway after Cip1/p21 induction and G1 arrest [2].
• Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention [2].
• 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 G1 arrest in cell cycle progression [2].

Chemical compound and disease context of SILYMARIN

• RESULTS: Iron overload caused a dramatic accumulation of malondialdehyde-protein adducts into iron-filled periportal hepatocytes that was decreased appreciably by silybin treatment [1].
• We investigated the effect of silibinin on androgen-independent prostate cancer PC-3 cells [6].
• These findings suggest that silibinin inhibits in vivo lung tumor growth and reduces systemic toxicity of doxorubicin with an enhanced therapeutic efficacy most likely via an inhibition of doxorubicin-induced chemoresistance involving NFkappaB signaling [7].
• The aim of this study was to test the antiproliferative activity of silybin, a flavonoid, on human ovarian and breast cancer cell lines [8].
• In order to exclude an inhibition of the anti-tumour activity of cisplatin and 4-hydroperoxy-ifosfamide by co-administration of silibinin, in vitro studies were performed in three established human testicular cancer cell lines [9].

Biological context of SILYMARIN

• Together, these results show a strong preventive efficacy of silibinin against photocarcinogenesis, which involves the inhibition of DNA synthesis, cell proliferation, and cell cycle progression and an induction of apoptosis [5].
• On the basis of these observations, here we assessed in vivo growth inhibitory potential of silibinin against advanced human prostate cancer (PCA) [10].
• In additional studies assessing biological availability of silibinin in nude mice and its antiproliferative activity at such doses in DU145 cells in culture, silibinin levels in plasma and prostate were found to be in the range of 7-13 microg/ml and 3.7-4.6 microg/g, respectively [10].
• We also observed that silibinin reduced insulin receptor substrate 1 tyrosine phosphorylation, indicating an inhibitory effect on the insulin-like growth factor I receptor-mediated signaling pathway [6].
• An IGFBP-3 antisense oligodeoxynucleotide that attenuated silibinin-induced IGFBP-3 gene expression and protein accumulation reduced the antiproliferative action of silibinin [6].

Anatomical context of SILYMARIN

• Selective inhibition of leukotriene formation by Kupffer cells can at least partly account for the hepatoprotective properties of silibinin [11].
• In the present study, we employed a well established JB6 mouse epithelial cell model to define the molecular mechanism of efficacy of a naturally occurring flavonoid silibinin against ultraviolet B (UVB)-induced skin tumorigenesis [3].
• Here, we provide evidence for molecular events associated with antiangiogenic efficacy of pharmacologically achievable doses of silibinin in endothelial cell culture system [12].
• Here, using pure active agent in silymarin, namely silibinin, we show its antiproliferative and apoptotic effects, and associated molecular alterations in human colon carcinoma HT-29 cells [4].
• Our data show that silibinin almost completely (P<0.001) inhibits growth of human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells (HMVEC-dermal origin) together with induction of cell death in a dose- and time-dependent manner [12].

Associations of SILYMARIN with other chemical compounds

• Silymarin and silibinin were shown for the first time to suppress the activity of the DNA topoisomerase IIalpha gene promoter in DU145 cells and, among the pure compounds, isosilybin B was again the most effective [13].
• Pretreatment of isolated rat hepatocyte couplets with silibinin, the major, active component of SIL, counteracted the estradiol 17beta-glucuronide-induced decrease in the percentage of couplets secreting apically the fluorescent bile acid analogue, cholyl-lysyl-fluorescein [14].
• Silymarin is a purified extract from milk thistle (Silybum marianun (L.) Gaertn), composed of a mixture of four isomeric flavonolignans: silibinin (its main, active component), isosilibinin, silydianin and silychristin [15].
• Immunohistochemical 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 [7].
• Cisplatin alone at 2 microg/ml dose produced 48% cell growth inhibition, whereas a combination with 50-100 microM silibinin resulted in 63-80% (p<0.05-0.001) growth inhibition [16].

Gene context of SILYMARIN

• To investigate in vivo molecular mechanisms of silibinin efficacy, tumors and uninvolved skin from tumor-bearing mice were examined immunohistochemically for proliferation, p53, apoptosis, and activated caspase-3 [5].
• Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells [4].
• The use of MEK1 inhibitor, PD98059, showed that inhibition of ERK1/2 signaling, in part, contributes to silibinin-caused cell growth inhibition [17].
• Together, the data suggest that an inhibition of ERK1/2 activation and an increased activation of JNK1/2 and p38 by silibinin could be possible underlying molecular events involved in inhibition of proliferation and induction of apoptosis in A431 cells [17].
• BACKGROUND: Our previous study found that silymarin (SM) and its major pure component silibinin (SB) have anti-angiogenic effects via decreased vascular endothelium growth factor (VEGF) secretion of LoVo cells (colon cancer) [18].

Analytical, diagnostic and therapeutic context of SILYMARIN

• Topical application of silibinin before or immediately after UVB exposure or its dietary feeding resulted in a strong protection against photocarcinogenesis, in terms of tumor multiplicity (60-66%; P < 0.001), tumor volume per mouse (93-97%; P < 0.001) and tumor volume per tumor (80-91%; P < 0.001) [5].
• At these biologically achievable silibinin concentrations, increased IGFBP-3 level in DU145 cell culture medium and a strong DU145 cell growth inhibition were observed that were irreversible in the absence of silibinin in culture medium [10].
• Recently, we observed that suppression of tumor xenograft growth by silibinin was associated with reduction in tumor vasculature and an increased apoptosis [12].
• These results indicate that silibinin could be used to enhance the effectiveness of TNFalpha-based chemotherapy in advanced PCA [19].
• At molecular level, cell cycle effects of silibinin were assessed by immunoblotting and in-bead kinase assays [20].

References