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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01 Jan 2022
TL;DR: In this article , Silybum marianum total extract (STE), silymarin (Sm), and silibinin (Sb) were evaluated against experimentally-induced HCC in rats.
Abstract: Hepatocellular carcinoma (HCC) has been identified as one of the most deadly malignancies with limited therapeutic efficacy worldwide. However, understanding the molecular mechanisms of crosstalk between signaling pathways in HCC and predicting cancer cell responses to targeted therapeutic interventions remain to be challenge. Thus, in this study, we aimed to evaluate the anticancerous efficacy of Silybum marianum total extract (STE), silymarin (Sm), and silibinin (Sb) against experimentally-induced HCC in rats. In vitro investigations were also performed and the anticancer effects against HCC cell lines (HepG2 and Huh7) were confirmed. Wistar rats were given diethylnitrosamine (DEN)/2-acetylaminofluorene (AAF)/carbon tetrachloride (CCl4) and were orally treated with STE (200 mg/kg body weight (bw)), Sm (150 mg/kg bw), and Sb (5 mg/kg bw) every other day from the 1st or 16th week to the 25th week of DEN/AAF/CCl4 injection. Treatment with STE, Sm, and Sb inhibited the growth of cancerous lesions in DEN/AAF/CCl4-treated rats. This inhibition was associated with inhibition of Ki-67 expression and repression of HGF/cMet, Wnt/β-catenin, and PI3K/Akt/mTOR signaling pathways. STE, Sm, and Sb improved liver function biomarkers and tumor markers (AFP, CEA, and CA19.9) and increased total protein and albumin levels in serum. STE, Sm, and Sb treatment was also noted to reduce the hepatic production of lipid peroxides, increase hepatic glutathione content, and induce the activities of hepatic antioxidant enzymes in DEN/AAF/CCl4-treated rats. These results indicate that STE, Sm, and Sb exert anti-HCC effects through multiple pathways, including suppression of Ki-67 expression and HGF/cMet, Wnt/β-catenin, and PI3K/Akt/mTOR pathways and enhancement of antioxidant defense mechanisms.
15 citations
TL;DR: In vitro potential genotoxic and cytotoxic antitumor effect of silymarin on HepG2 cells at achievable plasma level concentrations is demonstrated and biopharmacotherapy with chemotherapeutic agents are of interest in the issue of adjuvant therapy.
Abstract: The aim of this study was to investigate genotoxic and cytotoxic effects of doxorubicin, silymarin, or in combination on HepG2 cells for 24 and 48 h. Both doxorubicin and silymarin caused dose-dependent inhibition of cell proliferation. After 48 h of treatment, doxorubicin application caused dramatically increased ratio of apoptotic cells. Both 24 and 48 h of silymarin and doxorubicin-silymarin combination caused significant increases in the rate of apoptotic cells. Applications of doxorubicin and silymarin separately for 24 h led to deoxyribonucleic acid (DNA) damages. After 48 h of incubation, doxorubicin-induced genotoxic damage was 2-fold higher than the silymarin-induced damage. After 24 and 48 h, DNA damage in response to combined applications of doxorubicin and silymarin was indifferent from silymarin- and doxorubicin-induced damage respectively. There was not any difference in genotoxicity levels between incubation periods in combined applications of doxorubicin and silymarin. Lipid peroxidation levels increased in all applications. Biopharmacotherapy with chemotherapeutic agents are of interest in the issue of adjuvant therapy. Here, we demonstrate in vitro potential genotoxic and cytotoxic antitumor effect of silymarin on HepG2 cells at achievable plasma level concentrations.
14 citations
Cites methods from "Effects and mechanisms of silibinin..."
...Considering HCC, in vitro growth inhibitory effects of 120 mM silibinin were reported by Lah et al on HuH7, HepG2, Hep3B, and PLC/PRF/5 cells.(25) Inhibition of HepG2 cell growth by 100 mg/mL application of silymarin was also reported....
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TL;DR: A 66-year-old Taiwanese male patient with liver cirrhosis related to chronic hepatitis C presented with hepatocellular carcinoma with portal vein thrombosis and was told to undergo surgery because of no further decrease in tumour size and an increase in tumours marker in imaging studies.
Abstract: Spontaneous regression of advanced hepatocellular carcinoma is extremely rare. A 66-year-old Taiwanese male patient with liver cirrhosis related to chronic hepatitis C presented with hepatocellular carcinoma with portal vein thrombosis. At first, he refused curative therapy, except for silymarin medicine. Spontaneous regression of hepatocellular carcinoma occurred with a decline in tumour size and tumour marker in imaging studies. The patient agreed to undergo surgery approximately 14 months after presentation because of no further decrease in tumour size and an increase in tumour marker in the imaging studies. The resected tumour was hepatocellular carcinoma with portal vein thromboses. Presently, the patient is alive and in good condition without any symptoms or tumour recurrence. We concluded that this was a rare case of spontaneous regression of advanced hepatocellular carcinoma.
14 citations
TL;DR: It is shown that silibinin can improve some testicular parameters as well as testosterone levels, and significant increase was observed in group of animals treated with 150 mg/kg of silibInin concerning the diameter of primary spermatocyte and diameter of sperMatide.
Abstract: Article history: Received on: 28/10/2012 Accepted on: 14/11/2012 Available online: 28/11/2012 Silibinin (silybin) is one of the structural isomers of the flavonoid silymarin, and it has wide variety of phytotherapeutic applications and the aim of this study was to investigate the effects of different doses of silibinin on testicular tissue of mice. Twenty male Swiss albino mice were divided into four groups. Each group consist of five animal, (Group 1) (negative control) animals were administered single intraperitoneal (IP) daily dose of phosphate buffer for 5 days, Groups ( 2, 3, and 4) were given a single IP daily dose of either (50, 100 or 150 mg/kg B.wt.) of silibinin respectively for 5 days. Microscopic examinations of sperms, histological examinations of testes and serum testosterone level had been measured. It was found that silibinin in doses of (100 or 150) mg/Kg produced a significant increase (P<0.05) in the level of testosterone in comparison with group 1. Also, silibinin in dose of 100 mg/Kg showed a significant increase in the diameter of spermatide, and significant increase was observed in group of animals treated with 150 mg/kg of silibinin concerning the diameter of primary spermatocyte and diameter of spermatide. The results indicate that silibinin can improve some testicular parameters as well as testosterone levels.
13 citations
Cites background from "Effects and mechanisms of silibinin..."
...It was found that in cancer cells, silibinin alters cell cycle regulators and induces apoptosis, both through antioxidant and anti-inflammatory properties (Mokhtari et al., 2008; Raina et al., 2008; Verschoyle et al., 2008; Lah et al., 2007)....
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01 Jan 2012
TL;DR: This review focuses on the development of phytochemical-loaded polymeric nanoparticles and their application as potential anticancer therapeutic agents.
Abstract: Cancer continues to be one of the leading causes of death worldwide. Repeated treatment with chemotherapeutics has resulted in tumors that are resistant to these agents. So, it is becoming necessary to identify natural products that target multiple signaling pathways and cause growth inhibitory effects on human cancer cells without resulting in toxicity issues in normal cells. Curcumin, epigallocatechingallate (EGCG; green tea extract), resveratrol, saponins, silymarin, and grape seed extract (GSE) are some of the phytochemicals with significant anticancer potential that we will be focusing on in this review. Curcumin, a natural diphenolic compound derived from turmeric Curcuma longa, has proven to be a modulator of intracellular signaling pathways that control cancer cell growth, inflammation, invasion and apoptosis, revealing its anticancer potential. EGCG and GSE are two popular plant extracts that have attracted much attention in recent years due to their antioxidant, antimicrobial, anticarcinogenic, and anti-inflammatory properties. Saponins are a group of naturally occurring plant glycosides, of which at least 150 kinds of natural saponins have been found to possess significant anticancer properties. Silymarin, a mixture of mainly three flavonolignans (silybin, silychristin and silydianin), is extracted from the milk thistle and possesses potential biological properties. Even though these agents are potent anticancer agents, they are limited by their solubility, hydrophobicity, and low bioavailability. Polymeric nanocarriers provide an efficient platform for overcoming the factors that limit application of phytochemicals as therapeutic agents. This review focuses on the development of phytochemical-loaded polymeric nanoparticles and their application as potential anticancer therapeutic agents.
13 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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