Effects and mechanisms of silibinin on human hepatoma cell lines.
28 Oct 2007-World Journal of Gastroenterology (Baishideng Publishing Group Inc)-Vol. 13, Iss: 40, pp 5299-5305
TL;DR: It is demonstrated that silibinin significantly reduced the growth of HuH7, HepG2, Hep3B, and PLC/PRF/5 human hepatoma cells and increased acetylation of histone H3 and H4, indicating a possible role of altered histone acetylations in silib inin-reduced HCC cell proliferation.
Abstract: AIM: To investigate in vitro effects and mechanisms of silibinin on hepatocellular carcinoma (HCC) cell growth.
METHODS: Human HCC cell lines were treated with different doses of silibinin. The effects of silibinin on HCC cell growth and proliferation, apoptosis, cell cycle progression, histone acetylation, and other related signal transductions were systematically examined.
RESULTS: We demonstrated that silibinin significantly reduced the growth of HuH7, HepG2, Hep3B, and PLC/PRF/5 human hepatoma cells. Silibinin-reduced HuH7 cell growth was associated with significantly up-regulated p21/CDK4 and p27/CDK4 complexes, down-regulated Rb-phosphorylation and E2F1/DP1 complex. Silibinin promoted apoptosis of HuH7 cells that was associated with down-regulated survivin and up-regulated activated caspase-3 and -9. Silibinin's anti-angiogenic effects were indicated by down-regulated metalloproteinase-2 (MMP2) and CD34. We found that silibinin-reduced growth of HuH7 cells was associated with increased activity of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and decreased p-Akt production, indicating the role of PTEN/PI3K/Akt pathway in silibinin-mediated anti-HCC effects. We also demonstrated that silibinin increased acetylation of histone H3 and H4 (AC-H3 and AC-H4), indicating a possible role of altered histone acetylation in silibinin-reduced HCC cell proliferation.
CONCLUSION: Our results defined silibinin's in vitro anti-HCC effects and possible mechanisms, and provided a rationale to further test silibinin for HCC chemoprevention.
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TL;DR: Silibinin may have a beneficial effect on the protection of the liver by measuring gene expression and liver tissue protein levels of tumor necrosis factor-α, interleukin-6, monocyte chemoattractant protein-1, matrix metalloproteinases matrix metaloproteinase and tissue inhibitor of matrix meetallop proteinases-2.
Abstract: OBJECTIVES We investigated the positive effect of silibinin after IV administration as silibinin-hydroxypropyl-β-cyclodextrin lyophilized product, by measuring gene expression and liver tissue protein levels of tumor necrosis factor-α, interleukin-6, monocyte chemoattractant protein-1, matrix metalloproteinases matrix metalloproteinases and tissue inhibitor of matrix metalloproteinases-2. METHODS 63 Wistar rats of age 13.24±4.40 weeks underwent ischemia/reperfusion (I/R) injury of the liver. The animals were randomized into three groups: Sham (S; n = 7); Control (C; n-28); silibinin (Si; n-28). The C and Si groups underwent 45 min ischemia. Si received silibinin-hydroxypropyl-β-cyclodextrin intravenously immediately before reperfusion at a dose of 5 mg/kg. Both groups were further divided into 4 subgroups, based on euthanasia time (i.e., 60, 120, 180 and 240 min). KEY FINDINGS qRT-PCR results confirmed the statistically significant reduction of the expression of the pro-inflammatory factors at 240 min after I/R injury (tumor necrosis factor-α: P < 0.05; MCR1: P < 0.05) and matrix metalloproteinases (matrix metalloproteinases 2: P < 0.05; matrix metalloproteinases 3: P < 0.05) and the increase of tissue inhibitor of matrix metalloproteinases-2 in liver tissue in the Si group. Moreover, results of immunohistochemistry levels confirmed that at 240 min pro-inflammatory factors (tumor necrosis factor-α: P < 0.05; MCR1: P < 0.05) and matrix metalloproteinases ( matrix metalloproteinases 2: P < 0.05; matrix metalloproteinases 3: P < 0.05) had a statistically significantly lower expression in the Si group while tissue inhibitor of matrix metalloproteinases-2 had a higher expression. CONCLUSIONS Silibinin may have a beneficial effect on the protection of the liver.
3 citations
TL;DR: Silymarin administration inhibited the reactive oxygen species generation and reduced the tumoral cells’ apoptosis, suggesting that natural compound administered before photodynamic therapy did not improve the therapy’s effect.
Abstract: Several studies have shown that some anti-oxidant natural compounds in combination with photodynamic therapy (PDT) can enhance the effectiveness of treatment The aim of this study is to evaluate the effect of silymarin (SIL) in combination with 5,10,15,20-tetra-sulphonato-phenyl-porphyrin (TSPP) based photodynamic therapy, on experimental tumors 30 Wistar rats with Walker carcinosarcoma, were divided into 6 groups: group 0 (control) — control, untreated group; group 1 (TSPP) — one dose of TSPP; group 2 (SIL) — silymarin; group 3 (PDT) — TSPP and irradiation 24 h after; group 4 (SIL+PDT) — silymarin, TSPP and irradiation 24 h after; group 5 (SIL+IR) and group 6 (IR) — irradiation and in addition, group 5 received SIL Silymarin administered before photodynamic therapy decreased the lipid peroxidation (p < 005) and modulated the antioxidant defense in tumor treated with PDT and silymarin suggesting that silymarin administration along with photodynamic therapy has an anti-oxidant effect The caspase — 8 level and -3 activity increased in PDT and PDT + SIL groups compared to the control; between the two groups there was a significant difference in term of apoptosis in favor to PDT In conclusion, silymarin administration inhibited the reactive oxygen species generation and reduced the tumoral cells’ apoptosis, suggesting that natural compound administered before photodynamic therapy did not improve the therapy’s effect
3 citations
Patent•
22 May 2012
TL;DR: A nutritional supplement consisting of medicinal plants and natural herbs in the form of capsules, packed with raw material through which patients can regain their health so they can work and their daily lives normally, by strengthening their immune systems as discussed by the authors.
Abstract: This medicine is a nutritional supplement consisting of medicinal plants and natural herbs in the form of capsules, packed with raw material Through which patients can regain their health so they can work and their daily lives normally, by strengthening their immune systems In this way, the body can resist the virus of hepatitis C by restoring the balance of the immune system, enabling it to produce copious amounts of interferon by lymphocytes
2 citations
TL;DR: TNSEs reduced LoVo cell proliferation, and caused apoptosis and cell-cycle arrest in LoVo cells, which might be associated with regulation of the PI3K/AKT signaling pathway.
Abstract: To further explore the anti-cancer effect of Tounong Powder (透脓散) extracts (TNSEs) on human colon cancer LoVo cells and examine the possible molecular mechanisms. The contents of TNSEs were determined by liquid chromatograph-mass spectrometer (LC-MS) analysis after extraction with water and methanol. Variations of cell morphological features were observed using fluorescence microscopy. Cytotoxicity was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle distribution and apoptosis were analyzed using flow cytometry at different TNSE doses (0, 62.5, 125, or 250 μg/mL). Protein expressions of phosphatidylinositol 3-kinase (PI3K), phosphate protein kinase B (p-AKT), phosphate mammalian target of rapamycin (p-mTOR), p-p70s6k1, cleaved caspase-9 and -3 were detected using Western blot analysis. TNSEs induced cell growth inhibition in a concentration- and time-dependent manner. Flow cytometric analysis showed apoptotic cells and cell cycle arrest at the G phase after TNSEs treatment compared with controls. Furthermore, TNSEs significantly down-regulated the proteins PI3K, p-AKT, p-mTOR, and p-p70s6k1, and up-regulated the proteins cleaved caspase-9 and -3 dosedependently, as determined by Western blot. TNSEs reduced LoVo cell proliferation, and caused apoptosis and cell-cycle arrest in LoVo cells. This effect might be associated with regulation of the PI3K/AKT signaling pathway.
2 citations
TL;DR: The antioxidant effects of silibinin on HCC cells, which may influence the expressions of cytokine genes are determined by the concentration and the characteristics of cancer cells.
2 citations
References
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TL;DR: The PTEN product has a protein tyrosine phosphatase domain and extensive homology to tensin, a protein that interacts with actin filaments at focal adhesions as discussed by the authors.
Abstract: Mapping of homozygous deletions on human chromosome 10q23 has led to the isolation of a candidate tumor suppressor gene, PTEN, that appears to be mutated at considerable frequency in human cancers. In preliminary screens, mutations of PTEN were detected in 31% (13/42) of glioblastoma cell lines and xenografts, 100% (4/4) of prostate cancer cell lines, 6% (4/65) of breast cancer cell lines and xenografts, and 17% (3/18) of primary glioblastomas. The predicted PTEN product has a protein tyrosine phosphatase domain and extensive homology to tensin, a protein that interacts with actin filaments at focal adhesions. These homologies suggest that PTEN may suppress tumor cell growth by antagonizing protein tyrosine kinases and may regulate tumor cell invasion and metastasis through interactions at focal adhesions.
4,927 citations
"Effects and mechanisms of silibinin..." refers background in this paper
.... PTEN is a negative regulator of PI3K-Akt signaling [ 29 ]...
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TL;DR: The incidence of hepatocellular carcinoma increased significantly among younger persons (40 to 60 years old) during the period from 1991 to 1995 as compared with earlier periods, and the age-specific incidence of this cancer has progressively shifted toward younger people.
Abstract: Background and Methods Clinical observations have suggested that the number of cases of hepatocellular carcinoma has increased in the United States. We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) data base to determine the age-adjusted incidence of hepatocellular carcinoma from 1976 to 1995, data from the U.S. vital-statistics data base to determine age-adjusted mortality rates from 1981 to 1995, and data from the Department of Veterans Affairs to determine age-adjusted rates of hospitalization for the disease from 1983 to 1997. Results The incidence of histologically proved hepatocellular carcinoma increased from 1.4 per 100,000 population (95 percent confidence interval, 1.3 to 1.4) for the period from 1976 to 1980 to 2.4 per 100,000 (95 percent confidence interval, 2.3 to 2.4) for the period from 1991 to 1995. Among black men, the incidence was 6.1 per 100,000 for the period from 1991 to 1995, and among white men, it was 2.8 per 100,000. There was a 41 percent increase in ...
2,869 citations
"Effects and mechanisms of silibinin..." refers background in this paper
.... Recent studies have noted a significant rise in the incidence of HCC in the United States in the past 2 decades [ 2 ]...
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...Hepatocellular carcinoma (HCC) is one of the most common malignancies related to a high mortality globally [1, 2 ]...
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TL;DR: The amino termini of histones extend from the nucleosomal core and are modified by acetyltransferases and deacetylases during the cell cycle, which may direct histone assembly and help regulate the unfolding and activity of genes.
Abstract: 'The amino termini of histones extend from the nucleosomal core and are modified by acetyltransferases and deacetylases during the cell cycle These acetylation patterns may direct histone assembly and help regulate the unfolding and activity of genes
2,846 citations
"Effects and mechanisms of silibinin..." refers background in this paper
...Histone acetylation alters chromatin conformation by m a k i n g p r o m o t e r r e g i o n s m o r e a c c e s s i b l e t o transcription factors and permissive to transcriptional activation [ 34 ]...
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...Histone acetylation modifies nucleosome structure that leads to DNA relaxation, reduces the affinity of histone complexes with DNA, and enhances the access of transcriptional factor to DNA [ 34 ]...
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.... Studies have reported that histone acetylation is involved in cell proliferation, differentiation, and cell cycle regulation [ 34 ]...
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TL;DR: The results identify a strong candidate tumour suppressor gene at chromosome 10q23.3, whose loss of function appears to be associated with the oncogenesis of multiple human cancers.
Abstract: Deletions involving regions of chromosome 10 occur in the vast majority (> 90%) of human glioblastoma multiformes. A region at chromosome 10q23-24 was implicated to contain a tumour suppressor gene and the identification of homozygous deletions in four glioma cell lines further refined the location. We have identified a gene, designated MMAC1, that spans these deletions and encodes a widely expressed 5.5-kb mRNA. The predicted MMAC1 protein contains sequence motifs with significant homology to the catalytic domain of protein phosphatases and to the cytoskeletal proteins, tensin and auxilin. MMAC1 coding-region mutations were observed in a number of glioma, prostate, kidney and breast carcinoma cell lines or tumour specimens. Our results identify a strong candidate tumour suppressor gene at chromosome 10q23.3, whose loss of function appears to be associated with the oncogenesis of multiple human cancers.
2,777 citations
"Effects and mechanisms of silibinin..." refers background in this paper
.... PTEN is a tumor suppressor gene and the deletion or inactivation of this gene has been described in a variety of cancer cell lines [ 30 ,33,53]...
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...and one of the most frequently inactivated genes in malignancies [ 30 , 31]...
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TL;DR: Data suggest that in normal tissues and lymphoid neoplasms, PCNA immunolocalization can be used as an index of cell proliferation, however, in some forms of neoplasia, including breast and gastric cancer and in vitro cell lines, the simple relation between PCNA expression and cell proliferation is lost.
Abstract: Proliferating cell nuclear antigen (PCNA) is a 36 kD nuclear protein associated with the cell cycle A monoclonal antibody, PC10, that recognizes a fixation and processing resistant epitope has been used to investigate its tissue distribution Nuclear PCNA immunoreactivity is found in the proliferative compartment of normal tissues PCNA immunoreactivity is induced in lectin stimulated peripheral blood mononuclear cells in parallel with bromodeoxyuridine incorporation and the number of cells with PCNA immunoreactivity is reduced by induction of differentiation in HL60 cells In non-Hodgkin's lymphomas a linear relation between Ki67 and PCNA staining was demonstrated These data suggest that in normal tissues and lymphoid neoplasms, PCNA immunolocalization can be used as an index of cell proliferation However, in some forms of neoplasia, including breast and gastric cancer and in vitro cell lines, the simple relation between PCNA expression and cell proliferation is lost In some breast and pancreatic tumours there is apparent deregulation of PCNA with increased expression in tissues adjacent to the tumours The over-expression in some tumours and in adjacent morphologically normal tissue may represent autocrine or paracrine growth factor influence on PCNA gene expression
1,441 citations
"Effects and mechanisms of silibinin..." refers background or methods in this paper
...Both PCNA and Ki-67 are biomarkers for cell proliferation [ 40 ]...
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...Ki-67 is a commonly used biomarker for cell proliferation [ 40 ]...
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