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Journal ArticleDOI

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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Citations
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Journal ArticleDOI
TL;DR: In this article , the authors provide a thorough analysis of the studies conducted on the most important species of medicinal plants used in this disease, bioactive compounds and on the activity of herbal medicines in the evolution of chronic liver diseases.

1 citations

Book ChapterDOI
01 Jan 2017
TL;DR: The investigation of synergistic antineoplastic effect of pharmacological combination with antioxidants in vitro cell models may provide additional options for treatment of cancer patients.
Abstract: Liver cancer is a highly heterogeneous disease produced by a variety of risk factors including viral infection and hepatotoxins. The hepatocarcinogenesis process is associated to oxidative stress and takes several steps: initiation, promotion, and progression that have been well characterized in vivo models, such as in protocols with rodents. Also cell culture of human-derived cell lines of liver has been considered of great value as in vitro models for cancer research. Several pharmacological studies with potential antineoplastic and antioxidant compounds have been successfully performed in cultured cell lines because they provide advantages for experimentation with highly reproducible results. The limited treatment options in cancer patients are due to drug resistance and elevated heterogeneity of liver neoplasm; this encourages the investigation of synergistic antineoplastic effect of pharmacological combination with antioxidants in vitro cell models; this may provide additional options for treatment of cancer patients.

1 citations

Journal ArticleDOI
TL;DR: In this article , a review of the mechanisms of promising plant bioactives against hepatocellular carcinoma (HCC) is discussed and compared, and the current limitations in nanocarrier design, challenges related to the HCC microenvironment, and future opportunities are also discussed for the clinical translation of plant-based nanomedicines from bench to bedside.
Abstract: Hepatocellular carcinoma (HCC), accounting for 85% of liver cancer cases, continues to be the third leading cause of cancer-related deaths worldwide. Although various forms of chemotherapy and immunotherapy have been investigated in clinics, patients continue to suffer from high toxicity and undesirable side effects. Medicinal plants contain novel critical bioactives that can target multimodal oncogenic pathways; however, their clinical translation is often challenged due to poor aqueous solubility, low cellular uptake, and poor bioavailability. Nanoparticle-based drug delivery presents great opportunities in HCC therapy by increasing selectivity and transferring sufficient doses of bioactives to tumor areas with minimal damage to adjacent healthy cells. In fact, many phytochemicals encapsulated in FDA-approved nanocarriers have demonstrated the ability to modulate the tumor microenvironment. In this review, information about the mechanisms of promising plant bioactives against HCC is discussed and compared. Their benefits and risks as future nanotherapeutics are underscored. Nanocarriers that have been employed to encapsulate both pure bioactives and crude extracts for application in various HCC models are examined and compared. Finally, the current limitations in nanocarrier design, challenges related to the HCC microenvironment, and future opportunities are also discussed for the clinical translation of plant-based nanomedicines from bench to bedside.

1 citations

Book ChapterDOI
02 Jan 2013

1 citations

Book ChapterDOI
01 Jan 2012
TL;DR: Cancer chemoprevention through the use of diet-derived, safe and natural polyphenols certainly seems to be a promising and inexpensive way to alleviate the pressure that weighs down the healthcare system because of rapidly increasing number of cancer patients throughout the world.
Abstract: In today’s world, survival is mostly about making smart choices. Keeping our body healthy and disease free too is about making smart lifestyle and dietary choices. There is a growing sense that diet becomes a part of ‘who we are’ and ‘how we express ourselves’ in the world. As a matter of fact one question that is often raised is “why is diet so important”? The answer is that diet is the vehicle for obtaining the nutrients our bodies require to function optimally. What we eat and how much we eat dramatically influences the nutrition our cells receive. Therefore, the health and vitality of our bodies, on a cellular level, is directly determined by the state of nutrition. As a result, diet has become one of the fundamental contributors to both health and disease. Recent scientific evidence suggests that in addition to the presence of other dietary nutrients, diets are also an important source of essential dietary phytochemicals, also referred to as ‘polyphenols’. Growing body of literature indicates that some of these dietary compounds and their secondary metabolites can have a tremendous effect on the way our bodies respond to various challenges posed by various diseases and aging. Not only this, preclinical and clinical studies in the last decade have convincingly demonstrated that the health promoting effect of various dietary agents extend far beyond than what was initially perceived, and that some of these compounds also possess potent anti-cancer activities. In this regard, multiple lines of evidence have provided unprecedented clues that dietary and environmental factors not only regulate various cell-signaling and growth regulatory pathways within cancer cells, but also directly influence epigenetic mechanisms. Epigenetic changes subsequently permit re-expression of tumor suppressor genes that promote apoptosis and growth inhibition of the tumor cells- a novel and previously unrecognized molecular mechanism supporting the underlying chemopreventive potential of many dietary agents. The term ‘epigenetics’ refers to heritable changes that are not encoded in the DNA sequence itself, but plays an important role in the control of gene expression. In mammals, the three key epigenetic mechanisms include changes in DNA methylation, histone modifications and non-coding RNAs. Although epigenetic changes can be inherited in the somatic cells, unlike genetic alterations, these modifications are potentially reversible. This potentially reversible nature of epigenetic signatures within growth regulatory genes makes them attractive avenues for developing innovative and promising chemopreventive and therapeutic endeavors in the future. From a nutritional perspective, this is quite fascinating because people are becoming increasingly aware of the beneficial effects of various food sources that are rich in dietary polyphenols, also referred to as superfoods. Although at this point in time we may not appreciate the significance of the dietary changes we all are making, nonetheless, such a behavior sets the stage for generating more scientific and epidemiologic data that will further help in highlighting the concept of chemoprevention by dietary agents at an epigenetic level. Cancer chemoprevention through the use of diet-derived, safe and natural polyphenols certainly seems to be a promising and inexpensive way to alleviate the pressure that weighs down the healthcare system because of rapidly increasing number of cancer patients throughout the world.

1 citations

References
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Journal ArticleDOI
28 Mar 1997-Science
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 ]...

    [...]

Journal ArticleDOI
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 ]...

    [...]

  • ...Hepatocellular carcinoma (HCC) is one of the most common malignancies related to a high mortality globally [1, 2 ]...

    [...]

Journal ArticleDOI
25 Sep 1997-Nature
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 ]...

    [...]

  • ...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 ]...

    [...]

Journal ArticleDOI
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]...

    [...]

  • ...and one of the most frequently inactivated genes in malignancies [ 30 , 31]...

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Journal ArticleDOI
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 ]...

    [...]

  • ...Ki-67 is a commonly used biomarker for cell proliferation [ 40 ]...

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