stilbenes and Liver-Neoplasms

stilbenes has been researched along with Liver-Neoplasms* in 124 studies

Reviews

3 review(s) available for stilbenes and Liver-Neoplasms

ArticleYear
Preventive and therapeutic role of traditional Chinese herbal medicine in hepatocellular carcinoma.
    Journal of the Chinese Medical Association : JCMA, 2015, Volume: 78, Issue:3

    Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. The clinical management of HCC remains a substantial challenge. Although surgical resection of tumor tissues seems promising, a high recurrence and/or metastasis rate accounting for disease-related death has led to an urgent need for improved postsurgical preventive/therapeutic clinical intervention. Developing advanced target-therapy agents such as sorafenib appears to be the only effective clinical intervention for patients with HCC to date, but only limited trials have been conducted in this regard. Because of their enhanced preventive/therapeutic effects, traditional Chinese herbal medicine (CHM)-derived compounds are considered suitable agents for HCC treatment. The CHM-derived compounds also possess multilevel, multitarget, and coordinated intervention effects, making them ideal candidates for inhibition of tumor progression and HCC metastasis. This article reviews the anticancer activity of various CHMs with the hope of providing a better understanding of how to best use CHM for HCC treatment.

    Topics: Abietanes; Benzylisoquinolines; Berberine; Carcinoma, Hepatocellular; Curcumin; Drugs, Chinese Herbal; Humans; Liver Neoplasms; Medicine, Chinese Traditional; Resveratrol; Scutellaria baicalensis; Stilbenes

2015
Resveratrol in the chemoprevention and treatment of hepatocellular carcinoma.
    Cancer treatment reviews, 2010, Volume: 36, Issue:1

    Hepatocellular carcinoma (HCC) is one of the most common cancers and lethal diseases in the world. Although the majority of HCC cases occur in developing countries of Asia and Africa, the prevalence of liver cancer has risen considerably in Japan, Western Europe as well as the United States. HCC most commonly develops in patients with chronic liver disease, the etiology of which includes viral hepatitis (B and C), alcohol, obesity, iron overload and dietary carcinogens, including aflatoxins and nitrosamines. The current treatment modalities, including surgical resection and liver transplantation, have been found to be mostly ineffective. Hence, there is an obvious critical need to develop alternative strategies for the chemoprevention and treatment of HCC. Oxidative stress as well as inflammation has been implicated in the development and progression of hepatic neoplasia. Using naturally occurring phytochemicals and dietary compounds endowed with potent antioxidant and antiinflammatory properties is a novel approach to prevent and control HCC. One such compound, resveratrol, present in grapes, berries, peanuts as well as red wine, has emerged as a promising molecule that inhibits carcinogenesis with a pleiotropic mode of action. This review examines the current knowledge on mechanism-based in vitro and in vivo studies on the chemopreventive and chemotherapeutic potential of resveratrol in liver cancer. Pre-clinical and clinical toxicity studies as well as pharmacokinetic data of resveratrol have also been highlighted in this review. Future directions and challenges involved in the use of resveratrol for the prevention and treatment of HCC are also discussed.

    Topics: Anticarcinogenic Agents; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Resveratrol; Stilbenes

2010
Phytochemicals as potential chemopreventive and chemotherapeutic agents in hepatocarcinogenesis.
    European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP), 2009, Volume: 18, Issue:1

    Hepatocellular carcinoma (HCC) is the fifth commonest malignancy worldwide and the incidence is rising. Surgery, including transplantation resection, is currently the most effective treatment for HCC; however, recurrence rates are high and long-term survival is poor. Identifying novel chemopreventive and chemotherapeutic agents and targeting them to patients at high risk of developing HCC or following curative treatment may go some way towards improving prognosis. This review examines current knowledge regarding the chemopreventive and chemotherapeutic potential of phytochemicals in heptocarcinogenesis. Both in-vitro and animal studies demonstrate that several phytochemicals, including curcumin, resveratrol, green tea catechins, oltipraz and silibinin, possess promising chemopreventive and chemotherapeutic properties. Despite this, very few clinical trials have been performed. Problems regarding validation of biomarkers, agent delivery, side effects and patient selection are barriers that need to be overcome to determine the potential of such agents in clinical practice.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Brassicaceae; Caffeine; Capsaicin; Carcinoma, Hepatocellular; Catechin; Chemoprevention; Curcumin; Flavonoids; Humans; Liver Neoplasms; Phenols; Plant Extracts; Polyphenols; Resveratrol; Stilbenes

2009

Trials

2 trial(s) available for stilbenes and Liver-Neoplasms

ArticleYear
Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases--safety, pharmacokinetics, and pharmacodynamics.
    Cancer prevention research (Philadelphia, Pa.), 2011, Volume: 4, Issue:9

    The phytochemical resveratrol has undergone extensive preclinical investigation for its putative cancer chemopreventive properties. Low systemic availability of the parent compound due to rapid and extensive metabolism may confound its usefulness as a potential agent to prevent malignancies in organs remote from the site of absorption. Micronization allows increased drug absorption, thus increasing availability. Here we describe a pilot study of SRT501, micronized resveratrol, given as 5.0 g daily for 14 days, to patients with colorectal cancer and hepatic metastases scheduled to undergo hepatectomy. The purpose of the study was to assess the safety, pharmacokinetics, and pharmacodynamics of the formulation. SRT501 was found to be well tolerated. Mean plasma resveratrol levels following a single dose of SRT501 administration were 1,942 ± 1,422 ng/mL, exceeding those published for equivalent doses of nonmicronized resveratrol by 3.6-fold. Resveratrol was detectable in hepatic tissue following SRT501 administration (up to 2,287 ng/g). Cleaved caspase-3, a marker of apoptosis, significantly increased by 39% in malignant hepatic tissue following SRT501 treatment compared with tissue from the placebo-treated patients. SRT501 warrants further clinical exploration to assess its potential clinical utility.

    Topics: Aged; Antineoplastic Agents, Phytogenic; Caspase 3; Combined Modality Therapy; Double-Blind Method; Female; Hepatectomy; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pilot Projects; Placebos; Postoperative Complications; Resveratrol; Stilbenes; Titanium

2011
Phase II study of tamoxifen: report of 74 patients with stage IV breast cancer.
    Cancer treatment reports, 1976, Volume: 60, Issue:10

    Tamoxifen (NSC-180973), a synthetic antiestrogen, was studied for efficacy and toxicity in patients with metastatic breast adenocarcinoma. Two dose levels were used, 10 mg bid and 15 mg/m2 bid, in separate groups. In the 10-mg bid dosage group, 30 of the 31 patients were considered evaluable for efficacy. Five complete and 11 partial responses were recorded, for an overall response rate of 53%. In the 15-mg/m2 bid dosage group, 44 of the 45 patients were considered evaluable for efficacy. Three complete and 16 partial responses were recorded, for an overall response rate of 43%. All 76 patients were evaluated for toxicity. Side effects were generally mild, consisting mostly of hot flushes, transient leukopenia, transient thrombocytopenia, nausea, and fluid retention. A high degree of correlation between response and positive estrogen-receptor assay suggests the value of the test as a means to select patients for tamoxifen treatment. The conclusion from this study is that tamoxifen used as a single agent is an effective drug with minimal toxicity for treatment of metastatic breast adenocarcinoma.

    Topics: Adenocarcinoma; Adult; Aged; Breast Neoplasms; Clinical Trials as Topic; Dose-Response Relationship, Drug; Female; Humans; Liver Neoplasms; Lung Neoplasms; Middle Aged; Neoplasm Metastasis; Stilbenes; Tamoxifen

1976

Other Studies

119 other study(ies) available for stilbenes and Liver-Neoplasms

ArticleYear
Exploring anti-liver cancer targets and mechanisms of oxyresveratrol:
    Bioengineered, 2021, Volume: 12, Issue:2

    The aim of current study was to exhume the potential targets and molecular mechanisms of oxyresveratrol, a structurally re-constructed resveratrol, for treating liver cancer through bioinformatics investigation and experimentative validation. To start with, the network pharmacology approach and molecular docking technology were used to uncover all candidate targets of oxyresveratrol to treat liver cancer, accompanied with identified anti-liver cancer targets including estrogen receptor 1 (ESR1), epidermal growth factor receptor (EGFR). In addition, more pharmacological mechanisms of oxyresveratrol against liver cancer were revealed in details. In experimental verification, the clinical samples of liver cancer showed elevated ESR1, EGFR mRNA expressions. The

    Topics: Computer Simulation; Gene Ontology; Hep G2 Cells; Humans; Liver Neoplasms; Molecular Docking Simulation; Plant Extracts; Protein Interaction Maps; Reproducibility of Results; Signal Transduction; Stilbenes

2021
Galactose Modified Liposomes for Effective Co-Delivery of Doxorubicin and Combretastatin A4.
    International journal of nanomedicine, 2021, Volume: 16

    Tumor angiogenesis plays a crucial role in tumor development, and recent efforts have been focused on combining proapoptotic and antiangiogenic activities to enhance antitumor therapy.. In this study, galactose-modified liposomes (Gal-LPs) were prepared for co-delivery of doxorubicin (DOX) and combretastatin A4 phosphate (CA4P). The co-cultured system composed of BEL-7402 and human umbilical vein endothelial cells (HUVEC) cells was established to effectively evaluate in vitro anti-tumor activity through cell viability and cell migration assay. Furthermore, both in vivo bio-distribution and anti-hepatoma effect of DOX&CA4P/Gal-LPs were investigated on H22 tumor cell-bearing mice.. The results showed that DOX&CA4P/Gal-LPs were spherical with a mean particle size of 143 nm, and could readily be taken up by BEL-7402 cells. Compared with a mixture of free DOX and CA4P, the DOX&CA4P/Gal-LPs were more effective in inhibiting cell migration and exhibited stronger cytotoxicity against BEL-7402 cells alone or a co-cultured system. The in vitro studies showed that the co-cultured system was a more effective model to evaluate the anti-tumor activity of combination therapy. Moreover, DOX&CA4P/Gal-LPs exhibited a greater anti-hepatoma effect than other drug formulations, indicating that Gal-LPs could promote drug accumulation in the tumor region and improve the anti-tumor activity.. Gal-LPs co-loaded with chemotherapeutic and antiangiogenic drugs are a promising strategy for anti-hepatoma therapy.

    Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Survival; Doxorubicin; Drug Compounding; Galactose; Human Umbilical Vein Endothelial Cells; Humans; Liposomes; Liver Neoplasms; Mice; Particle Size; Stilbenes

2021
Pterostilbene Nanoparticles Downregulate Hypoxia-Inducible Factors in Hepatoma Cells Under Hypoxic Conditions.
    International journal of nanomedicine, 2021, Volume: 16

    Transcatheter arterial chemoembolization (TACE) is a common clinical treatment for hepatocellular carcinoma (HCC). However, hypoxia induction after treatment might trigger tumor invasiveness and metastasis. Although pterostilbene (PTS) has antitumor effects, its chemoprevention in HepG2 cells under hypoxia has not been investigated yet. In addition, the poor water solubility of raw PTS limits its clinical application. Here, we prepared nanoparticles of PTS (PSN) and compared their antihepatoma activities with those of raw PTS in HepG2 under hypoxic conditions.. The PTS nanoparticle formulation was prepared by nanoprecipitation, using Eudragit. The yield and encapsulation efficiency of PSN were 86.33% and >99%, respectively. The water solubility and drug release of PTS were effectively improved after nanoprecipitation corresponding to the reduction in particle size, amorphous transformation, and formation of hydrogen bonding with carriers. PSN had a better cytotoxic effect than raw PTS in HepG2 under pre- and post-hypoxia conditions. In addition, hypoxia- and apoptosis-related proteins in HepG2 cells under two different hypoxic conditions were significantly inhibited by PSN compared with the control group with hypoxia only, except for HIF-1α in the post-hypoxia group. PSN was also significantly better in inhibiting these proteins, except for Bcl2, under pre-hypoxic conditions.. Our results suggested that PSN could improve the water solubility and drug release of PTS and enhance the efficacy of HCC treatment under hypoxic conditions.

    Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Hypoxia; Cell Survival; Crystallization; Down-Regulation; Drug Liberation; Hep G2 Cells; Humans; Hydrogen Bonding; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms; Nanoparticles; Neoplasm Invasiveness; Particle Size; Proton Magnetic Resonance Spectroscopy; Solubility; Spectroscopy, Fourier Transform Infrared; Stilbenes; Tumor Hypoxia

2021
Combining combretastatin A4 phosphate with ginsenoside Rd synergistically inhibited hepatocellular carcinoma by reducing HIF-1α via PI3K/AKT/mTOR signalling pathway.
    The Journal of pharmacy and pharmacology, 2021, Mar-04, Volume: 73, Issue:2

    Combretastatin A4 phosphate (CA4P), a vascular disrupting agent (VDA), can cause rapid tumour vessel occlusion. Subsequently, extensive necrosis is discovered in the tumour center, which induces widespread hypoxia and the rise of the α subunit of hypoxia-inducible factor-1 (HIF-1α). The aim of this study was to evaluate the inhibition of hepatocellular carcinoma growth by combining CA4P with HIF-1 α inhibitor and investigate the mechanism of this combination.. Ginsenoside Rd (Rd) was used in combination with CA4P to estimate the inhibition effect in HepG2 cells and HepG2 xenograft mouse model. The efficacy of anti-tumour was evaluated by tumour growth curve. The protein expression of HIF-1α and PI3K/AKT/mTOR signalling pathway were analysed by western blot.. Combination of CA4P and Rd inhibited HepG2 cell proliferation and induced apoptosis in vivo and in vitro. It also increased the necrotic area of the tumour and delayed the tumour growth. Moreover, Rd down-regulated HIF-1α protein expression by inhibiting PI3K/AKT/mTOR signalling pathway.. Combination of CA4P and Rd had synergistic anti-tumour effects. The mechanism may be related to the inhibition of HIF-1α by PI3K/AKT/mTOR signalling pathway. This strategy provides a new thought for the combinative therapy of VDAs.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Hepatocellular; Drug Synergism; Ginsenosides; Hep G2 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Signal Transduction; Stilbenes; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

2021
Co-administration of combretastatin A4 nanoparticles and anti-PD-L1 for synergistic therapy of hepatocellular carcinoma.
    Journal of nanobiotechnology, 2021, May-01, Volume: 19, Issue:1

    According to data estimated by the WHO, primary liver cancer is currently the fourth most common malignant tumor and the second leading cause of death around the world. Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies, so effective therapy is highly desired for HCC.. In this study, the use of poly(L-Aspartic acid)-poly(ethylene glycol)/combretastatin A4 (CA4-NPs) was aimed to significantly disrupt new blood vessels in tumor tissues for targeted hepatic tumor therapy. Here, PEG-b-PAsp-g-CA4 showed significantly prolonged retention in plasma and tumor tissue. Most importantly, CA4-NPs were mainly distributed at the tumor site because of the triple target effects-enhanced permeability and retention (EPR) effect, acid-sensitive (pH = 5.5) effect to the tumor microenvironment (TME), and good selectivity of CA4 for central tumor blood vessel. Considering that CA4-NPs might induce severe hypoxic conditions resulting in high expression of HIF-1α in tumor tissues, which could induce the overexpression of PD-L1, herein we also used a programmed death-ligand 1 antibody (aPD-L1) to prevent immunosuppression. This way of complementary combination is able to achieve an ideal treatment effect in tumor site where CA4-NPs and aPD-L1 could respond to the inner area and peripheral area, respectively. As a result, a significant decrease in tumor volume and weight was observed in the combination group of CA4-NPs plus aPD-L1 compared with CA4-NPs or aPD-L1 monotherapy in subcutaneous Hepa1-6 hepatic tumor models.. We presented a new idea that co-administration of CA4-NPs and aPD-L1 possessed notable anti-tumor efficacy for HCC treatment.

    Topics: Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; B7-H1 Antigen; Carcinoma, Hepatocellular; Disease Models, Animal; Drug Synergism; Female; Humans; Liver Neoplasms; Mice; Mice, Inbred C57BL; Nanoparticles; Polyethylene Glycols; Stilbenes; Tumor Microenvironment

2021
Dual-Ligand-Modified Liposomes Co-Loaded with Anti-Angiogenic and Chemotherapeutic Drugs for Inhibiting Tumor Angiogenesis and Metastasis.
    International journal of nanomedicine, 2021, Volume: 16

    Tumor angiogenesis has been proven to potentiate tumor growth and metastasis; therefore, the strategies targeting tumor-related angiogenesis have great potentials in antitumor therapy.. Here, the GA&Gal dual-ligand-modified liposomes co-loaded with curcumin and combretastatin A-4 phosphate (CUCA/GA&Gal-Lip) were prepared and characterized. A novel "BEL-7402+HUVEC" co-cultured cell model was established to mimic tumor microenvironment. The cytotoxicity and migration assays were performed against the novel co-cultured model. Angiogenesis ability was evaluated by tube formation test, and in vivo metastatic ability was evaluated by lung metastasis test.. The result demonstrated that dual-ligand-modified liposomes showed greater inhibition of tumor angiogenesis and metastasis in comparison with other combined groups. Significantly, the mechanism analysis revealed that curcumin and combretastatin A-4 phosphate could inhibit tumor angiogenesis and metastasis via down-regulation of VEGF and VEGFR2 expression, respectively, and that GA&Gal-Lip could improve antitumor effect by GA/Gal-mediated active-targeting delivery.. CUCA/GA&Gal-Lip hold great potentials in hepatoma-targeting delivery of antitumor drugs and can achieve anti-angiogenic and anti-metastatic effects by simultaneously blocking VEGF/VEGFR2 signal pathway, therefore exhibiting superior anti-hepatoma efficacy.

    Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cell Line, Tumor; Curcumin; Drug Liberation; Gene Expression Regulation, Neoplastic; Human Umbilical Vein Endothelial Cells; Humans; Ligands; Liposomes; Liver Neoplasms; Lung Neoplasms; Mice, Inbred BALB C; Neovascularization, Pathologic; Stilbenes; Xenograft Model Antitumor Assays

2021
Self-assembling combretastatin A4 incorporated protamine/nanodiamond hybrids for combined anti-angiogenesis and mild photothermal therapy in liver cancer.
    Nanotechnology, 2021, Aug-23, Volume: 32, Issue:46

    Tumor angiogenesis has been identified as an important factor in the development and progression of tumors, and anti-angiogenesis therapy has been recognized as an effective tumor therapy pattern. The unique characteristics of nanodiamonds (NDs) have been explored for photothermal therapy (PTT) against cancer, while the efficiency of mild PTT mediated by bare NDs was limited. The combination of different therapies into a single nanoplatform has shown great potential for synergistic cancer treatment. In this investigation, we integrated hydrophobic antiangiogenesis agent combretastatin A4 (CA4) into the protamine sulfate (PS) functionalized NDs hybrids (NDs@PS) with a noncovalent self-assembling method (CA4-NDs@PS) for potential combined anti-angiogenesis and mild PTT in liver cancer. The resulted CA4-NDs@PS NDs exhibited high drug loading ability, good dispersibility and colloidal stability. The near-infrared (NIR) laser irradiation could trigger the release of CA4 from CA4-NDs@PS NDs and elevate the temperature of CA4-NDs@PS NDs aqueous solution.

    Topics: Angiogenesis Inhibitors; Animals; Cell Line, Tumor; Female; Hep G2 Cells; Humans; Liver Neoplasms; Mice; Mice, Inbred BALB C; Nanodiamonds; Phototherapy; Photothermal Therapy; Protamines; Stilbenes

2021
Combretastatin A-4 disodium phosphate and low dose gamma irradiation suppress hepatocellular carcinoma by downregulating ROCK1 and VEGF gene expression.
    Molecular biology reports, 2020, Volume: 47, Issue:3

    Hepatocellular carcinoma (HCC) is a tough opponent. HCC contributes to 14.8% of all cancer mortality in Egypt. There are many choices for management of HCC; however tumor relapse has been reported in animal and clinical studies. This study was conducted to investigate the impact of low dose γ-irradiation (LDR) and combretastatin A-4 disodium phosphate (CA-4DP) on HCC recurrence. HCC was induced in male Wistar albino rats by oral administration of N-nitrosodiethylamine (NDEA) for 17 weeks. We evaluated the expression of the endothelial cell marker (CD31) by immunostaining. Expression of Rho Associated Coiled-Coil Containing Protein Kinase 1(ROCK1) and Vascular endothelial growth factor (VEGF) expression was assessed by real-time PCR after (6, 24 and 48 h). Our results showed that expression of CD31 and gene expression of ROCK1 and VEGF was significantly repressed at all-time intervals by combination therapy ofLDR and CA-4DP as compared with untreated NDEA/HCC group and NDEA/HCC groups treated with either LDR or CA-4DP alone, (P < 0.05). Our study demonstrated the additive effect of LDR in combination with CA-4DP in suppression of HCC.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Chemoradiotherapy; Combined Modality Therapy; Diethylnitrosamine; Down-Regulation; Egypt; Gamma Rays; Gene Expression Regulation, Neoplastic; Liver Neoplasms; Male; Platelet Endothelial Cell Adhesion Molecule-1; Rats; Rats, Wistar; rho-Associated Kinases; Stilbenes; Treatment Outcome; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

2020
Synthesis and Evaluation of Diindole-Based MRI Contrast Agent for In Vivo Visualization of Necrosis.
    Molecular imaging and biology, 2020, Volume: 22, Issue:3

    Noninvasive imaging of cell necrosis can provide an early evaluation of tumor response to treatments. Here, we aimed to design and synthesize a novel diindole-based magnetic resonance imaging (MRI) contrast agent (Gd-bis-DOTA-diindolylmethane, Gd-DIM) for assessment of tumor response to therapy at an early stage.. The oil-water partition coefficient (Log P) and relaxivity of Gd-DIM were determined in vitro. Then, its necrosis avidity was examined in necrotic cells in vitro and in rat models with microwave ablation-induced muscle necrosis (MAMN) and ischemia reperfusion-induced liver necrosis (IRLN) by MRI. Visualization of tumor necrosis induced by combretastatin A-4 disodium phosphate (CA4P) was evaluated in rats bearing W256 orthotopic liver tumor by MRI. Finally, DNA binding assay was performed to explore the possible necrosis-avidity mechanism of Gd-DIM.. The Log P value and T1 relaxivity of Gd-DIM is - 2.15 ± 0.01 and 6.61 mM. Gd-DIM may serve as a promising necrosis-avid MRI contrast agent for early assessment of tumor response to therapy.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Contrast Media; Disease Models, Animal; Liver Neoplasms; Lung Neoplasms; Magnetic Resonance Imaging; Male; Necrosis; Rats; Rats, Sprague-Dawley; Stilbenes

2020
Nano-Gold Loaded with Resveratrol Enhance the Anti-Hepatoma Effect of Resveratrol
    Journal of biomedical nanotechnology, 2019, Feb-01, Volume: 15, Issue:2

    Nanomaterials-based drug delivery systems display potent applications in cancer therapy. We synthesized a novel anticancer drug, nano-gold loaded with resveratrol (Res-GNPs), which were characterized using UV-Prove, zetasizer and transmission electron microscope. MTT assay, flow cytometry, TUNEL, immunohistochemistry and western blot analysis were performed to explore the antitumor activity of Res-GNPs in liver cancer cells and tumor xenografts. Res-GNPs showed a stronger effect on inhibiting cell proliferation and promoting apoptosis in Hepg2 cells than that of free Res. Res-GNPs induced apoptosis in Hepg2 cells by down-regulating pro-caspase-9, pro-caspase-3, PI3K and Akt and upregulating caspase-8 and bax. In xenograft studies, Res-GNPs remarkably suppressed tumor growth, promoted tumor apoptosis and decreased the expression of vascular endothelial growth factor (VEGF) in tumor tissue. Furthermore, HE staining showed that no observable toxicity was found in heart, liver, kidney and spleen. The datum confirmed that Res-GNPs possess better antitumor effect than Res

    Topics: Apoptosis; Carcinoma, Hepatocellular; Gold; Humans; Liver Neoplasms; Metal Nanoparticles; Resveratrol; Stilbenes; Vascular Endothelial Growth Factor A

2019
Targeting SYK signaling in myeloid cells protects against liver fibrosis and hepatocarcinogenesis.
    Oncogene, 2019, Volume: 38, Issue:23

    Liver fibrosis and fibrosis-associated hepatocarcinogenesis are driven by chronic inflammation and are leading causes of morbidity and death worldwide. SYK signaling regulates critical processes in innate and adaptive immunity, as well as parenchymal cells. We discovered high SYK expression in the parenchymal hepatocyte, hepatic stellate cell (HSC), and the inflammatory compartments in the fibrotic liver. We postulated that targeting SYK would mitigate hepatic fibrosis and oncogenic progression. We found that inhibition of SYK with the selective small molecule inhibitors Piceatannol and PRT062607 markedly protected against toxin-induced hepatic fibrosis, associated hepatocellular injury and intra-hepatic inflammation, and hepatocarcinogenesis. SYK inhibition resulted in increased intra-tumoral expression of the p16 and p53 but decreased expression of Bcl-xL and SMAD4. Further, hepatic expression of genes regulating angiogenesis, apoptosis, cell cycle regulation, and cellular senescence were affected by targeting SYK. We found that SYK inhibition mitigated both HSC trans-differentiation and acquisition of an inflammatory phenotype in T cells, B cells, and myeloid cells. However, in vivo experiments employing selective targeted deletion of SYK indicated that only SYK deletion in the myeloid compartment was sufficient to confer protection against fibrogenic progression. Targeting SYK promoted myeloid cell differentiation into hepato-protective TNFα

    Topics: Animals; Carcinogenesis; Carcinoma, Hepatocellular; Cell Transdifferentiation; Cyclohexylamines; Female; Fibrosis; Hepatic Stellate Cells; Humans; Interleukin-8; Lectins, C-Type; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Mannose Receptor; Mannose-Binding Lectins; Mice; Mice, Inbred C57BL; Myeloid Cells; Neoplasms, Experimental; Oxidative Phosphorylation; Phenotype; Pyrimidines; Receptors, Cell Surface; Signal Transduction; Stilbenes; Syk Kinase; Transcriptome

2019
Co-administration of combretastatin A4 nanoparticles and sorafenib for systemic therapy of hepatocellular carcinoma.
    Acta biomaterialia, 2019, 07-01, Volume: 92

    Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Death; Cell Survival; Human Umbilical Vein Endothelial Cells; Humans; Ki-67 Antigen; Liver Neoplasms; Male; Mice, Inbred BALB C; Nanoparticles; Platelet Endothelial Cell Adhesion Molecule-1; Sorafenib; Stilbenes; Treatment Outcome; Vascular Endothelial Growth Factor A

2019
Inhibition of eIF2α dephosphorylation accelerates pterostilbene-induced cell death in human hepatocellular carcinoma cells in an ER stress and autophagy-dependent manner.
    Cell death & disease, 2019, 05-28, Volume: 10, Issue:6

    Hepatocellular carcinoma (HCC) is the one of the most common cancers worldwide. Because the side effects of current treatments are severe, new effective therapeutic strategies are urgently required. Pterostilbene (PT), a natural analogue of resveratrol, has diverse pharmacologic activities, including antioxidative, anti-inflammatory and antiproliferative activities. Here we demonstrated that PT inhibits HCC cell growth without the induction of apoptosis in an endoplasmic reticulum (ER) stress- and autophagy-dependent manner. Mechanistic studies indicated that the combination of salubrinal and PT modulates ER stress-related autophagy through the phospho-eukaryotic initiation factor 2α/activating transcription factor-4/LC3 pathway, leading to a further inhibition of eIF2α dephosphorylation and the potentiation of cell death. An in vivo xenograft analysis revealed that PT significantly reduced tumour growth in mice with a SK-Hep-1 tumour xenograft. Taken together, our results yield novel insights into the pivotal roles of PT in ER stress- and autophagy-dependent cell death in HCC cells.

    Topics: Activating Transcription Factor 4; Animals; Antineoplastic Agents; Apoptosis; Autophagosomes; Autophagy; Carcinoma, Hepatocellular; Cinnamates; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Female; Hep G2 Cells; Humans; Liver Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Microtubule-Associated Proteins; Signal Transduction; Stilbenes; Thiourea; Transplantation, Heterologous

2019
Stilbene compound trans-3,4,5,4´-tetramethoxystilbene, a potential anticancer drug, regulates constitutive androstane receptor (Car) target genes, but does not possess proliferative activity in mouse liver.
    Toxicology letters, 2019, Oct-01, Volume: 313

    The constitutive androstane receptor(CAR) activation is connected with mitogenic effects leading to liver hyperplasia and tumorigenesis in rodents. CAR activators, including phenobarbital, are considered rodent non-genotoxic carcinogens. Recently, trans-3,4,5,4´-tetramethoxystilbene(TMS), a potential anticancer drug (DMU-212), have been shown to alleviate N-nitrosodiethylamine/phenobarbital-induced liver carcinogenesis. We studied whether TMS inhibits mouse Car to protect from the PB-induced tumorigenesis. Unexpectedly, we identified TMS as a murine CAR agonist in reporter gene experiments, in mouse hepatocytes, and in C57BL/6 mice in vivo. TMS up-regulated Car target genes Cyp2b10, Cyp2c29 and Cyp2c55 mRNAs, but down-regulated expression of genes involved in gluconeogenesis and lipogenesis. TMS did not change or down-regulate genes involved in liver proliferation or apoptosis such as Mki67, Foxm1, Myc, Mcl1, Pcna, Bcl2, or Mdm2, which were up-regulated by another Car ligand TCPOBOP. TMS did not increase liver weight and had no significant effect on Ki67 and Pcna labeling indices in mouse liver in vivo. In murine hepatic AML12 cells, we confirmed a Car-independent proapoptotic effect of TMS. We conclude that TMS is a Car ligand with limited effects on hepatocyte proliferation, likely due to promoting apoptosis in mouse hepatic cells, while controlling Car target genes involved in xenobiotic and endobiotic metabolism.

    Topics: Animals; Anticarcinogenic Agents; Apoptosis; Aryl Hydrocarbon Hydroxylases; Binding Sites; Cell Proliferation; Constitutive Androstane Receptor; Cytochrome P450 Family 2; Gene Expression Regulation, Enzymologic; Gluconeogenesis; Hep G2 Cells; Hepatocytes; Humans; Lipogenesis; Liver; Liver Neoplasms; Male; Mice, Inbred C57BL; Molecular Docking Simulation; Protein Binding; Pyridines; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Steroid Hydroxylases; Stilbenes

2019
Oxyresveratrol prevents murine H22 hepatocellular carcinoma growth and lymph node metastasis via inhibiting tumor angiogenesis and lymphangiogenesis.
    Journal of natural medicines, 2018, Volume: 72, Issue:2

    The purpose of this study was to investigate the effects and mechanisms of oxyresveratrol (Oxyres) on hepatocellular carcinoma (HCC) in vitro and in vivo. The MTT and Transwell assays were performed to investigate the effects of Oxyres on cell proliferation and migration of two HCC cell lines, QGY-7701 and SMMC-7721 cells. H22 cells were subcutaneously injected into hind foot pads of 70 male mice to establish a lymph node metastasis model. These mice were randomly divided into seven groups as follows, control group, HCC group, Oxyres 20 mg/kg group, Oxyres 40 mg/kg group, Oxyres 60 mg/kg group, Resveratrol (Res) group, and Adriamycin (ADM) group. Oxyres, Res, and ADM were intraperitoneally injected daily for consecutive 21 days. Tumors and popliteal lymph node were isolated and embedded for histology analysis. Expressions of CD31 and vascular endothelial growth factor receptor-3 (VEGFR3) in tumors were detected by immunohistocehmistry. Expressions of vascular endothelial growth factor C (VEGF-C) were measured by Western blot. Oxyres significantly inhibited the proliferation and migration of QGY-7701 and SMMC-7721 cells. Oxyres significantly inhibited tumor growth (p < 0.001) and metastasis to sentinel lymph nodes (70%) in a dose-dependent manner. Oxyres showed a similar inhibition rate as Res. Oxyres also significantly decreased micro-blood vessel density and micro-lymphatic vessel density in tumors (p < 0.05). Expressions of CD31, VEGFR3, and VEGF-C of tumors were also inhibited by Oxyres (p < 0.05). Oxyres exerts anti-tumor effects against HCC through inhibiting both angiogenesis and lymph node metastasis, which suggests Oxyres be a potential therapeutic agent.

    Topics: Angiogenesis Inhibitors; Animals; Carcinoma, Hepatocellular; Cell Culture Techniques; Humans; Liver Neoplasms; Lymphangiogenesis; Lymphatic Metastasis; Male; Mice; Plant Extracts; Stilbenes

2018
Pterostilbene increases PTEN expression through the targeted downregulation of microRNA-19a in hepatocellular carcinoma.
    Molecular medicine reports, 2018, Volume: 17, Issue:4

    Pterostilbene (Pter) is reported to exhibit an anticancer effect in hepatocellular carcinoma (HCC). In order to explore the anticancer mechanism in HCC cells, the present study aimed to investigate whether pterostilbene (Pter) may increase phosphatase and tensin homolog (PTEN) expression through targeted downregulation of microRNA (miRNA/miR)-19a in hepatocellular carcinoma (HCC). The proliferation, apoptosis and cell cycle was analyzed in the SMMC‑7721 HCC cell line by MTT assays and flow cytometry methods. Cells were divided into five treatment groups: Pter treatment, miR‑19a inhibitor transfection, Pter + miR‑19a inhibitor, negative control transfection and blank control. The expression of miR‑19a and PTEN was detected by reverse transcription‑quantitative polymerase chain reaction and western blot analysis following treatment. Furthermore, a luciferase reporter gene assay was performed to determine whether the PTEN gene was a direct target of miR‑19a. The results demonstrated that Pter treatment or miR‑19a inhibitor transfection downregulated miR‑19a and induced PTEN/Akt pathway regulation, which led to proliferation inhibition, cell cycle arrest in the S phase, increased apoptosis and reduced cell invasion. These results indicated that Pter may increase PTEN expression through the direct downregulation of miR‑19a in HCC. Therefore, miR‑19a may have potential as a novel molecular marker for HCC and Pter may be a promising clinical target with the potential to be developed as a HCC therapy.

    Topics: 3' Untranslated Regions; Apoptosis; Carcinoma, Hepatocellular; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Genes, Reporter; Humans; Liver Neoplasms; MicroRNAs; PTEN Phosphohydrolase; RNA Interference; Signal Transduction; Stilbenes

2018
Quantitative Evaluation of Combretastatin A4 Phosphate Early Efficacy in a Tumor Model with Dynamic Contrast-Enhanced Ultrasound.
    Ultrasound in medicine & biology, 2018, Volume: 44, Issue:4

    Combretastatin A4 phosphate (CA4P) is a vascular disrupting agent that rapidly shuts down blood supply to tumors. Early monitoring of tumor perfusion plays a crucial role in determining the optimal strategy to managing treatment and guiding future therapy. The aim of this study was to investigate the potential value of dynamic contrast-enhanced ultrasound (CEUS) in quantitative evaluation of tumor perfusion at an early stage in CA4P therapy. Central and peripheral perfusion of tumors was detected by CEUS pre-treatment (0 h) and 2, 12 and 48 h after CA4P injection. Two perfusion parameters, maximum intensity (IMAX) and time to peak (TTP), were calculated from the time-intensity curve. After CEUS, the efficacy of CA4P was immediately confirmed by immunofluorescence assay and hematoxylin and eosin, Hoechst 33342 and fluorescein isothiocyanate-lectin staining. In CEUS of the center region of tumors, IMAX gradually decreased from 0 to 12 h and regrew at 48 h (p < 0.01). TTP increased only at 2 h. In the peripheral regions, IMAX did not change obviously from 0 to 12 h (p > 0.05) and just increased at 48 h (p < 0.01). The TTP of peripheral regions had the same tendency to vary tendency as that of center regions. In addition, microvascular density (MVD), vascular perfusion and necrotic area of the tumor were quantitatively analyzed. A close correlation between IMAX and MVD was observed in the center areas of tumors (r = 0.72, p < 0.01), whereas the correlation between IMAX and MVD in peripheral areas was weak (r = 0.37, p < 0.01). However, IMAX was positively correlated with tumor perfusion in both center and peripheral areas of tumors (r = 0.82, p < 0.01, and r = 0.63, p < 0.01, respectively). Consequently, IMAX was a reliable indicator of tumor perfusion evaluation by CEUS. The use of CEUS to quantify tumor perfusion could a promising method for the early detection of tumor responses in anti-vascular treatment.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Contrast Media; Disease Models, Animal; Evaluation Studies as Topic; Female; Image Enhancement; Liver; Liver Neoplasms; Mice; Mice, Inbred BALB C; Phospholipids; Stilbenes; Sulfur Hexafluoride; Treatment Outcome; Ultrasonography

2018
Pterostilbene inhibits MTA1/HDAC1 complex leading to PTEN acetylation in hepatocellular carcinoma.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2018, Volume: 101

    The aim of this study is to investigate the inhibition of cancer growth by pterostilbene through Metastasis-Associated Protein 1 (MTA1) and the histone deacetylase 1 (HDAC1) complex in hepatocellular carcinoma (HCC).. We investigate the antitumor effects of pterostilbene (PTER) in HCC. The SMMC-7721 hepatoma cell line was cultured and treated with PTER for different time depending on the experiment. After treatment, we tested the cellular expression of proteins by Western blot and the expression of MTA1 mRNA by real-time PCR. And the immunoprecipitation was performed to confirm the acetylation in PTEN. Animal models have been established to confirm the anti-cancer effects of PTER.. PTER treatment could downregulate the expression of MTA1, and HDAC1 and elevates the Ac-PTEN ratio in tumors. The results suggest that PTER can decrease the expression of MTA1 and destabilize the MTA1/HDAC1 complex allowing acetylation/activation of PTEN on Lys. We demonstrated that PTER suppressed the growth, and invasion of HCC and was effective in regulating the levels of the MTA1/HDAC1/NuRD complex, promoting PTEN acetylation and apoptosis in HCC. Our findings suggest that the novel epigenetic nature of PTER anticancer activity opens up new avenues for primary chemoprevention, as well as anticancer and antimetastatic treatment.

    Topics: Acetylation; Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Chromatin Assembly and Disassembly; Down-Regulation; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Histone Deacetylase 1; Histone Deacetylases; Humans; Liver Neoplasms; Mi-2 Nucleosome Remodeling and Deacetylase Complex; Mice, Nude; Models, Biological; Neoplasm Invasiveness; PTEN Phosphohydrolase; Repressor Proteins; RNA, Messenger; Stilbenes; Trans-Activators; Transcriptional Activation

2018
The first study on therapeutic efficacies of a vascular disrupting agent CA4P among primary hepatocellular carcinomas with a full spectrum of differentiation and vascularity: Correlation of MRI-microangiography-histopathology in rats.
    International journal of cancer, 2018, 10-01, Volume: 143, Issue:7

    To better inform the next clinical trials of vascular disrupting agent combretastatin-A4-phosphate (CA4P) in patients with hepatic malignancies, this preclinical study aimed at evaluating CA4P therapeutic efficacy in rats with primary hepatocellular carcinomas (HCCs) of a full spectrum of differentiation and vascularity by magnetic resonance imaging (MRI), microangiography and histopathology. Ninety-six HCCs were raised in 25 rats by diethylnitrosamine gavage. Tumor growth was monitored by T2-/T1-weighted-MRI (T2WI, T1WI) using a 3.0 T scanner. Early vascular response and later intratumoral necrosis were detected by dynamic-contrast-enhanced (DCE) MRI and diffusion-weighted-imaging (DWI) before, 1 and 12 hr after CA4P iv-administration. In vivo MRI-findings were validated by postmortem-techniques. Multi-parametric MRI revealed rapid CA4P-induced tumor vascular shutdown within 1 hr, followed by variable intratumoral necrosis at 12 hr. Tumor volumes decreased by 10% at 1 hr (p < 0.05), but resumed at 12 hr. Correlations of semi-quantitative DCE parameter initial-area-under-the-gadolinium-curve (IAUGC30) with histopathology proved partial vascular closure and compensational reopening (p < 0.05). The higher grades of vascularity prevented those residual tumor tissues from CA4P-caused ischemic necrosis. By histopathology using a 4-scale cellular-differentiation criteria and a 4-grade tumor-vascularity classification, percentage of CA4P-induced necrosis negatively correlated with HCC differentiation (r = -0.404, p < 0.001) and tumor vascularity (r = -0.370, p < 0.001). Ordinal-logistic-regression helped to predict early tumor responses to CA4P in terms of tumoral differentiation and vascularity. Our study demonstrated that CA4P could induce vascular shutdown in primary HCCs within 1 hr, resulting in various degrees of tumor necrosis at 12 hr. MRI as a real-time imaging biomarker may help to define tumor vascularity and differentiation and further to predict CA4P therapeutic outcomes.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Contrast Media; Humans; Liver Neoplasms; Magnetic Resonance Imaging; Male; Neovascularization, Pathologic; Rats; Rats, Sprague-Dawley; Stilbenes; Tumor Burden; Tumor Cells, Cultured

2018
Shufeng Jiedu Capsule and its active ingredients induce apoptosis, inhibit migration and invasion, and enhances doxorubicin therapeutic efficacy in hepatocellular carcinoma.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2018, Volume: 99

    Shufeng Jiedu Capsule (SFJDC), a traditional Chinese medicine, has been used widely as antiviral, antibacterial, antitumor, and anti-inflammatory drugs. Previous studies indicated that some active ingredients of Shufeng Jiedu Capsule, such as resveratrol and quercetin, could suppress hepatocellular carcinoma (HCC) cells through various signaling pathways. However, anti-HCC activity of SFJDC as a complementary medicine remains unexplored. Here, we use a combination of Shufeng Jiedu Capsule and doxorubicin to treat HCC cells and investigated the effects and mechanisms of SFJDC and its ingredientsin vitro.. In this study, two HCC cell lines, HepG2 and HepG2.2.15, were employed and all cells were separated into seven groups: doxorubicin group, SFJDC group, combination of doxorubicin and SFJDC group, resveratrol group, quercetin group, resveratrol and quercetin group, and control group. Through this research, the cellular functional experiments, such as MTT assay, Hoechst 33,258 staining, would healing assay, and transwell assay, were took to observe the effects of those agents on proliferation, apoptosis, migration and invasion of cells. Then, apoptosis and invasion related genes and proteins were detected by real-time PCR and western blot to illuminate the signaling pathways.. The combination group induced more significant apoptosis and inhibition of migration and invasion by affecting proteins and mRNA of apoptosis, migration, and invasion related elements, such as Bcl-2, Bax, mTOR, and NF-?B. Furthermore, the research suggested SFJDC, as a mixture of a number of ingredients, had stronger activities than particular component or simple mixture of a few components.. SFJDC and its active ingredients could play a role as complementary medicine to increase antitumor effect of doxorubicin by targeting mitochondrial, Akt/mTOR, and NF-?B signaling pathways.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Doxorubicin; Drugs, Chinese Herbal; Hep G2 Cells; Humans; Liver Neoplasms; Neoplasm Invasiveness; Quercetin; Real-Time Polymerase Chain Reaction; Resveratrol; Signal Transduction; Stilbenes

2018
Resveratrol inhibited the progression of human hepatocellular carcinoma by inducing autophagy via regulating p53 and the phosphoinositide 3‑kinase/protein kinase B pathway.
    Oncology reports, 2018, Volume: 40, Issue:5

    Resveratrol, a natural product, has been revealed to exert antitumor effects in multiple types of tumors. However, the antitumor effects of resveratrol on hepatocellular carcinoma (HCC) and its potential underlying mechanisms have not yet been elucidated. The present study demonstrated that resveratrol inhibited viability, proliferation, invasion and migration of HCC cells significantly in a time‑ and dose‑dependent manner, indicating that resveratrol exerted antitumor effects in HCC. Furthermore, relative expression of autophagy‑related proteins Beclin1 and LC3 II/I ratio was increased while p62 expression was decreased by resveratrol treatment dose‑dependently. The LC3+ puncta formation, which represented autophagosome formation was also markedly dose‑dependently upregulated by resveratrol treatment, suggesting that resveratrol induced autophagy in HCC cells. In addition, treatment with autophagy inhibitor 3‑methyladenine (3‑MA) counteracted the inhibitory effect of resveratrol on HCC cell proliferation, invasion and migration, indicating that suppressing autophagy may hamper the antitumor effect of resveratrol in HCC. It was revealed that resveratrol upregulated the expression of p53 while decreasing the ratio of phosphorylated protein kinase B (p‑Akt)/Akt in HCC cells. Treatment with p53 inhibitor pifithrin‑α and Akt activator insulin‑like growth factor‑1 decreased the expression of Beclin1 while significantly promoting cell proliferation, invasion and migration compared with the resveratrol treatment group. Taken together, the results of the present study revealed that resveratrol inhibited the proliferation and mobility of HCC cells through inducing autophagy via activating p53 and inhibiting phosphoinositide 3‑kinase/Akt. Enhancing autophagy can augment the antitumor effects of resveratrol in HCC. Therefore, combining resveratrol with an autophagy inducer may be a viable option for treating HCC.

    Topics: Adenine; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Benzothiazoles; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Liver Neoplasms; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Resveratrol; Signal Transduction; Stilbenes; Toluene; Tumor Suppressor Protein p53; Up-Regulation

2018
Inhibitory effects of resveratrol on hepatitis B virus X protein-induced hepatocellular carcinoma.
    Journal of veterinary science, 2017, Dec-31, Volume: 18, Issue:4

    Liver cancer occurs very frequently worldwide and hepatocellular carcinoma (HCC) accounts for more than 80% of total primary liver cancer cases. In this study, the anticarcinogenic effects of resveratrol against hepatitis B virus (HBV)-induced HCC were investigated by using HBV X-protein-overexpressing Huh7 (Huh7-HBx) human hepatoma cells. MTT assay showed that resveratrol decreased cell viability. Fluorescence-activated cell-sorter analysis showed that resveratrol induced G1 cell cycle arrest without increasing the sub-G1 phase cell population. Therefore, we evaluated its effect on regulation of cyclin D1, which is critically involved in G1/S transition. Resveratrol lowered cyclin D1 transcription. Western blot analysis of the effects of resveratrol on upstream cyclin D1 transcriptional signaling, extracellular signal-related kinase (ERK), p90

    Topics: Animals; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cyclin D1; Hepatitis B virus; Humans; Inhibitor of Apoptosis Proteins; Liver Neoplasms; Mice, Inbred BALB C; Mice, Nude; Neoplasms, Experimental; Repressor Proteins; Resveratrol; Signal Transduction; STAT3 Transcription Factor; Stilbenes; Survivin; Trans-Activators; Viral Regulatory and Accessory Proteins

2017
Resveratrol inhibits hepatocellular carcinoma progression driven by hepatic stellate cells by targeting Gli-1.
    Molecular and cellular biochemistry, 2017, Volume: 434, Issue:1-2

    Hepatocellular carcinoma (HCC) is characterized by hypervascularity. Hepatic stellate cells (HSCs) play very important roles in HCC malignant progression, as these cells facilitate HCC tumorigenesis and metastasis. We demonstrated that HSCs induce angiogenesis in HCC by upregulating the expression of Gli-1, which stimulates reactive oxygen species (ROS) production and potentiates increases in HCC cell invasiveness. Resveratrol abolished HSC-induced angiogenesis and suppressed ROS production and IL-6 and CXCR4 receptor expression in HepG2 cells by down-regulating Gli-1 expression. These findings indicate that Gli-1 may be a target for the prevention of angiogenesis in HCC and that resveratrol may have beneficial effects with respect to preventing HCC progression.

    Topics: Carcinoma, Hepatocellular; Disease Progression; Hep G2 Cells; Hepatic Stellate Cells; Human Umbilical Vein Endothelial Cells; Humans; Interleukin-6; Liver Neoplasms; Neoplasm Invasiveness; Neovascularization, Pathologic; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Resveratrol; Stilbenes; Vascular Endothelial Growth Factor A; Zinc Finger Protein GLI1

2017
Resveratrol-loaded glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles: Preparation, characterization, and targeting effect on liver tumors.
    Journal of biomaterials applications, 2017, Volume: 32, Issue:2

    In this study, glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles were prepared to establish a tumor targeting nano-sized drug delivery system. Glycyrrhizic acid was coupled to human serum albumin, and resveratrol was encapsulated in glycyrrhizic acid-conjugated human serum albumin by high-pressure homogenization emulsification. The average particle size of sample nanoparticles prepared under the optimal conditions was 108.1 ± 5.3 nm with a polydispersity index (PDI) of 0.001, and the amount of glycyrrhizic acid coupled with human serum albumin was 112.56 µg/mg. The drug encapsulation efficiency and drug loading efficiency were 83.6 and 11.5%, respectively. The glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles were characterized through laser light scattering, scanning electron microscopy, Fourier-transform infrared spectroscopy, X-ray diffraction, differential scanning calorimetry, thermogravimetric analyses, and gas chromatography. The characterization results showed that resveratrol in glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles existed in amorphous state and the residual amounts of chloroform and methanol in nanoparticles were separately less than the international conference on harmonization (ICH) limit. The in vitro drug-release study showed that the nanoparticles released the drug slowly and continuously. The inhibitory rate of glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2 H-tetrazolium bromide method. The IC50 values of glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles and resveratrol were 62.5 and 95.5 µg/ml, respectively. The target ability of glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles for HepG2 cells was evaluated using fluorescence-modified albumin techniques. The uptake rate of glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles was higher than that of pure resveratrol and increased with increased nanoparticles concentration. The in vivo body distribution of glycyrrhizic acid-conjugated human serum albumin nanoparticles wrapping resveratrol nanoparticles labeled with the near-infrared fluorophore Cy5 was monitored in H22 tumor-bearing mi

    Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Survival; Delayed-Action Preparations; Drug Delivery Systems; Glycyrrhizic Acid; Hep G2 Cells; Humans; Liver; Liver Neoplasms; Male; Mice; Nanoparticles; Resveratrol; Serum Albumin, Human; Stilbenes

2017
Endocytic pathways of optimized resveratrol cubosomes capturing into human hepatoma cells.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2017, Volume: 93

    Resveratrol (RSV) is a natural polyphenolic compound with high affinity to hepatocytes. It has numerous benefits as anticancer, antioxidant, immunomodulatory and cardioprotective actions. Nevertheless, RSV therapeutic applications are hindered by its low solubility, light sensitivity and extensive first-pass metabolism. Cubosomes are colloidally stable dispersed liquid crystalline nanoparticles. The incorporation of RSV into cubosomes could overcome some of its physicochemical limitations. A Design-Expert

    Topics: Carcinoma, Hepatocellular; Endocytosis; Hep G2 Cells; Humans; Liquid Crystals; Liver Neoplasms; Nanoparticles; Particle Size; Resveratrol; Solubility; Stilbenes

2017
A comparative assessment of antiproliferative properties of resveratrol and ethanol leaf extract of Anogeissus leiocarpus (DC) Guill and Perr against HepG2 hepatocarcinoma cells.
    BMC complementary and alternative medicine, 2017, Aug-02, Volume: 17, Issue:1

    Epidemiological and experimental evidences have shown cancer as a leading cause of death worldwide. Although the folklore use of plants as a reliable source of health-restoring principles is well-documented, the search for more of such plants that are active against diseases, such as cancer, continues. We report here a laboratory-based evidence of the relevance of an ethanol leaf extract of Anogeissus leiocarpus (A2L) in comparison with resveratrol, a natural polyphenol, in cancer therapy.. The quantitative assessment of flavonoid and phenolic contents involved quercetin and gallic acid as standards, respectively were determined using spectrophotometry. Cytotoxicity was determined fluorometrically using propidium-iodide-staining method. Antioxidant status, adenosine triphosphate (ATP) levels, caspase activities and mitochondrial integrity were assessed using fluorometry/luminometry.. The antioxidant assay demonstrated that A2L possesses a strong antioxidant capacity as compared with the reference compounds, ascorbic acid and butylated hydroxytoluene. This is further buttressed by the significantly high level of phenolics obtained in the quantitative assessment of the extract. A 72-h post-treatment examination indicated that both A2L and resveratrol modulate the proliferation of HepG2 liver carcinoma cells in a time- and concentration-dependent manner. Determination of the total nuclei area, propidium-iodide negative and positive nuclei areas all further buttress the modulation of cell proliferation by A2L and resveratrol with the indication that the observed cell death is due to apoptosis and necrosis at lower and higher concentrations of treatments respectively. At lower concentrations (0.39-3.13 μg/mL), resveratrol possesses higher tendencies to activate caspases 3 and 7. Bioenergetically, both resveratrol and A2L do not adversely affect the cells at lower concentrations (0.39-6.25 μg/mL for resveratrol and 12.5-100.0 μg/mL for A2L) except at higher concentrations (12.5-25.0 μg/mL for resveratrol and 200-800 μg/mL for A2L) which are more pronounced in A2L-treated cells. Furthermore, the antioxidant status of HepG2 cells is not perturbed by resveratrol as compared with A2L. Assessment of 24-h post-treatment mitochondrial function shows that resveratrol is not mitotoxic as compared with A2L which exhibits mitotoxicity at its highest concentration.. Taken together, findings from this study showed that A2L possesses strong antiproliferative activity and its prospect in the management of hepatocellular carcinoma deserves further investigation.

    Topics: Adenosine Triphosphate; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; Carcinoma, Hepatocellular; Caspases; Cell Proliferation; Combretaceae; Flavonoids; Hep G2 Cells; Humans; Liver Neoplasms; Mitochondria; Necrosis; Phenols; Phytotherapy; Plant Extracts; Plant Leaves; Resveratrol; Stilbenes

2017
The novel resveratrol derivative 3,5-diethoxy-3',4'-dihydroxy-trans-stilbene induces mitochondrial ROS-mediated ER stress and cell death in human hepatoma cells in vitro.
    Acta pharmacologica Sinica, 2017, Volume: 38, Issue:11

    Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Hepatocellular; Dose-Response Relationship, Drug; Endoplasmic Reticulum Stress; Hep G2 Cells; Humans; Inhibitory Concentration 50; Liver Neoplasms; Membrane Potential, Mitochondrial; Mitochondria; Oxidative Stress; Reactive Oxygen Species; Stilbenes; Time Factors

2017
Vascular disrupting agent in pancreatic and hepatic tumour allografts: observations of location-dependent efficacy by MRI, microangiography and histomorphology.
    British journal of cancer, 2017, Nov-07, Volume: 117, Issue:10

    Tumours growing in organs of different vascular environment could exhibit diverse responses to vascular disrupting agent (VDA). This study was aimed to identify in vivo imaging biomarkers for evaluation of pancreatic and hepatic tumours and comparison of their responses to a VDA Combretastatin A4 Phosphate (CA4P) using multiparametric MRI.. Male WAG/Rij rats were used for orthotopic pancreatic head tumour and hepatic tumour implantation; tumour growth was monitored by 3D isotropic MRI using a 3.0-T clinic scanner. Therapeutic intervention using CA4P was investigated by in vivo quantitative MRI measurements including T2/T1 relaxation mapping, diffusion kurtosis imaging and dynamic contrast-enhancement (DCE) imaging. Animals were scarified 10 h after CA4P treatment for ex vivo validation using microangiography and histomorphology.. State-of-the-art clinical MRI protocols were successfully adapted for imaging small animal tumour with high reliability. One hour after CA4P injection, marked vascular shutdown was detected with DCE MRI in both pancreatic and hepatic tumours. However, 10 h later, therapeutic necrosis was limited in pancreatic tumours compared with that in hepatic tumours (P<0.01). Heterogeneous therapeutic changes were depicted in tumour lesions using pixel-wise Tofts model, which was generated from dynamic T1 mapping. In addition, tumour responses including haemorrhage, oedema and necrosis were detected using quantitative T2/T1 relaxation maps and diffusion kurtosis images, and were validated using histomorphology.. Using multiparametric imaging biomarkers, hepatic tumours were found to be significantly more responsive to CA4P than pancreatic tumours, which could be of reference for designing future clinical trials on this agent.

    Topics: Allografts; Angiography; Animals; Antineoplastic Agents, Phytogenic; Image Processing, Computer-Assisted; Liver Neoplasms; Magnetic Resonance Imaging; Neovascularization, Pathologic; Pancreatic Neoplasms; Rats; Stilbenes

2017
Resveratrol enhances anticancer effects of paclitaxel in HepG2 human liver cancer cells.
    BMC complementary and alternative medicine, 2017, Oct-04, Volume: 17, Issue:1

    The aim of this in vitro study was to measure the enhanced anticancer effects of Res (resveratrol) on PA (paclitaxel) in HepG2 human liver cancer cells.. The MTT (thiazolyl blue tetrazolium bromide, 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide), flow cytometry, qPCR (real-time quantitative polymerase chain reaction) and western blot assay were used for cells growth inhibitory effects, cells apoptosis (DNA content of sub-G1), mRNA and protein expressions, respectively.. The 10 μg/mL of Res had no growth inhibitory effect on Nthy-ori 3-1 normal cells or HepG2 cancer cells meanwhile the 5 or 10 μg/mL of PA also had no growth inhibitory effect on Nthy-ori 3-1 normal cells. Where as PA-L (5 μg/mL) and PA-H (10 μg/mL) had the growth inhibitory effects in HepG2 cancer cells, and Res increase these growth inhibitory effects. By flow cytometry experiment, after Res (5 μg/mL) + PA-H (10 μg/mL) treatment, the HepG2 cells showed the most apoptosis in cells as compared to other treatments groups, and after additionally treated with Res, both the apoptosis cells of two concentrations PA were raised. As PA raised it also raised the mRNA and protein expressions of caspase-3, caspase-8, caspase-9, Bax (Bcl-2 assaciated X protein), p53, p21, IκB-α (inhibitor of NF-κB alpha), Fas (factor associated suicide), FasL (factor associated suicide ligand), TIMP-1 (tissue inhibitor of metalloproteinases 1), TIMP-2 (tissue inhibitor of metalloproteinases 2) and decrease Bcl-2 (B cell leukemia 2), Bcl-xL (B cell leukemia extra large), HIAP-1 (cIAP-1, cellular inhibitor of apoptosis 1), HIAP-2 (cIAP-2, cellular inhibitor of apoptosis 2), NF-κB (nuclear factor kappa B), COX-2 (cyclooxygenase 2), iNOS (inducible nitric oxide synthase), MMP-2 (metalloproteinase 2), MMP-9 (metalloproteinase 9), EGF (epidermal growth factor), EGFR (epidermal growth factor receptor), VEGF (vascular endothelial growth factor), Fit-1 (VEGFR-1, vascular endothelial growth factor receptor 1). Meanwhile, the 5 μg/mL of Res could enhance these mRNA expressions changes as compared to the control cells.. From these results, we can conclude that Res could raise the anticancer effects of PA in HepG2 cells, Res could be used as a good sensitizing agent for PA.

    Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Drug Synergism; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Liver Neoplasms; Paclitaxel; Resveratrol; RNA, Messenger; Stilbenes

2017
Resveratrol inhibits proliferation and migration through SIRT1 mediated post‑translational modification of PI3K/AKT signaling in hepatocellular carcinoma cells.
    Molecular medicine reports, 2017, Volume: 16, Issue:6

    Resveratrol (RES), a polyphenolic compound present in grapes and red wine, has potential anticancer properties. The present study aimed to examine the effects of resveratrol and its underlying mechanism on hepatocellular carcinoma (HCC) cell lines HepG2, Bel‑7402 and SMMC‑7721. It was demonstrated that resveratrol inhibited the viability and proliferation of HCC cells assessed by MTT and EdU assays. TUNEL assay revealed that resveratrol induced cell apoptosis by increasing HCC apoptosis rate from 3±0.78% to 16±1.12% with upregulation of B‑cell lymphoma (Bcl)‑2 associated X, apoptosis regulator and cleaved‑poly (ADP‑Ribose) polymerase 1 (PARP), and downregulation of Bcl‑2, caspase‑3, caspase‑7 and PARP. As a sirtuin (SIRT) 1 activator, resveratrol elevated SIRT1 protein expression and its enzyme activity and decreased expression levels of phosphorylated (p)‑phosphoinositide‑3‑kinase (PI3K), p‑AKT Serine/Threonine Kinase 1 (AKT), and its downstream target p‑Forkhead Box O3a in HepG2 cells. Furthermore, inhibition of SIRT1 enzymatic activity by EX527 resulted in increased phosphorylation levels of PI3K and AKT. This demonstrated that resveratrol inhibited the PI3K/AKT pathway by SIRT1 activation. In addition to inhibition of cancer cell migration, tumor suppressor gene DLC1 Rho GTPase activating protein level was upregulated and its phosphorylation was enhanced by AKT with resveratrol treatment. These findings suggested that resveratrol inhibits proliferation and migration through SIRT1 mediated post‑translational modification of PI3K/AKT pathway in HCC cells.

    Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Humans; Liver Neoplasms; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Resveratrol; Signal Transduction; Stilbenes

2017
Identification of (Z)-2,3-Diphenylacrylonitrileas Anti-Cancer Molecule in Persian Gulf Sea Cucumber Holothuria parva.
    Marine drugs, 2017, Oct-16, Volume: 15, Issue:10

    Hepatocellular carcinoma (HCC), also named cancerous hepatoma, is the most common type of malignant neoplasia of the liver. In this research, we screened the Persian Gulf sea cucumber

    Topics: 2-Acetylaminofluorene; Acrylonitrile; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Chromatography, Thin Layer; Cytochromes c; Diethylnitrosamine; Holothuria; Humans; Indian Ocean; Liver; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Membrane Potential, Mitochondrial; Mitochondria, Liver; Rats; Rats, Wistar; Reactive Oxygen Species; Stilbenes

2017
Resveratrol suppresses human hepatocellular carcinoma via targeting HGF-c-Met signaling pathway.
    Oncology reports, 2017, Volume: 37, Issue:2

    Resveratrol, one of the major polyphenols found in red wine, is suggested to have a role as a chemo-prevention or chemotherapy agent in various human cancer models. Herein, we report that resveratrol has a profound antitumor effect on human hepatocellular carcinoma (HCC) cells by down-regulation of the HGF-c-Met signaling pathway. Resveratrol inhibited anchorage-dependent and -independent growth of HCC cells in a dose-dependent manner. Short-term resveratrol exposure substantially decreased HGF-induced c-Met signaling pathway activation, and long-term exposure to resveratrol markedly inhibited c-Met expression on the cell membrane. Additionally, resveratrol suppressed HGF-induced cell invasion, and knockdown of c-Met decreased the sensitivity of HCC cells to resveratrol treatment. Finally, the antitumor activity of resveratrol was validated in xenograft model and resveratrol prominently restrained tumor growth in vivo. In summary, our results suggested that c-Met offers a candidate molecular target for hepatocellular carcinoma management.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Gene Knockdown Techniques; Hepatocyte Growth Factor; Humans; Liver Neoplasms; Mice, Nude; Molecular Targeted Therapy; Phosphorylation; Proto-Oncogene Proteins c-met; Resveratrol; Signal Transduction; Stilbenes; Xenograft Model Antitumor Assays

2017
Vincristine and ɛ-viniferine-loaded PLGA-b-PEG nanoparticles: pharmaceutical characteristics, cellular uptake and cytotoxicity.
    Journal of microencapsulation, 2017, Volume: 34, Issue:1

    The objective of this study was to prepare the ɛ-viniferine and vincristine-loaded PLGA-b-PEG nanoparticle and to investigate advantages of these formulations on the cytotoxicity of HepG2 cells. Prepared nanoparticle has shown a homogeneous distribution with 113 ± 0.43 nm particle size and 0.323 ± 0.01 polydispersity index. Zeta potential was determined as -35.03 ± 1.0 mV. The drug-loading percentages were 6.01 ± 0.23 and 2.01 ± 0.07 for ɛ-viniferine and vincristine, respectively. The cellular uptake efficiency of coumarin-6-loaded nanoparticles was increased up to 87.8% after 4 h. Nanoparticles loaded with high concentrations of both drugs showed a cytotoxic effect on HepG2 cells, having the percentage of cell viability of between 43.23% and 47.37%. Unfortunately, the percentage of apoptotic cells after treated with drugs-loaded nanaoparticles (10.93%) was similar to free forms of drugs (12.1%) that might be due to low ɛ-viniferine release in biological pH at 24 h.

    Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Benzofurans; Drug Carriers; Hep G2 Cells; Humans; Liver; Liver Neoplasms; Nanoparticles; Polyethylene Glycols; Polyglactin 910; Stilbenes; Vincristine

2017
Stepwise pH-responsive nanoparticles containing charge-reversible pullulan-based shells and poly(β-amino ester)/poly(lactic-co-glycolic acid) cores as carriers of anticancer drugs for combination therapy on hepatocellular carcinoma.
    Journal of controlled release : official journal of the Controlled Release Society, 2016, Mar-28, Volume: 226

    Stepwise pH-responsive nanoparticle system containing charge reversible pullulan-based (CAPL) shell and poly(β-amino ester) (PBAE)/poly(lactic-co-glycolic acid) (PLAG) core is designed to be used as carriers of paclitaxel (PTX) and combretastatin A4 (CA4) for combining antiangiogenesis and chemotherapy to treat hepatocellular carcinoma (HCC). CAPL-coated PBAE/PLGA (CAPL/PBAE/PLGA) nanoparticles displayed step-by-step responses to weakly acidic tumor microenvironment (pH ≈6.5) and endo/lysosome (pH ≈5.5) respectively through the cleavage of β-carboxylic amide bond in CAPL and the "proton-sponge" effect of PBAE, thus realized the efficient and orderly releases of CA4 and PTX. In human HCC HepG2 cells and human umbilical vein endothelial cells, CAPL/PBAE/PLGA nanoparticles significantly enhanced synergistic effects of PTX and CA4 on cell proliferation and cell migration. In HepG2 tumor-bearing mice, CAPL/PBAE/PLGA nanoparticles showed excellent tumor-targeting capability and remarkably increased inhibitory effects of PTX and CA4 on tumor growth and angiogenesis. In conclusion, this novel nanoparticle system is a promising candidate as carrier for drugs against HCC.

    Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Proliferation; Delayed-Action Preparations; Glucans; Hep G2 Cells; Human Umbilical Vein Endothelial Cells; Humans; Hydrogen-Ion Concentration; Lactic Acid; Liver; Liver Neoplasms; Mice; Mice, Nude; Nanoparticles; Paclitaxel; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Stilbenes

2016
CA-1H, a novel oxazole bearing analogue of combretastatin A-4, disrupts the tumor vasculatures and inhibits the tumor growth via inhibiting tubulin polymerization.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2016, Volume: 80

    Vascular disrupting agents destroy established tumor vasculatures selectively, and have achieved encouraging antitumor activity in both pre-clinical and clinical trials. In the present study, we reported the vascular disruption and antitumor effects of CA-1H and its prodrug CA-1HP, oxazole bearing analogues of combretastatin A-4 (CA4). CA-1H was a tighter binder of tubulin than CA4 with the same binding site to chochcine and CA4, and inhibited tubulin polymerization both in cell free system and in human umbilical vein endothelial cells (HUVECs). Furthermore, CA-1H significantly disrupted the microtubulin skeleton in proliferating HUVECs rather than the quiescent ones, damaged the HUVECs-preformed tubes markedly, and lead to necrosis in tumor tissues in NCI-H1975 xenograft mice. Continuous administration for 19 days, CA-1HP could inhibit the NCI-H1975 xenograft tumor growth significantly without obvious weight loss and normal tissue damage, in addition, CA-1HP also inhibited the tumor growth in H22 hepatocellular carcinoma bearing mice; and combination CA-1HP with cisplatin showed more potent antitumor activity than used alone. Taken together, our present investigation suggested that CA-1H was a potential vascular disrupting agent for further development of antitumor drugs.

    Topics: Animals; Binding Sites; Cell Line, Tumor; Cell Proliferation; Cell Shape; Cytoskeleton; Human Umbilical Vein Endothelial Cells; Humans; Liver Neoplasms; Mice, Inbred BALB C; Mice, Nude; Molecular Docking Simulation; Necrosis; Neovascularization, Pathologic; Neovascularization, Physiologic; Oxazoles; Polymerization; Stilbenes; Tubulin; Xenograft Model Antitumor Assays

2016
(Z)-3,5,4'-Trimethoxystilbene Limits Hepatitis C and Cancer Pathophysiology by Blocking Microtubule Dynamics and Cell-Cycle Progression.
    Cancer research, 2016, 08-15, Volume: 76, Issue:16

    Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Chronic hepatitis C virus (HCV) infection causes induction of several tumors/cancer stem cell (CSC) markers and is known to be a major risk factor for development of HCC. Therefore, drugs that simultaneously target viral replication and CSC properties are needed for a risk-free treatment of advanced stage liver diseases, including HCC. Here, we demonstrated that (Z)-3,5,4'-trimethoxystilbene (Z-TMS) exhibits potent antitumor and anti-HCV activities without exhibiting cytotoxicity to human hepatocytes in vitro or in mice livers. Diethylnitrosamine (DEN)/carbon tetrachloride (CCl4) extensively induced expression of DCLK1 (a CSC marker) in the livers of C57BL/6 mice following hepatic injury. Z-TMS exhibited hepatoprotective effects against DEN/CCl4-induced injury by reducing DCLK1 expression and improving histologic outcomes. The drug caused bundling of DCLK1 with microtubules and blocked cell-cycle progression at G2-M phase in hepatoma cells via downregulation of CDK1, induction of p21(cip1/waf1) expression, and inhibition of Akt (Ser(473)) phosphorylation. Z-TMS also inhibited proliferation of erlotinib-resistant lung adenocarcinoma cells (H1975) bearing the T790M EGFR mutation, most likely by promoting autophagy and nuclear fragmentation. In conclusion, Z-TMS appears to be a unique therapeutic agent targeting HCV and concurrently eliminating cells with neoplastic potential during chronic liver diseases, including HCC. It may also be a valuable drug for targeting drug-resistant carcinomas and cancers of the lungs, pancreas, colon, and intestine, in which DCLK1 is involved in tumorigenesis. Cancer Res; 76(16); 4887-96. ©2016 AACR.

    Topics: Animals; Antineoplastic Agents; Antiviral Agents; Blotting, Western; Carcinoma, Hepatocellular; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Flow Cytometry; Hepatitis C, Chronic; Humans; Liver Neoplasms; Mice; Mice, Inbred C57BL; Microtubules; Neoplastic Stem Cells; Stilbenes; Xenograft Model Antitumor Assays

2016
Hepatocellular Carcinoma: Intra-arterial Delivery of Doxorubicin-loaded Hollow Gold Nanospheres for Photothermal Ablation-Chemoembolization Therapy in Rats.
    Radiology, 2016, Volume: 281, Issue:2

    Purpose To determine if combretastatin A-4 phosphate disodium (CA4P) can enhance the tumor uptake of doxorubicin (Dox)-loaded, polyethylene glycol (PEG)-coated hollow gold nanospheres (HAuNS) mixed with ethiodized oil for improved photothermal ablation (PTA)-chemoembolization therapy (CET) of hepatocellular carcinoma (HCC) in rats. Materials and Methods Animal experiments were approved by the institutional animal care and use committee and performed from February 2014 to April 2015. Male Sprague-Dawley rats (n = 45; age, 12 weeks) were inoculated with N1S1 HCC cells in the liver, and 8 days later, were randomly divided into two groups of 10 rats. Group 1 rats received intrahepatic arterial injection of PEG-HAuNS and ethiodized oil alone; group 2 received pretreatment with CA4P and injection of PEG-HAuNS and ethiodized oil 5 minutes later. The gold content of tumor and liver tissue at 1 hour or 24 hours after injection was quantified by using neutron activation analysis (n = 5 per time point). Five rats received pretreatment CA4P, PEG-copper 64-HAuNS, and ethiodized oil and underwent micro-positron emission tomography (PET)/computed tomography (CT). In a separate study, three groups of six rats with HCC were injected with saline solution (control group); CA4P, Dox-loaded PEG-coated HAuNS (Dox@PEG-HAuNS), and ethiodized oil (CET group); or CA4P, Dox@PEG-HAuNS, ethiodized oil, and near-infrared irradiation (PTA-CET group). Temperature was recorded during laser irradiation. Findings were verified at postmortem histopathologic and/or autoradiographic examination. Wilcoxon rank-sum test and Pearson correlation analyses were performed. Results PEG-HAuNS uptake in CA4P-pretreated HCC tumors was significantly higher than that in non-CA4P-pretreated tumors at both 1 hour (P < .03) and 24 hours (P < .01). Mean ± standard deviation of tumor-to-liver PEG-HAuNS uptake ratios at 1 hour and 24 hours, respectively, were 5.63 ± 3.09 and 1.68 ± 0.77 in the CA4P-treated group and 1.29 ± 2.40 and 0.14 ± 0.11 in the non-CA4P-treated group. Micro-PET/CT allowed clear delineation of tumors, enabling quantitative imaging analysis. Laser irradiation increased temperature to 60°C and 43°C in the tumor and adjacent liver, respectively. Mean HCC tumor volumes 10 days after therapy were 1.68 cm

    Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Chemoembolization, Therapeutic; Disease Models, Animal; Doxorubicin; Drug Carriers; Ethiodized Oil; Gold; Hyperthermia, Induced; Liver Neoplasms; Male; Nanospheres; Polyethylene Glycols; Positron Emission Tomography Computed Tomography; Random Allocation; Rats; Rats, Sprague-Dawley; Stilbenes

2016
Combretastatin A-1 phosphate, a microtubule inhibitor, acts on both hepatocellular carcinoma cells and tumor-associated macrophages by inhibiting the Wnt/β-catenin pathway.
    Cancer letters, 2016, 09-28, Volume: 380, Issue:1

    Combretastatin A-1 phosphate (CA1P) is a microtubule polymerization inhibitor that binds to the colchicine-binding site of tubulin. We demonstrated that CA1P has outstanding anti-cancer activity against hepatocellular carcinoma (HCC) in vitro and in vivo. As determined by fluorescence staining and western blots (WBs), CA1P induced reactive oxygen species (ROS) accumulation and apoptosis in HepG2 cells with a down-regulation of Mcl-1. Additional studies indicated that CA1P induced microtubule depolymerization-mediated AKT inactivation, which resulted in GSK-3β activation, Wnt/β-Catenin pathway inhibition, and Mcl-1 down-regulation. The induction of HepG2 cell apoptosis by CA1P was prevented by a GSK-3β-specific inhibitor. Furthermore, immunohistochemistry studies on hepatocellular carcinoma mouse models showed that CA1P had activity against tumor-associated macrophages (TAMs). CA1P induced TAM apoptosis in vitro through the same mechanism observed with HepG2 cells, and it eliminated TAMs in the tumor microenvironment (TME) in vivo. In TME, the expression of TGF-β and TNF-α was also altered. The adoptive transfer of macrophages partly rescued the growth of tumor inhibited by CA1P. These findings indicate that CA1P has great potential to impact both cancer cells and the microenvironment, and our results should accelerate the application of CA1P for HCC therapy in clinic.

    Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Proliferation; Dose-Response Relationship, Drug; Glycogen Synthase Kinase 3 beta; Hep G2 Cells; Humans; Inhibitory Concentration 50; Liver Neoplasms; Macrophages; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Stilbenes; Transforming Growth Factor beta; Tubulin Modulators; Tumor Burden; Tumor Microenvironment; Tumor Necrosis Factor-alpha; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

2016
Vascular disruptive agent OXi4503 and anti-angiogenic agent Sunitinib combination treatment prolong survival of mice with CRC liver metastasis.
    BMC cancer, 2016, 07-26, Volume: 16

    Preclinical research indicate that vascular disrupting agent (VDA) treatment induces extensive tumor death but also a systemic mobilization of bone marrow derived cells including endothelial progenitor cells (EPC) leading to revascularization and renewed growth within the residual tumor. This study investigates if combination of VDA with the anti-angiogenic agent Sunitinib increases the treatment efficacy in a colorectal liver metastases mouse model.. CBA mice with established liver metastases were given a single dose of OXi4503 at day 16 post tumor induction, a daily dose of Sunitinib starting at day 14 or day 16 post tumor induction or a combination of Sunitinib given daily from day 14 or day 16 post tumor induction in combination with a single dose of OXi4503 at day 16. Treatment was terminated at day 21 post tumor induction and its effects were assessed using stereological and immunohistochemical techniques. Long term effects were assessed in a survival study.. Combination with long (7 day) Sunitinib treatment lead to liver toxicity but this was ameliorated in the shorter (5 day) treatment without significantly altering the effects on tumor reduction. Combination treatment resulted in significant reduction of viable tumor, reduction in tumor vasculature, reduction in tumor proliferation, increase in tumor apoptosis and prolonged mouse survival compared to control and single arm treatments. Complete tumor eradication was not achieved. Redistribution of E-cadherin and strong up regulation of ZEB1 and Vimentin were observed in the surviving tumor; indicative of epithelial to mesenchymal transition (EMT), a mechanism that could contribute to tumor resistance.. Combination treatment significantly reduces viable tumor and prolongs animal survival. EMT in the surviving tumor may prevent total tumor eradication and could provide novel targets for a more lasting treatment.

    Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cadherins; Chemical and Drug Induced Liver Injury; Colorectal Neoplasms; Diphosphates; Epithelial-Mesenchymal Transition; Humans; Indoles; Liver Neoplasms; Male; Mice; Mice, Inbred CBA; Protein Kinase Inhibitors; Pyrroles; Stilbenes; Sunitinib; Vimentin; Xenograft Model Antitumor Assays; Zinc Finger E-box-Binding Homeobox 1

2016
Pterostilbene inhibits hepatocellular carcinoma through p53/SOD2/ROS-mediated mitochondrial apoptosis.
    Oncology reports, 2016, Volume: 36, Issue:6

    Hepatocellular carcinoma (HCC) is one of the most common malignancies and the second cause of cancer-related deaths around the world. Pterostilbene (PTE), is a natural analog of resveratrol, possessing diverse pharmacological activities. In the present study, we aimed to examine the effect of PTE on tumor growth in mouse models of HCC and to elucidate the possible molecular mechanism in vivo and in vitro. We showed that PTE dose-dependently suppressed tumor growth in mice induced by diethylnitrosamine plus carbon tetrachloride, as evidenced by a decrease in the number of tumors and in the maximum size of the tumors. PTE concentration-dependently inhibited cell viability and proliferation in HepG2 cells. PTE increased caspase-3 activities and apoptosis in liver tumor tissues and cells, indicating the activation of the mitochondrial apoptotic pathway. PFTα, superoxide dismutase 2 (SOD2) lentivirus and N-acetylcysteine (NAC) significantly inhibited PTE-induced inhibition of tumor growth and cell proliferation and increase in apoptosis. PTE dose-dependently increased reactive oxygen species (ROS) levels both in liver tumor tissues and cells, which were inhibited by PFTα, SOD2 lentivirus and NAC. PTE resulted in a significant decrease in SOD2 expression in liver tumor tissues and cells, which were inhibited by PFTα, but not NAC, indicating that PTE-induced ROS generation was attributed to p53-mediated downregulation of SOD2. Collectively, PTE increased p53 expression, decreased SOD2 expression, and resulted in an increase in the ROS levels and the activation of the mitochondrial apoptotic pathway, leading to inhibition of tumor growth and cell proliferation. These data demonstrated that the p53/SOD2/ROS pathway is critical for PTE-mediated inhibition of tumor growth and HCC cell proliferation.

    Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Hep G2 Cells; Humans; Liver Neoplasms; Mice, Inbred C57BL; Mitochondria; Reactive Oxygen Species; Stilbenes; Superoxide Dismutase; Tumor Burden; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

2016
Trapping effect on a small molecular drug with vascular-disrupting agent CA4P in rodent H22 hepatic tumor model: in vivo magnetic resonance imaging and postmortem inductively coupled plasma atomic emission spectroscopy.
    Journal of drug targeting, 2015, Volume: 23, Issue:5

    The aim of the present study is to verify the trapping effect of combretastatin A-4-phosphate (CA4P) on small molecular drugs in rodent tumors. Mice with H22 hepatocarcinoma were randomized into groups A and B. Magnetic resonance imaging (MRI) of T1WI, T2WI, and DWI was performed as baseline. Mice in group A were injected with Gd-DTPA and PBS. Mice in group B were injected with Gd-DTPA and CA4P. All mice undergo CE-T1WI at 0 h, 3 h, 6 h, 12 h, and 24 h. Enhancing efficacy of the two groups on CE-T1WI was compared with the signal-to-noise ratio (SNR) calculated. Concentrations of gadolinium measured by ICP-AES in the tumor were compared between groups. On the early CE-T1WI, tumors were equally enhanced in both groups. On the delayed CE-T1WI, the enhancing effect of group A was weaker than that of group B. The SNR and the concentration of gadolinium within the tumor of group A were lower than that of group B at 6 h, 12 h, and 24 h after administration. This study indicates that CA4P could improve the retention of Gd-DTPA in the tumor and MRI allowed dynamically monitoring trapping effects of CA4P on local retention of Gd-DTPA as a small molecular drug.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Contrast Media; Disease Models, Animal; Gadolinium DTPA; Liver Neoplasms; Magnetic Resonance Imaging; Male; Mice; Spectrophotometry, Atomic; Stilbenes; Time Factors; Tissue Distribution

2015
By reducing hexokinase 2, resveratrol induces apoptosis in HCC cells addicted to aerobic glycolysis and inhibits tumor growth in mice.
    Oncotarget, 2015, May-30, Volume: 6, Issue:15

    Cancer cells exhibit an altered metabolic phenotype known as the aerobic glycolysis. The expression of HK2 changes the metabolic phenotype of cells to support cancerous growth. In the present study, we investigated the inhibitory effect of resveratrol on HK2 expression and hepatocellular carcinoma (HCC) cell glycolysis. Aerobic glycolysis was observed in four HCC cell lines compared to the normal hepatic cells. Resveratrol sensitized aerobic glycolytic HCC cells to apoptosis, and this effect was attenuated by glycolytic inhibitors. The induction of mitochondrial apoptosis was associated with the decrease of HK2 expression by resveratrol in HCC cells. In addition, resveratrol enhanced sorafenib induced cell growth inhibition in aerobic glycolytic HCC cells. Combination treatment with both reagents inhibited the growth and promoted apoptosis of HCC-bearing mice. The reduction of HK2 by resveratrol provides a new dimension to clinical HCC therapies aimed at preventing disease progression.

    Topics: Aerobiosis; Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Growth Processes; Cell Line, Tumor; Glycolysis; Hep G2 Cells; Hexokinase; Humans; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Random Allocation; Resveratrol; Stilbenes

2015
Permethylated Anigopreissin A inhibits human hepatoma cell proliferation by mitochondria-induced apoptosis.
    Chemico-biological interactions, 2015, Jul-25, Volume: 237

    Anigopreissin A belongs to stilbene di- and oligomeric forms containing a benzofuran ring system whose biological activity is unknown. Recently, a completely protected Anigopreissin A - Permethylated Anigopreissin A - has been synthesized. We use MTT bioassay to assess Permethylated Anigopreissin A cytotoxicity in different human cell lines. Furthermore, fluorescence microscopy, caspase activity, real-time PCR and Western-blot methods are employed to evaluate apoptotic cell death pathway in liver cancer cells. Permethylated Anigopreissin A kills different types of human cancer cells but does not affect non-tumorigenic cells. The Permethylated Anigopreissin A concentration that causes 50% inhibition of liver tumor cells is 0.24μM. Hepatoma cells treated with Permethylated Anigopreissin A arrest their cell cycle in G1 phase. We also demonstrate that Permethylated Anigopreissin A-triggered cell death occurs by apoptosis. Decrease of the BCL2 expression levels, loss of the mitochondrial membrane potential, release of cytochrome c and increase of caspase 9 activity highlight a key role for mitochondria in Permethylated Anigopreissin A-induced apoptosis. Our study shows that Permethylated Anigopreissin A kills liver cancer cells through intrinsic apoptotic pathway.

    Topics: Apoptosis; Benzofurans; Blotting, Western; Carcinoma, Hepatocellular; Cell Cycle; Cell Proliferation; Hep G2 Cells; Humans; Liver Neoplasms; Membrane Potential, Mitochondrial; Methylation; Real-Time Polymerase Chain Reaction; Stilbenes

2015
Texture analysis of (125)I-A5B7 anti-CEA antibody SPECT differentiates metastatic colorectal cancer model phenotypes and anti-vascular therapy response.
    British journal of cancer, 2015, Jun-09, Volume: 112, Issue:12

    We aimed to test the ability of texture analysis to differentiate the spatial heterogeneity of (125)I-A5B7 anti-carcinoembryonic antigen antibody distribution by nano-single photon emission computed tomography (SPECT) in well-differentiated (SW1222) and poorly differentiated (LS174T) hepatic metastatic colorectal cancer models before and after combretastatin A1 di-phosphate anti-vascular therapy.. Nano-SPECT imaging was performed following tail vein injection of 20 MBq (125)I-A5B7 in control CD1 nude mice (LS174T, n=3 and SW1222, n=4), and CA1P-treated mice (LS174T, n=3; SW1222, n=4) with liver metastases. Grey-level co-occurrence matrix textural features (uniformity, homogeneity, entropy and contrast) were calculated in up to three liver metastases in 14 mice from control and treatment groups.. Before treatment, the LS174T metastases (n=7) were more heterogeneous than SW1222 metastases (n=12) (uniformity, P=0.028; homogeneity, P=0.01; contrast, P=0.045). Following CA1P, LS174T metastases (n=8) showed less heterogeneity than untreated LS174T controls (uniformity, P=0.021; entropy, P=0.006). Combretastatin A1 di-phosphate-treated SW1222 metastases (n=11) showed no difference in texture features compared with controls (all P>0.05).. Supporting the potential for novel imaging biomarkers, texture analysis of (125)I-A5B7 SPECT shows differences in spatial heterogeneity of antibody distribution between well-differentiated (SW1222) and poorly differentiated (LS174T) liver metastases before treatment. Following anti-vascular treatment, LS174T metastases, but not SW1222 metastases, were less heterogeneous.

    Topics: Angiogenesis Inhibitors; Animals; Antibodies, Monoclonal; Carcinoembryonic Antigen; Cell Line, Tumor; Colorectal Neoplasms; Diphosphates; Female; Heterografts; Humans; Iodine Radioisotopes; Liver Neoplasms; Mice; Mice, Nude; Neoplasm Metastasis; Phenotype; Radiopharmaceuticals; Stilbenes; Tomography, Emission-Computed, Single-Photon

2015
Structural modification of resveratrol leads to increased anti-tumor activity, but causes profound changes in the mode of action.
    Toxicology and applied pharmacology, 2015, Aug-15, Volume: 287, Issue:1

    (Z)-3,5,4'-Trimethoxystilbene (Z-TMS) is a resveratrol analog with increased antiproliferative activity towards a number of cancer cell lines compared to resveratrol, which has been shown to inhibit tubulin polymerization in vitro. The purpose of this study was to investigate if Z-TMS still shows potential for the prevention of metabolic diseases as known for resveratrol. Cell growth inhibition was determined with IC50 values for Z-TMS between 0.115μM and 0.473μM (resveratrol: 110.7μM to 190.2μM). Flow cytometric analysis revealed a G2/M arrest after Z-TMS treatment, whereas resveratrol caused S phase arrest. Furthermore, Z-TMS was shown to impair microtubule polymerization. Beneficial effects on lipid accumulation were observed for resveratrol, but not for Z-TMS in an in vitro steatosis model. (E)-Resveratrol was confirmed to elevate cAMP levels, and knockdown of AMPK attenuated the antiproliferative activity, while Z-TMS did not show significant effects in these experiments. SIRT1 and AMPK activities were further measured indirectly via induction of the target gene small heterodimer partner (SHP). Thereby, (E)-resveratrol, but not Z-TMS, showed potent induction of SHP mRNA levels in an AMPK- and SIRT1-dependent manner, as confirmed by knockdown experiments. We provide evidence that Z-TMS does not show beneficial metabolic effects, probably due to loss of activity towards resveratrol target genes. Moreover, our data support previous findings that Z-TMS acts as an inhibitor of tubulin polymerization. These findings confirm that the methylation of resveratrol leads to profound changes in the mode of action, which should be taken into consideration when conducting lead structure optimization approaches.

    Topics: AMP-Activated Protein Kinases; Antineoplastic Agents; Caco-2 Cells; Cell Cycle Checkpoints; Cell Proliferation; Colonic Neoplasms; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Hep G2 Cells; HT29 Cells; Humans; Liver Neoplasms; Microtubules; Molecular Structure; Resveratrol; RNA Interference; Sirtuin 1; Stilbenes; Structure-Activity Relationship; Transfection; Tubulin Modulators

2015
In Vitro Safety/Protection Assessment of Resveratrol and Pterostilbene in a Human Hepatoma Cell Line (HepG2).
    Natural product communications, 2015, Volume: 10, Issue:8

    The aim of this work was to evaluate in vitro the genotoxic and/or antigenotoxic effects of resveratrol (RESV) and pterostilbene (PTER) on HepG2 cells. Moreover, additional tests were performed to evaluate early and late apoptosis events induced by the tested stilbenes. RESV and PTER did not show any genotoxic activity. As regards antigenotoxicity testing, RESV and PTER showed a typical, U-shaped hormetic dose-response relationship characterized by a biphasic trend with small quantities having opposite effects to large ones. HepG2 cells treated with PTER exhibited a marked increase in early apoptosis (40.1%) at 250 microM; whereas, the highest concentration tested for both RESV and PTER significantly increased the proportion of HepG2 cells undergoing late apoptosis (32.5 and 51.2%, respectively). The observed pro-apoptotic activity could, at least in part, explain the hormetic response observed when the compounds were tested for antigenotoxicity (i.e., in the presence of induced DNA damage).

    Topics: Apoptosis; Carcinoma, Hepatocellular; DNA Damage; Hep G2 Cells; Humans; Liver Neoplasms; Protective Agents; Resveratrol; Stilbenes

2015
Towards novel anti-tumor strategies for hepatic cancer: ɛ-viniferin in combination with vincristine displays pharmacodynamic synergy at lower doses in HepG2 cells.
    Omics : a journal of integrative biology, 2014, Volume: 18, Issue:5

    Hepatocellular carcinoma is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. The efficacy of novel combination treatments are increasingly evaluated with use of integrative biology research and development (R&D) strategies and methodological triangulation. We investigated the anti-tumor effect of ɛ-viniferin alone, and the putative synergy of ɛ-viniferin with vincristine on the growth of HepG2 cells in vitro. Growth inhibition and apoptosis induction were determined by MTT assay and annexin V/propidium iodide (PI), respectively. Morphological changes and DNA fragmentation were investigated under electron microscopy and by agarose gel electrophoresis, respectively. The results collectively showed that treating cells with ɛ-viniferin and vincristine significantly inhibited cell viability at lower doses as compared to each agent applied alone. IC(50) values for ɛ-viniferin and vincristine were determined as 98.3 and 52.5 μM at 24 h, respectively. IC(50) value of ɛ-viniferin in combination with vincristine was 15.8+11.25 μM (mean/SD) at 24 h. The viability of cells treated with 17.9 μM vincristine alone for 24 h was 79.62%; it reduced to 26.53% when 25 μM ɛ-viniferin was added in combination with vincristine (p<0.05). We found that combination of drugs promoted the sensitivity of cells against to vincristine treatment. The effect of combined use was in support of a synergistic pharmacodynamic effect. Moreover, low doses of the combination regimen induced phosphatidyl re-localization, morphological changes, and DNA fragmentation, and therefore caused apoptotic death. This study thus suggests that low concentrations of ɛ-viniferin and vincristine can enhance the anti-tumor effects efficiently by inducing HepG2 cell apoptosis. Further studies in other model systems are warranted with a view to potential future applications in the clinic of such combination regimens and their putative mechanism of action in the observed synergy reported here.

    Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Benzofurans; Carcinoma, Hepatocellular; Cell Shape; Cell Survival; DNA Fragmentation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug Synergism; Hep G2 Cells; Humans; Inhibitory Concentration 50; Liver Neoplasms; Stilbenes; Vincristine

2014
Resveratrol-4-O-D-(2'-galloyl)-glucopyranoside isolated from Polygonum cuspidatum exhibits anti-hepatocellular carcinoma viability by inducing apoptosis via the JNK and ERK pathway.
    Molecules (Basel, Switzerland), 2014, Jan-27, Volume: 19, Issue:2

    Resveratrol-4-O-D-(2'-galloyl)-glucopyranoside (RESG) is one of the active compounds isolated from Polygonum cuspidatum. The purpose of our present study was to investigate the anti-hepatocellular carcinoma effect of RESG in vitro and in vivo, and the possible mechanisms in vitro. In vitro, our results showed that RESG could significantly inhibit the human hepatocellular carcinoma viability in the MTT assay, in a dose- and time-dependent manner. Furthermore, our results demonstrated that RESG could induce SMMC-7721 cell apoptosis and activate caspases 3 and caspases 9 by using Annexin V-FITC staining and western blot, respectively. In vivo, RESG also showed efficacy in SMMC-7721 xenograft model in nude mice, and further molecule mechanisms were investigated in vitro. The results showed that RESG up-regulated the p-JNK expressions, whereas it down-regulated the p-ERK expressions. Above results demonstrated that RESG is a potential therapeutic agent for hepatocellular carcinoma via JNK and ERK pathway to induce apoptosis. Our finding provided a basis for further development of RESG as an anticancer agent.

    Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cell Survival; Fallopia japonica; Glucuronides; Humans; Liver Neoplasms; MAP Kinase Signaling System; Membrane Potential, Mitochondrial; Mice; Plant Extracts; Stilbenes; Xenograft Model Antitumor Assays

2014
3,4,5,4'-trans-tetramethoxystilbene (DMU-212) modulates the activation of NF-κB, AP-1, and STAT3 transcription factors in rat liver carcinogenesis induced by initiation-promotion regimen.
    Molecular and cellular biochemistry, 2014, Volume: 391, Issue:1-2

    It has been reported that methylated analog of resveratrol, 3,4,5,4'-trans-tetramethoxystilbene (DMU-212), demonstrates strong antiproliferative, and proapoptotic activity. The aim of this study was to evaluate the effect of DMU-212 on the activation of nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and signal transducer and activator of transcription 3 (STAT3) transcription factors, using a two-stage model of rat hepatocarcinogenesis (HCC) in Wistar rats. Initiation was performed by a single intraperitoneal injection of N-nitrosodiethylamine (NDEA) (200 mg/kg) followed by promotion with phenobarbital (PB) (0.05%) in drinking water. DMU-212 was administered by gavage in a dose of 20 or 50 mg/kg b.w. two times a week for 16 weeks. There was a significant increase in the activation of all investigated hepatic transcription factors in the NDEA/PB-induced rats. The activation of NF-κB induced by NDEA/PB treatment was suppressed by DMU-212 as evidenced by a reduction of p65 and p50 subunits translocation, DNA binding capacity, increased retention of IκB, and the reduced IKK activity. Moreover, DMU-212 reduced the level of iNOS protein induced by NDEA/PB. Treatment with DMU-212 alone increased the constitutive AP-1 subunits c-Jun and c-Fos levels and c-Jun binding to TRE consensus site. The combined treatment diminished c-Fos level and DNA binding. At a dose of 50 mg/kg, DMU-212 decreased also the STAT3 activation induced by NDEA/PB. These data indicate that DMU-212 may suppress pro-inflammatory transcription factors, particularly NF-κB, and in consequence iNOS expression in rat model of HCC which makes DMU-212 a good candidate for the development of HCC chemopreventive agent.

    Topics: Animals; Carcinogenesis; Cyclooxygenase 2; I-kappa B Proteins; Liver; Liver Neoplasms; Male; NF-kappa B; Nitric Oxide Synthase Type II; Rats, Wistar; STAT3 Transcription Factor; Stilbenes; Transcription Factor AP-1

2014
COH-203, a novel microtubule inhibitor, exhibits potent anti-tumor activity via p53-dependent senescence in hepatocellular carcinoma.
    Biochemical and biophysical research communications, 2014, Dec-12, Volume: 455, Issue:3-4

    5-(3-Hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-3H-1,2-dithiol-3-one (COH-203) is a novel synthesized analogue of combretastatin A-4 that can be classified as a microtubule inhibitor. In this study, we evaluated the anti-hepatoma effect of COH-203 in vitro and in vivo and explored the underlying molecular mechanisms. COH-203 was shown to be more effective in inhibiting the proliferation of liver cancer cells compared with normal liver cells. COH-203 also displayed potent anti-tumor activity in a hepatocellular carcinoma xenograft model without significant toxicity. Mechanistic studies demonstrated that treatment with COH-203 induced mitotic arrest by inhibiting tubulin polymerization in BEL-7402 liver cancer cells. Long-term COH-203 treatment in BEL-7402 cells led to mitotic slippage followed by senescence via the p14(Arf)-p53-p21 and p16(INK4α)-Rb pathways. Furthermore, suppression of p53 via pifithrin-α (p53 inhibitor) and p53-siRNA attenuated COH-203-induced senescence in BEL-7402 cells, suggesting that COH-203 induced senescence p53-dependently. In conclusion, we report for the first time that COH-203, one compound in the combretastatin family, promotes anti-proliferative activity through the induction of p-53 dependent senescence. Our findings will provide a molecular rationale for the development of COH-203 as a promising anti-tumor agent.

    Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cellular Senescence; Heterocyclic Compounds, 1-Ring; Humans; Liver; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Microtubules; RNA, Small Interfering; Stilbenes; Tubulin; Tubulin Modulators; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

2014
The antimetastatic effects of resveratrol on hepatocellular carcinoma through the downregulation of a metastasis-associated protease by SP-1 modulation.
    PloS one, 2013, Volume: 8, Issue:2

    The mortality and morbidity rates from cancer metastasis have not declined in Taiwan, especially because of hepatocellular carcinoma (HCC). Resveratrol has been shown to have benefits such as cardioprotection, providing antioxidative, anti-inflammatory, anti-cancer properties in previous studies. Therefore, HCC cells were subjected to treatment with resveratrol and then analyzed to determine the effects of resveratrol on the migration and invasion.. Modified Boyden chamber assays revealed that resveratrol treatment significantly inhibited cell migration and invasion capacities of Huh7 cell lines that have low cytotoxicity in vitro, even at a high concentration of 100 µM. The results of casein zymography and western blotting revealed that the activities and protein levels of the urokinase-type plasminogen activator (u-PA) were inhibited by resveratrol. Western blot analysis also showed that resveratrol inhibits phosphorylation of JNK1/2. Tests of the mRNA level, real-time PCR, and promoter assays evaluated the inhibitory effects of resveratrol on u-PA expression in HCC cells. The chromatin immunoprecipitation (ChIP) assay showed that reactive in transcription protein of nuclear factor SP-1 was inhibited by resveratrol.. Resveratrol inhibits u-PA expression and the metastasis of HCC cells and is a powerful chemopreventive agent. The inhibitory effects were associated with the downregulation of the transcription factors of SP-1 signaling pathways.

    Topics: Anticarcinogenic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Neoplasm Invasiveness; Phosphorylation; Resveratrol; Signal Transduction; Sp1 Transcription Factor; Stilbenes; Urokinase-Type Plasminogen Activator

2013
Long-term ethanol exposure-induced hepatocellular carcinoma cell migration and invasion through lysyl oxidase activation are attenuated by combined treatment with pterostilbene and curcumin analogues.
    Journal of agricultural and food chemistry, 2013, May-08, Volume: 61, Issue:18

    Ethanol consumption induces hepatocellular carcinoma (HCC) cell metastasis by changing the extracellular matrix (ECM). Lysyl oxidase (LOX) catalyzes the cross-linkage of collagen or elastin in the ECM. LOX protein and mRNA overexpression (>21-fold compared with controls, n = 6) was detected in cirrhotic HCC patients with a history of alcoholism. LOX protein expression was induced in HCC cells after long-term treatment with ethanol (10 mM) for 20-40 passages (denoted E20-E40 cells). Pterostilbene (PSB, 1 μM) displayed significant potency to reduce LOX-mediated activity in E40 cells when combined with curcumin and its analogues. The ability of E40 cells to form colonies in soft agar was reduced by both genetic depletion of LOX and by chemical inhibitors of LOX expression. This study suggests that targeting LOX expression with food components such as PSB and curcumin may be a novel strategy to overcome ethanol-induced HCC cell metastasis in liver cancer patients.

    Topics: Adult; Aged; Alcoholism; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Collagen; Curcumin; Elastin; Ethanol; Extracellular Matrix; Female; Gene Expression Regulation; Humans; Laser Capture Microdissection; Liver Neoplasms; Male; Middle Aged; Protein-Lysine 6-Oxidase; Real-Time Polymerase Chain Reaction; RNA, Messenger; Stilbenes

2013
Trans-resveratrol loaded chitosan nanoparticles modified with biotin and avidin to target hepatic carcinoma.
    International journal of pharmaceutics, 2013, Aug-16, Volume: 452, Issue:1-2

    Conventional liver targeted system focuses on delivering drugs to liver, bringing toxicity on hepatic normal tissues. The purpose of this study is to construct a new system capable of specially targeting to hepatic carcinoma instead of the whole liver. Based on the fact that nanoparticles (NPs) bound with either biotin or avidin tend to accumulate in tumors and avidin-attached reagents were quickly eliminated from blood circulation and assembled in liver, trans-resveratrol loaded chitosan nanoparticles (CS-NPs), CS-NPs with the surface modified either by biotin (B-CS-NPs) or by both biotin and avidin (A-B-CS-NPs) were prepared and their physiochemical properties were investigated. The in vitro release profiles of the three NPs all conformed to bioexponential equation. Pharmacokinetic experiment indicated that A-B-CS-NPs rapidly assembled in liver after injection, with the highest liver targeting index of 2.70, while the modification of biotin attenuated the liver targeting ability of NPs. Inhibitory study on HepG2 cells declared that compared to trans-resveratrol solution and CS-NPs, both B-CS-NPs and A-B-CS-NPs significantly improved the anticancer activity. When incubated with HepG2 cells at high concentration for longer time, A-B-CS-NPs exhibited superior cytotoxicity than B-CS-NPs. This study exclaims that A-B-CS-NPs may be a potent drug delivery vector specially targeting to hepatic carcinoma.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Avidin; Biotin; Cell Survival; Chitosan; Drug Delivery Systems; Female; Hep G2 Cells; Humans; Liver; Liver Neoplasms; Male; Mice; Nanoparticles; Resveratrol; Stilbenes

2013
pH-sensitive pullulan-based nanoparticle carrier of methotrexate and combretastatin A4 for the combination therapy against hepatocellular carcinoma.
    Biomaterials, 2013, Volume: 34, Issue:29

    This study designs a pH-sensitive nanoparticle carrier of methotrexate (MTX) and combretastatin A4 (CA4) based on pullulan for the combination therapy against hepatocellular carcinoma (HCC). Briefly, N-urocanyl pullulan (URPA) with the degree of substitution (DS) of 5.2% was synthesized and then conjugated with MTX to form MTX-URPA, in which MTX content was 17.8%. MTX-URPA nanoparticles prepared by the dialysis method had spherical shape and the mean size of 187.1 nm, and showed high affinity for HepG2 cells. CA4 was successfully loaded into MTX-URPA nanoparticles and exhibited pH-sensitive in vitro release property. After intravenous injection to PLC/PRF/5-bearing nude mice, CA4 loaded MTX-URPA (CA4/MTX-URPA) nanoparticles achieved the enhanced antitumor and anti-angiogenic effects, the prolonged circulation time in blood, and the increased distributions both in the liver and the tumor. In conclusion, this drug carrier system has significant liver-targeting property and exhibits advantages for the combination therapy against hepatocellular carcinoma.

    Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Delayed-Action Preparations; Glucans; Hep G2 Cells; Humans; Hydrogen-Ion Concentration; Liver; Liver Neoplasms; Methotrexate; Mice; Mice, Inbred BALB C; Mice, Nude; Models, Molecular; Nanoparticles; Stilbenes

2013
Methionine adenosyltransferase 2B, HuR, and sirtuin 1 protein cross-talk impacts on the effect of resveratrol on apoptosis and growth in liver cancer cells.
    The Journal of biological chemistry, 2013, Aug-09, Volume: 288, Issue:32

    Resveratrol is growth-suppressive and pro-apoptotic in liver cancer cells. Methionine adenosyltransferase 2B (MAT2B) encodes for two dominant variants V1 and V2 that positively regulate growth, and V1 is anti-apoptotic when overexpressed. Interestingly, crystal structure analysis of MAT2B protein (MATβ) protomer revealed two resveratrol binding pockets, which raises the question of the role of MAT2B in resveratrol biological activities. We found that resveratrol induced the expression of MAT2BV1 and V2 in a time- and dose-dependent manner by increasing transcription, mRNA, and protein stabilization. Following resveratrol treatment, HuR expression increased first, followed by SIRT1 and MAT2B. SIRT1 induction contributes to increased MAT2B transcription whereas HuR induction increased MAT2B mRNA stability. MATβ interacts with HuR and SIRT1, and resveratrol treatment enhanced these interactions while reducing the interaction between MATβ and MATα2. Because MATβ lowers the Ki of MATα2 for S-adenosylmethionine (AdoMet), this allowed steady-state AdoMet level to rise. Interaction among MATβ, SIRT1, and HuR increased stability of these proteins. Induction of MAT2B is a compensatory response to resveratrol as knocking down MAT2BV1 potentiated the resveratrol pro-apoptotic and growth-suppressive effects, whereas the opposite occurred with V1 overexpression. The same effect on growth occurred with MAT2BV2. In conclusion, resveratrol induces HuR, SIRT1, and MAT2B expression; the last may represent a compensatory response against apoptosis and growth inhibition. However, MATβ induction also facilitates SIRT1 activation, as the interaction stabilizes SIRT1. This complex interplay among MATβ, HuR, and SIRT1 has not been previously reported and suggests that these proteins may regulate each other's signaling.

    Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Proliferation; ELAV Proteins; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Hep G2 Cells; Humans; Liver Neoplasms; Methionine Adenosyltransferase; Neoplasm Proteins; Resveratrol; RNA Stability; RNA, Messenger; RNA, Neoplasm; Sirtuin 1; Stilbenes

2013
Resveratrol as a pan-HDAC inhibitor alters the acetylation status of histone [corrected] proteins in human-derived hepatoblastoma cells.
    PloS one, 2013, Volume: 8, Issue:8

    The polyphenolic alcohol resveratrol has demonstrated promising activities for the prevention and treatment of cancer. Different modes of action have been described for resveratrol including the activation of sirtuins, which represent the class III histone deacetylases (HDACs). However, little is known about the activity of resveratrol on the classical HDACs of class I, II and IV, although these classes are involved in cancer development or progression and inhibitors of HDACs (HDACi) are currently under investigation as promising novel anticancer drugs. We could show by in silico docking studies that resveratrol has the chemical structure to inhibit the activity of different human HDAC enzymes. In vitro analyses of overall HDAC inhibition and a detailed HDAC profiling showed that resveratrol inhibited all eleven human HDACs of class I, II and IV in a dose-dependent manner. Transferring this molecular mechanism into cancer therapy strategies, resveratrol treatment was analyzed on solid tumor cell lines. Despite the fact that hepatocellular carcinoma (HCC) is known to be particularly resistant against conventional chemotherapeutics, treatment of HCC with established HDACi already has shown promising results. Testing of resveratrol on hepatoma cell lines HepG2, Hep3B and HuH7 revealed a dose-dependent antiproliferative effect on all cell lines. Interestingly, only for HepG2 cells a specific inhibition of HDACs and in turn a histone hyperacetylation caused by resveratrol was detected. Additional testing of human blood samples demonstrated a HDACi activity by resveratrol ex vivo. Concluding toxicity studies showed that primary human hepatocytes tolerated resveratrol, whereas in vivo chicken embryotoxicity assays demonstrated severe toxicity at high concentrations. Taken together, this novel pan-HDACi activity opens up a new perspective of resveratrol for cancer therapy alone or in combination with other chemotherapeutics. Moreover, resveratrol may serve as a lead structure for chemical optimization of bioavailability, pharmacology or HDAC inhibition.

    Topics: Acetylation; Animals; Cell Death; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chick Embryo; Computer Simulation; Hepatoblastoma; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Liver Neoplasms; Molecular Docking Simulation; Resveratrol; Stilbenes

2013
Synergistic anti-proliferative effect of resveratrol and etoposide on human hepatocellular and colon cancer cell lines.
    European journal of pharmacology, 2013, Oct-15, Volume: 718, Issue:1-3

    Resveratrol is an active component of grape, which has been shown to inhibit proliferation of a wide variety of tumor cells. The ability of resveratrol to enhance anti-proliferative effects of etoposide in wild type p53 liver carcinoma (HepG2) and colon cancer (HCT-116) cells was investigated with focusing on p53 activation. HepG2 cells and HCT-116 cells were treated with resveratrol and/or etoposide in a time- and dose-dependent manner and their proliferative response was evaluated by XTT assay. The expression of p53 protein was assessed using Western blot. Resveratrol exerted anti-proliferative activity on both cell types in a dose (25-100 μM)- and time (24-72 h)-dependent manner. Interestingly in HepG2 cells, resveratrol exhibited the same levels of cytotoxicity as etoposide (10 μM) when the cells treated with ≥ 25 μM for 48-72 h. In contrast to HepG2, resveratrol significantly enhanced anti-proliferative effects of etoposide in HCT-116 cells. P53 expression was up-regulated by resveratrol and etoposide and pre-incubation of both cells with resveratrol increased levels of etoposide-induced p53 expression. In line with cytotoxicity effect, combination therapy showed stronger activation of p53 in HCT-116 compared to HepG2. It seems that resveratrol exerts differential synergistic effect with etoposide on proliferation of cancer cells from different origin which is mainly accompanied by p53 activation. Our data represent a future strategy to provide much safer and more effective treatment for colon cancer.

    Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Drug Synergism; Etoposide; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Resveratrol; Stilbenes; Tumor Suppressor Protein p53

2013
Resveratrol suppresses the STAT3 signaling pathway and inhibits proliferation of high glucose-exposed HepG2 cells partly through SIRT1.
    Oncology reports, 2013, Volume: 30, Issue:6

    Hepatocellular carcinoma is the most common type of liver cancer. The risk of hepatocellular carcinoma for type 2 diabetic patients is greater than that for non-diabetic individuals although the mechanism is unclear. The cancer suppressor resveratrol inhibits cancer cell proliferation partly through the STAT3 signaling pathway. However, the effects of resveratrol on STAT3 in high glucose-exposed HepG2 cells and the role of SIRT1 are not clear to date. The aim of the present study was to investigate the effects of resveratrol on STAT3 and SIRT1 regarding the proliferation of high glucose-exposed HepG2 cells. HepG2 cells were cultured in DMEM containing glucose (2.8, 5.5 and 25 mM) and resveratrol (0, 10 and 100 µM). HepG2 cell proliferation and viability were analyzed by MTT assays. The levels of p-STAT3 and SIRT1 were analyzed by western blotting, and RT-PCR methods were used to detect the transcription levels of cyclin B1, cyclin D1, VEGF and MMP-9. SIRT1-specific short-interfering RNA was used to investigate the role of SIRT1 in p-STAT3 signaling. A high glucose concentration (25 mM) induced HepG2 cell proliferation. This effect was suppressed by resveratrol (100 µM), and the effect on the p-STAT3 signaling pathway was found to be SIRT1-dependent. Our findings may provide new insights into the mechanism by which resveratrol suppresses HepG2 cell proliferation under conditions of high glucose. Furthermore, this information may provide the basis for a novel therapeutic strategy for hepatocellular carcinoma patients suffering from either diabetes or hyperglycemia.

    Topics: Carcinoma, Hepatocellular; Cell Proliferation; Cell Survival; Diabetes Mellitus, Type 2; Gene Expression Regulation, Neoplastic; Glucose; Hep G2 Cells; Humans; Liver Neoplasms; Resveratrol; RNA, Small Interfering; Signal Transduction; Sirtuin 1; STAT3 Transcription Factor; Stilbenes

2013
Treatment with the vascular disruptive agent OXi4503 induces an immediate and widespread epithelial to mesenchymal transition in the surviving tumor.
    Cancer medicine, 2013, Volume: 2, Issue:5

    Epithelial to mesenchymal transition (EMT) is considered an important mechanism in tumor resistance to drug treatments; however, in vivo observation of this process has been limited. In this study we demonstrated an immediate and widespread EMT involving all surviving tumor cells following treatment of a mouse model of colorectal liver metastases with the vascular disruptive agent OXi4503. EMT was characterized by significant downregulation of E-cadherin, relocation and nuclear accumulation of β-catenin as well as significant upregulation of ZEB1 and vimentin. Concomitantly, significant temporal upregulation in hypoxia and the pro-angiogenic growth factors hypoxia-inducible factor 1-alpha, hepatocyte growth factor, vascular endothelial growth factor and transforming growth factor-beta were seen within the surviving tumor. The process of EMT was transient and by 5 days after treatment tumor cell reversion to epithelial morphology was evident. This reversal, termed mesenchymal to epithelial transition (MET) is a process implicated in the development of new metastases but has not been observed in vivo histologically. Similar EMT changes were observed in response to other antitumor treatments including chemotherapy, thermal ablation, and antiangiogenic treatments in our mouse colorectal metastasis model and in a murine orthotopic breast cancer model after OXi4503 treatment. These results suggest that EMT may be an early mechanism adopted by tumors in response to injury and hypoxic stress, such that inhibition of EMT in combination with other therapies could play a significant role in future cancer therapy.

    Topics: Angiogenic Proteins; Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Cadherins; Cell Hypoxia; Colorectal Neoplasms; Diphosphates; Down-Regulation; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred CBA; Neoplasm Proteins; Neoplasm Transplantation; Neoplasm, Residual; Stilbenes; Up-Regulation

2013
Riccardin D-26, a synthesized macrocyclic bisbibenzyl compound, inhibits human hepatocellular carcinoma growth through induction of apoptosis in p53-dependent way.
    Cancer letters, 2013, Jan-01, Volume: 328, Issue:1

    Riccardin D-26 is a synthesized macrocyclic bisbibenzyl compound. We investigated the effect of Riccardin D-26 on human hepatocellular carcinomas. Riccardin D-26 possessed stronger activity against SMMC-7721 cells than human normal liver cells. Riccardin D-26 injection effectively delayed the growth of SMMC-7721 xenografts in mice without significant toxicity. This effect of Riccardin D-26 was associated with the status of p53 and its targets, bax and p21(Waf1)(/)(Cip1). Riccardin D-26 activated p53 expression and induced cancer cells to apoptosis through the p53-mediated transcription-dependent and -independent pathway. Overall, Riccardin D-26 may inhibit hepatocellular carcinoma growth through induction of apoptosis in p53-dependent pathway.

    Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Female; Humans; Liver Neoplasms; Macrocyclic Compounds; Mice; Mice, Inbred BALB C; Phenyl Ethers; Stilbenes; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

2013
A resveratrol analog, phoyunbene B, induces G2/M cell cycle arrest and apoptosis in HepG2 liver cancer cells.
    Bioorganic & medicinal chemistry letters, 2012, Mar-01, Volume: 22, Issue:5

    Among the seven natural resveratrol analogs separated and identified from Pholidota yunnanensis R(OLFE), we found phoyunbene B (PYB, trans-3,4'-dihydroxy-2',3',5-trimethoxystilbene) was more effective in inhibiting the growth of HepG2 hepatocellular carcinoma cells than resveratrol. The inhibitory effect of PYB in HepG2 cells was due to its induction of G2/M cell cycle arrest and apoptosis. Induction of G2/M phase cell cycle arrest by PYB was associated with its up-regulation of Cyclin B1, while its induction of apoptosis was accompanied with its down-regulation of Bcl-2 and up-regulation of Bax. Our in vitro invasion/migration assays also showed that PYB could inhibit the invasion of hepatocellular carcinoma cells.

    Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Hepatocellular; G2 Phase Cell Cycle Checkpoints; Hep G2 Cells; Humans; Liver Neoplasms; M Phase Cell Cycle Checkpoints; Orchidaceae; Resveratrol; Stilbenes

2012
[Effects of resveratrol on apoptosis and ROS production in Hepa 1-6 hepatocarcinoma cells].
    Zhong yao cai = Zhongyaocai = Journal of Chinese medicinal materials, 2012, Volume: 35, Issue:3

    To observe the effects of resveratrol on apoptosis and ROS production in murine hepatocarcinoma Hepa 1-6 cells in vitro.. Hepa 1-6 cells were treated with different dose of resveratrol (20 micromol/L, 40 micromol/L, 80 micromol/L). Cell proliferation was detected with MTT assay at 24 h, 48 h and 72 h. Hoechst 33258 staining was used to visualize apoptotic morphology. Cell apoptosis was detected by flow cytometry analysis. Activated caspase-3 was detected by western blot. Intracellular ROS production was observed by 2',7'-dichlorofluorescin diacetate (DCF-DA) staining.. Compared with the control, upon treatment with 20-80 micromol/L resveratrol for 24 h, 48 h or 72 h, the proliferation of Hepa 1-6 cells was significantly inhibited in a time-dose dependent manner. 20-80 micromol/L resveratrol also induced apoptosis and apoptotic morphology change in Hepa 1-6 cells accompanied with caspase-3 activation and ROS generation.. Resveratrol could inhibit cell proliferation, induce apoptosis in murine hepatocarcinoma Hepa 1-6 cells, and the mechanism may associated with caspase-3 activation and ROS production.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Flow Cytometry; Liver Neoplasms; Mice; Plants, Medicinal; Reactive Oxygen Species; Resveratrol; Stilbenes

2012
SIRT1 sensitizes hepatocellular carcinoma cells expressing hepatitis B virus X protein to oxidative stress-induced apoptosis.
    Biochemical and biophysical research communications, 2012, Dec-07, Volume: 429, Issue:1-2

    We previously showed that SIRT1 deacetylase inhibits proliferation of hepatocellular carcinoma cells expressing hepatitis B virus (HBV) X protein (HBX), by destabilization of β-catenin. Here, we report another role for SIRT1 in HBX-mediated resistance to oxidative stress. Ectopic expression and enhanced activity of SIRT1 sensitize Hep3B cells stably expressing HBX to oxidative stress-induced apoptosis. SIRT1 mutant analysis showed that nuclear localization of SIRT1 is not required for sensitization of oxidation-mediated apoptosis. Furthermore, ectopic expression of SIRT1 and treatment with resveratrol (a SIRT1 activator) attenuated JNK phosphorylation, which is a prerequisite for resistance to oxidative stress-induced apoptosis. Conversely, suppression of SIRT1 activity with nicotinamide inhibited the effect of resveratrol on JNK phosphorylation, leading to restoration of resistance to oxidation-induced apoptosis. Taken together, these results suggest that up-regulation of SIRT1 under oxidative stress may be a therapeutic strategy for treatment of hepatocellular carcinoma cells related to HBV through inhibition of JNK activation.

    Topics: Antioxidants; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Nucleus; Humans; Liver Neoplasms; MAP Kinase Kinase 4; Oxidative Stress; Phosphorylation; Resveratrol; RNA, Small Interfering; Sirtuin 1; Stilbenes; Trans-Activators; Up-Regulation; Viral Regulatory and Accessory Proteins

2012
Spatial morphological and molecular differences within solid tumors may contribute to the failure of vascular disruptive agent treatments.
    BMC cancer, 2012, Nov-15, Volume: 12

    Treatment of solid tumors with vascular disrupting agent OXi4503 results in over 90% tumor destruction. However, a thin rim of viable cells persists in the tumor periphery following treatment, contributing to subsequent recurrence. This study investigates inherent differences in the microenvironment of the tumor periphery that contribute to treatment resistance.. Using a murine colorectal liver metastases model, spatial morphological and molecular differences within the periphery and the center of the tumor that may account for differences in resistance to OXi4503 treatment were investigated. H&E staining and immunostaining were used to examine vessel maturity and stability, hypoxia and HIF1α levels, accumulation of immune cells, expression of proangiogenic factors/receptors (VEGF, TGF-β, b-FGF, and AT1R) and expression of EMT markers (ZEB1, vimentin, E-cadherin and β-catenin) in the periphery and center of established tumors. The effects of OXi4503 on tumor vessels and cell kinetics were also investigated.. Significant differences were found between tumor periphery and central regions, including association of the periphery with mature vessels, higher accumulation of immune cells, increased growth factor expression, minimal levels of hypoxia and increased evidence of EMT. OXi4503 treatment resulted in collapse of vessels in the tumor center; however vasculature in the periphery remained patent. Similarly, tumor apoptosis and proliferation were differentially modulated between centre and periphery after treatment.. The molecular and morphological differences between tumor periphery and center may account for the observed differential resistance to OXi4503 treatment and could provide targets for drug development to totally eliminate metastases.

    Topics: Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Cadherins; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Diphosphates; Drug Resistance, Neoplasm; Fibroblast Growth Factors; Homeodomain Proteins; Hypoxia-Inducible Factor 1, alpha Subunit; Kruppel-Like Transcription Factors; Liver Neoplasms; Male; Mice; Mice, Inbred CBA; Stilbenes; Transforming Growth Factor beta; Tumor Microenvironment; Vascular Endothelial Growth Factor A; Vimentin; Zinc Finger E-box-Binding Homeobox 1

2012
Chemopreventive doses of resveratrol do not produce cardiotoxicity in a rodent model of hepatocellular carcinoma.
    Investigational new drugs, 2011, Volume: 29, Issue:2

    Hepatocellular carcinoma (HCC), one of the most lethal cancers, results in more than one million fatalities worldwide every year. In view of the limited therapeutic alternatives and poor prognosis of liver cancer, preventive control approaches, notably chemoprevention, have been considered to be the best strategy in lowering the present prevalence of the disease. Resveratrol, a naturally occurring antioxidant and antiinflammatory agent found in grapes and red wine, inhibits carcinogenesis with a pleiotropic mode of action. Recently, we have reported that dietary resveratrol significantly prevents chemically-induced liver tumorigenesis in rats. One of the mechanisms of resveratrol-mediated chemoprevention of hepatocarcinogenesis could be related to its antiinflammatory action through hepatic cyclooxygenase (COX-2) inhibition. Although several COX-2 inhibitors are known to exert chemopreventive efficacy, not all are considered ideal candidates for chemoprevention due to the risk of adverse cardiovascular events. Accordingly, the objective of the present study was to evaluate the role of resveratrol on cardiac performance during experimental hepatocarcinogenesis initiated with diethylnitrosamine and promoted by phenobarbital. Rats had free access to diet supplemented with resveratrol four weeks before the carcinogen injection and 14 weeks thereafter. The cardiotoxicity of resveratrol was assessed by monitoring the cardiac function using transthoracic echocardiography as well as Western blot analysis of cardiac tissue. Long-term dietary administration of resveratrol dose-dependently suppressed hepatic tumor multiplicity, the principal endpoint for evaluating the chemopreventive potential of a candidate agent. The chemopreventive effects of resveratrol were also reflected in histopathological assessment of hepatic tissues. Resveratrol did not exhibit any cardiotoxicity but rather improved the cardiac function in a dose-responsive fashion. Our results indicate that resveratrol-mediated chemoprevention of rat liver carcinogenesis is devoid of any adverse cardiovascular events. Resveratrol may be developed as a chemopreventive as well as therapeutic drug for human HCC.

    Topics: Animals; Behavior, Animal; Blotting, Western; Carcinoma, Hepatocellular; Cardiotoxins; Chemoprevention; Disease Models, Animal; Dose-Response Relationship, Drug; Echocardiography; Feeding Behavior; Female; Heart; Hepatocytes; Humans; Liver; Liver Neoplasms; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Systole

2011
Downregulation of cyclin D1 is associated with decreased levels of p38 MAP kinases, Akt/PKB and Pak1 during chemopreventive effects of resveratrol in liver cancer cells.
    Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie, 2011, Volume: 63, Issue:1-2

    Resveratrol is a naturally occurring phytoalexin with antioxidant activity. The chemopreventive effects of resveratrol against various types of cancer are well known, though the underlying molecular mechanisms of its action are still not identified. Hepatocellular carcinoma (HCC) is a one of the most lethal malignancies and there is no effective treatment till date. It is known that cyclin D1 is overexpressed in liver cancers. Accordingly we have studied the chemopreventive effects of resveratrol on cyclin D1 expression and the signaling pathways that regulate cyclin D1 in HepG2 cells. Flow cytometry and PCNA western blot data showed that resveratrol inhibits proliferation of HepG2 cells. Also, resveratrol treatment downregulated cyclin D1 as well as p38 MAP kinase, Akt and Pak1 expression and activity in HepG2 cells, suggesting that growth inhibitory activity of resveratrol is associated with the downregulation of cell proliferation and survival pathways. Furthermore, resveratrol treated cells showed increase in ERK activity suggesting possible sensitization to apoptosis. Thus in the present study, we report a three-dimensional relationship between the growth inhibitory effects of resveratrol - decrease in the levels of cyclin D1 - and downregulation of cell proliferation and survival pathways in HepG2 cells leading to cellular degenerative changes. These observations suggest that resveratrol has good potential as effective chemopreventive agent against liver cancer and warrant further studies.

    Topics: Anticarcinogenic Agents; Blotting, Western; Cell Proliferation; Cell Survival; Cyclin D1; Down-Regulation; Flow Cytometry; Hep G2 Cells; Humans; Liver; Liver Neoplasms; Microscopy, Confocal; p21-Activated Kinases; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-akt; Resveratrol; Signal Transduction; Stilbenes

2011
Identification of components of grape powder with anti-apoptotic effects.
    Toxicology and industrial health, 2011, Volume: 27, Issue:1

    This study is to investigate the mechanism underlying the anti-apoptotic effects of freeze-dried grape powder (FDGP) and identify the polyphenolic compounds involved. We examined apoptotic signaling pathways affected by FDGP and by its active components, including epicatechin, cyanidin, quercetin, and resveratrol, in human Huh7 hepatoma cells by assaying cell viability assays, the activities of caspase 3 and caspase 7, and the expression of endoplasmic reticulum stress-associated proteins. FDGP dramatically decreased taurodeoxycholic acid (TDCA)-induced production of reactive oxygen species (ROS). Assessment of individual active components revealed that at concentrations corresponding to 300 μg/mL FDGP, only quercetin demonstrated cytoprotective effects against mitochondrial-mediated apoptosis. In contrast, increased concentrations of other individual polyphenolic compounds were required to produce measurable cytoprotective effect. Only combinations of all four polyphenolic compounds (epicatechin, cyanidin, quercetin, and resveratrol) restored a degree of the anti-apoptotic effects seen with FDGP. The pretreatment of FDGP at 30 μg/mL concentration could reverse the thapsigargin-induced effects on the expression of endoplasmic reticulum stress-associated proteins. In conclusion, FDGP reduced oxidative stress, endoplasmic reticulum stress, and apoptosis. The mechanisms involved in the anti-apoptotic effects of FDGP included reduced generation of ROS, and reduced processing of certain caspases. We demonstrated that quercetin, epicatechin, and cyanidin are active compounds within FDGP that attenuate apoptosis. These findings contribute to our understanding of the molecular mechanisms of anti-apoptotic and anti-oxidant effects of grape and are expected to assist in developing clinical protocols to treat a variety of stress-mediated conditions.

    Topics: Anthocyanins; Apoptosis; Carcinoma, Hepatocellular; Caspase 3; Caspase 7; Catechin; Cell Death; Cell Line, Tumor; Cell Survival; Endoplasmic Reticulum; Food, Preserved; Freeze Drying; Fruit; Humans; Liver Neoplasms; Mitochondria, Liver; Oxidative Stress; Quercetin; Reactive Oxygen Species; Resveratrol; Stilbenes; Taurodeoxycholic Acid; Vitis

2011
Resveratrol, a phytoestrogen found in red wine, down-regulates protein S expression in HepG2 cells.
    Thrombosis research, 2011, Volume: 127, Issue:1

    INTRODUATION: Resveratrol, a phytoestrogen present at a high concentration in red wine, has been reported to possess many health benefit effects that are protective against age-related diseases. Protein S (PS), an important anticoagulant factor in the protein C (PC) anticoagulant pathway, is mainly synthesized by hepatocytes, and its plasma level is decreased in high-estrogen conditions such as pregnancy and oral contraceptive use. The aim of this study was to investigate whether resveratrol affects PS expression in HepG2 cells.. The secreted and intracellular levels of PS were determined by an enzyme-linked ligandsorbent assay and Western blotting. The mRNA expressions of PS, PC and β chain of C4b-binding protein (C4BP-β) were analyzed by reverse transcription-polymerase chain reaction. The PS gene promotor activities in HepG2 cells transiently expressing estrogen receptor (ER) α were examined by a luciferase reporter assay.. Resveratrol dose- and time-dependently down-regulated the PS expression in HepG2 cells at a transcriptional level, resulting in a significant decrease in secreted PS; however, the PC and C4BP-β mRNA expressions were not affected. This action of resveratrol was not mediated through either the ER signaling or those of mitogen-activated protein kinases and protein kinase C. Piceatannol, a hydroxylated metabolite of resveratrol, and genistein, an isoflavone found in soy products, also down-regulated the PS expression.. Resveratrol down-regulates the PS expression in HepG2 cells in an ER-independent manner, and the two phenolic hydroxyls at carbon-3 and -5 of resveratrol may be involved in this function.

    Topics: Blood Proteins; Blotting, Western; Carcinoma, Hepatocellular; Dose-Response Relationship, Drug; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Estrogen Receptor alpha; Gene Expression Regulation, Neoplastic; Genistein; Hep G2 Cells; Histocompatibility Antigens; Humans; Liver Neoplasms; Molecular Structure; Phytoestrogens; Promoter Regions, Genetic; Protein C; Protein S; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Structure-Activity Relationship; Time Factors; Transcription, Genetic; Transfection; Wine

2011
Nuclear factor E2-related factor 2-mediated induction of NAD(P)H:quinone oxidoreductase 1 by 3,5-dimethoxy-trans-stilbene.
    Journal of pharmacological sciences, 2011, Volume: 116, Issue:1

    NAD(P)H:quinone oxidoreductase 1 (NQO1), a phase II enzyme, plays an important role in the detoxification or chemoprotection of carcinogens, and induction of this enzyme is a target for the prevention of carcinogenesis. Natural stilbenoids have potential cancer chemopreventive activities, potentially through affecting NQO1 activity. Along this line, several stilbenoids were evaluated to procure more potent compounds for inducing NQO1 activity in cultured murine Hepa 1c1c7 cells. As a result, we found that 3,5-dimethoxy-trans-stilbene (DMS) possesses potent NQO1 induction activity through up-regulation of both protein and mRNA expression of NQO1 as determined by Western blot and reverse transcription-polymerase chain reaction analysis, respectively. DMS also increased protein expression of heme oxygenase-1 (HO-1), another phase II enzyme. This induction of NQO1 and HO-1 by DMS was closely related to the regulation of nuclear factor E2-related factor 2 (Nrf2). The translocation and activation of Nrf2 by DMS was also involved in the modulation of the upstream signal transduction molecule, protein kinase C δ. These findings suggest that DMS might have a cancer chemopreventive activity by inducing detoxifying enzymes such as NQO1 and HO-1.

    Topics: Animals; Anticarcinogenic Agents; Antioxidants; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Nucleus; DNA-Binding Proteins; Enzyme Induction; Genes, Reporter; Heme Oxygenase-1; Liver Neoplasms; Membrane Proteins; Mice; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Promoter Regions, Genetic; Protein Kinase C-delta; Protein Transport; Response Elements; RNA, Messenger; Signal Transduction; Stilbenes

2011
Resveratrol prevents inflammation-dependent hepatic melanoma metastasis by inhibiting the secretion and effects of interleukin-18.
    Journal of translational medicine, 2011, May-12, Volume: 9

    Implantation and growth of metastatic cancer cells at distant organs is promoted by inflammation-dependent mechanisms. A hepatic melanoma metastasis model where a majority of metastases are generated via interleukin-18-dependent mechanisms was used to test whether anti-inflammatory properties of resveratrol can interfere with mechanisms of metastasis.. Two experimental treatment schedules were used: 1) Mice received one daily oral dose of 1 mg/kg resveratrol after cancer cell injection and the metastasis number and volume were determined on day 12. 2) Mice received one daily oral dose of 1 mg/kg resveratrol along the 5 days prior to the injection of cancer cells and both interleukin-18 (IL-18) concentration in the hepatic blood and microvascular retention of luciferase-transfected B16M cells were determined on the 18th hour. In vitro, primary cultured hepatic sinusoidal endothelial cells were treated with B16M-conditioned medium to mimic their in vivo activation by tumor-derived factors and the effect of resveratrol on IL-18 secretion, on vascular cell adhesion molecule-1 (VCAM-1) expression and on tumor cell adhesion were studied. The effect of resveratrol on melanoma cell activation by IL-18 was also studied.. Resveratrol remarkably inhibited hepatic retention and metastatic growth of melanoma cells by 50% and 75%, respectively. The mechanism involved IL-18 blockade at three levels: First, resveratrol prevented IL-18 augmentation in the blood of melanoma cell-infiltrated livers. Second, resveratrol inhibited IL-18-dependent expression of VCAM-1 by tumor-activated hepatic sinusoidal endothelium, preventing melanoma cell adhesion to the microvasculature. Third, resveratrol inhibited adhesion- and proliferation-stimulating effects of IL-18 on metastatic melanoma cells through hydrogen peroxide-dependent nuclear factor-kappaB translocation blockade on these cells.. These results demonstrate multiple sites for therapeutic intervention using resveratrol within the prometastatic microenvironment generated by tumor-induced hepatic IL-18, and suggest a remarkable effect of resveratrol in the prevention of inflammation-dependent melanoma metastasis in the liver.

    Topics: Animals; Cell Adhesion; Cell Proliferation; Endothelium; Inflammation; Interleukin-18; Liver; Liver Neoplasms; Melanoma; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Microvessels; Models, Biological; Neoplasm Transplantation; Resveratrol; Stilbenes; Tumor Microenvironment; Vascular Cell Adhesion Molecule-1

2011
Resveratrol inhibits protein translation in hepatic cells.
    PloS one, 2011, Volume: 6, Issue:12

    Resveratrol is a plant-derived polyphenol that extends lifespan and healthspan in model organism. Despite extensive investigation, the biological processes mediating resveratrol's effects have yet to be elucidated. Because repression of translation shares many of resveratrol's beneficial effects, we hypothesized that resveratrol was a modulator of protein synthesis. We studied the effect of the drug on the H4-II-E rat hepatoma cell line. Initial studies showed that resveratrol inhibited global protein synthesis. Given the role of the mammalian Target of Rapamycin (mTOR) in regulating protein synthesis, we examined the effect of resveratrol on mTOR signaling. Resveratrol inhibited mTOR self-phosphorylation and the phosphorylation of mTOR targets S6K1 and eIF4E-BP1. It attenuated the formation of the translation initiation complex eIF4F and increased the phosphorylation of eIF2α. The latter event, also a mechanism for translation inhibition, was not recapitulated by mTOR inhibitors. The effects on mTOR signaling were independent of effects on AMP-activated kinase or AKT. We conclude that resveratrol is an inhibitor of global protein synthesis, and that this effect is mediated through modulation of mTOR-dependent and independent signaling.

    Topics: AMP-Activated Protein Kinases; Animals; Carcinoma, Hepatocellular; Cell Proliferation; Cell Survival; Enzyme Activation; Eukaryotic Initiation Factor-2; Eukaryotic Initiation Factor-4F; Liver; Liver Neoplasms; Phosphorylation; Protein Biosynthesis; Protein Kinase Inhibitors; Protein Stability; Proto-Oncogene Proteins c-akt; Rats; Resveratrol; Signal Transduction; Sirolimus; Stilbenes; TOR Serine-Threonine Kinases; Transcription Factors

2011
Evaluation of anti-invasion effect of resveratrol and related methoxy analogues on human hepatocarcinoma cells.
    Journal of agricultural and food chemistry, 2010, Mar-10, Volume: 58, Issue:5

    Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is also highly metastatic. Metastasis is considered to be the major cause of death in cancer patients. Resveratrol (3,5,4'-trihydroxystilbene) and related analogues have been reported as candidates to prevent cancer growth and invasion. The bioactivity of resveratrol-related analogues could be altered due to the presence and positioning of methoxy groups on the basic resveratrol chemical structure. This study investigated the effects and mechanism of action of resveratrol and its methoxy analogues on invasion of human hepatocarcinoma cells. The migratory and invasive abilities of phorbol 12-myristate 13-acetate (PMA)-treated HepG2 and PMA-untreated Hep3B cells were both reduced in a dose-dependent manner by treatment with resveratrol and 3,5,4'-trimethoxy-trans-stilbene (MR-3). Upon incubation of PMA-treated HepG2 cells with resveratrol (0-50 microM) or MR-3 (0-50 microM), the MMP-9 activity decreased but TIMP-1 protein increased in a dose-dependent manner. With resveratrol (0-50 microM) or MR-3 (0-1 microM) treatment on PMA-untreated Hep3B cells, both of the MMP-9 and MMP-2 activities decreased but TIMP-2 protein increased in a dose-dependent manner. These results suggest that resveratrol and its related methoxy analogue MR-3 might exert anti-invasive activity against hepatoma cells through regulation of MMP-2, MMP-9, TIMP-1, and TIMP-2. Further analysis with semiquantitative RT-PCR showed that the regulation of MMP-9 and TIMP-2 expressions by resveratrol and MR-3 in hepatoma cells may be on the transcriptional level but on the translational or post-translational level for TIMP-1.

    Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Humans; Liver Neoplasms; Neoplasm Invasiveness; Resveratrol; Stilbenes

2010
Suppression of the inflammatory cascade is implicated in resveratrol chemoprevention of experimental hepatocarcinogenesis.
    Pharmaceutical research, 2010, Volume: 27, Issue:6

    Resveratrol, present in grapes and red wine, has been found to prevent diethylnitrosamine (DENA)-initiated rat liver tumorigenesis, though the chemopreventive mechanisms are not completely elucidated. The current study was designed to explore whether the antiinflammatory properties of resveratrol play a role in its antihepatocarcinogenic action.. Liver samples were harvested from a 20-week chemopreventive study in which resveratrol (50, 100 and 300 mg/kg) was shown to inhibit DENA-induced hepatocyte nodules in Sprague-Dawley rats in a dose-responsive manner. Hepatic preneoplastic and inflammatory markers, namely heat shock protein (HSP70), cyclooxygenase-2 (COX-2) and nuclear factor-kappaB (NF-kappaB), were studied using immunohistochemical as well as Western blot techniques.. Resveratrol dose-dependently suppressed DENA-induced increased expressions of hepatic HSP70 and COX-2. Resveratrol also attenuated the DENA-mediated translocation of NF-kappaB p65 from the cytosol to the nucleus with stabilization of inhibitory kappaB.. The present findings indicate that resveratrol exerts chemoprevention of hepatocarcinogenesis possibly through antiinflammatory effects during DENA-evoked rat liver carcinogenesis by suppressing elevated levels of HSP70, COX-2 as well as NF-kappaB. These beneficial effects combined with an excellent safety profile encourage the development of resveratrol for chemoprevention and intervention of human HCC that remains a devastating disease.

    Topics: Animals; Anticarcinogenic Agents; Chemoprevention; Cyclooxygenase 2; Diethylnitrosamine; Female; HSP70 Heat-Shock Proteins; Humans; Inflammation; Liver; Liver Neoplasms; NF-kappa B; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

2010
A nanocapsular combinatorial sequential drug delivery system for antiangiogenesis and anticancer activities.
    Biomaterials, 2010, Volume: 31, Issue:27

    We reported a precise engineered nanocapsule encapsulating a neovasculature disruption agent, combretastatin A4 (CA4) in a matrix that was made up of paclitaxel (PTX) conjugated amphiphilic polyester. The nanocapsule was able to release CA4 and PTX sequentially for temporal antiangiogenesis and anticancer activities. The nanocapsule has a small particle size at 68 nm with narrow size distribution (approximately 0.15). Cellular uptake of the nanocapsule was efficient, and detectable at as early as 20 min, and drugs sequestered in the nanocapsule could exert effective therapeutic effects on tumor neovasculature and cancer cells, respectively. Biodistribution experiments demonstrated the long circulation of nanocapsule in body fluid and the preferential accumulation of nanocapsule in tumor. Both in vivo artificial pro-angiogenesis and tumor xenograft assays demonstrated the promising therapeutic effect of the nanocapsule on tumor vasculature disruption, tumor cell proliferation inhibition and tumor cell apoptosis induction. The intrasplenic liver metastasis experiment also confirmed the liver metastatic prevention capacity of this nanocapsule. In summary, the findings indicated that this dual drug loaded nanocapsule with sequential drug delivery capacity is a promising candidate in combinatorial therapy in fighting against cancer, and may open an avenue for cancer therapy and diagnosis.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line; Cell Line, Tumor; Cell Proliferation; Drug Delivery Systems; Endocytosis; Endothelial Cells; Humans; Immunohistochemistry; Liver Neoplasms; Male; Mice; Nanocapsules; Neoplasm Metastasis; Neovascularization, Pathologic; Paclitaxel; Stilbenes

2010
Long-term ethanol exposure causes human liver cancer cells to become resistant to mitomycin C treatment through the inactivation of bad-mediated apoptosis.
    Molecular carcinogenesis, 2010, Volume: 49, Issue:8

    The aim of this study was to test whether long-term ethanol consumption confers therapeutic resistance to human liver cancer patients infected with hepatitis B virus (HBV). Chronic ethanol-treated cells were established by consecutively culturing a human hepatocellular carcinoma cell line, Hep 3B, which contains integrated HBV sequences, for 20-40 passages with or without 10 mM ethanol (designated as E20-E40 and C20-C40, respectively). Flow cytometry analysis demonstrated that a growth promoting effect of long-term ethanol treatment was induced in the E40 cells through preferential acceleration of S-phase in these cells. Lower protein expression levels of p16, p21/Cip1, and p27/Kip1 were detected in the ethanol-treated E40 cells. We further demonstrated that long-term ethanol-treated E40 cells develop drug resistance in response to mitomycin C (MMC) treatment (>8 microM). Immunoblot analysis revealed that caspase-8-mediated mitochondrial apoptotic signals (such as Bad) were inactivated in the MMC-resistant E40 cells. Immunoprecipitation experiments demonstrated that the sequestration of phosphorylated Bad (Ser-112) through its binding with 14-3-3 was detected more profoundly in the MMC-resistant E40 cells. Next, we examined the therapeutic efficacy of MMC (10 mg MMC/kg body weight, three times per week) in severe combined immunodeficient (SCID) mice bearing E40- and C40-xenografted tumors. Significant reductions (>3-fold) in tumor growth were detected in MMC-treated C40-xenografted mice. In vivo and in vitro studies demonstrated that AKT- and extracellular signal-regulated kinase (ERK)-mediated survival factors inhibited the Bad-induced mitochondrial apoptotic signals that were involved in E40 tumor cells and that conferred resistance to MMC.

    Topics: Apoptosis; Caspase 8; Ethanol; Flow Cytometry; Humans; Liver Neoplasms; Mitochondria; Mitomycin; Stilbenes

2010
Resveratrol arrests cell cycle and induces apoptosis in human hepatocellular carcinoma Huh-7 cells.
    Journal of medicinal food, 2010, Volume: 13, Issue:6

    Resveratrol has been shown to possess anticancer, anti-aging, anti-inflammatory, antimicrobial, and neuroprotective activities. In this study, we examined the antiproliferative properties of resveratrol and its molecular mechanism(s) of action in Huh-7 cells, a new human hepatoma cell line system for hepatitis C virus. Results showed that resveratrol significantly inhibited Huh-7 cell proliferation (50% inhibitory concentration = 22.4 μg/mL) and effectively induced cell cycle arrest and apoptosis. It up-regulated p21/WAF1 expression in a p53-independent manner, but the expressions of cyclin E, cyclin A, and cyclin-dependent kinase 2 were down-regulated. It also caused an increase in the ratio of pro-apoptotic/anti-apoptotic protein, which was associated with the mitochondrial membrane depolarization and the increase in caspase activity. Resveratrol showed no effect on Fas, Fas ligand, extracellular signal regulated kinase (ERK) 1/2, and p38 expression but down-regulated phospho-ERK and phospho-p38 expression. In addition, resveratrol was noted to trigger autophagic cell death through the increased expression of autophagy-related Atg5, Atg7, Atg9, and Atg12 proteins. These results suggest that resveratrol could be an important chemoprevention agent for hepatoma of hepatitis C virus infection.

    Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Carcinoma, Hepatocellular; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Down-Regulation; Humans; Inhibitory Concentration 50; Liver Neoplasms; MAP Kinase Signaling System; Resveratrol; S Phase; Stilbenes; Time Factors; Up-Regulation

2010
Treatment of rodent liver tumor with combretastatin a4 phosphate: noninvasive therapeutic evaluation using multiparametric magnetic resonance imaging in correlation with microangiography and histology.
    Investigative radiology, 2009, Volume: 44, Issue:1

    To document tumoricidal events after intravenous administration of a vascular targeting agent combretastatin A-4-phosphate (CA4P) in rodent liver tumors by using multiparametric magnetic resonance imaging (MRI) in correlation with microangiography and histopathology.. Thirty rhabdomyosarcomas of 8 to 14 mm in diameter were obtained 16 days after implantation in liver lobes of 15 rats. Using a 1.5T magnet and a 4-channel wrist coil, T2-weighted imaging (T2WI), pre- and postcontrast T1-weighted imaging (T1WI), diffusion-weighted imaging (DWI), and dynamic susceptibility imaging (DSI) with relative blood volume (rBV) and flow (rBF) maps were acquired at baseline, 1 hour, 6 hours, and 48 hours after iv injection of CA4P at 10 mg/kg and vehicle in 9 treated and 6 control rats, respectively. In vivo data including signal intensity (SI), tumor volume, apparent diffusion coefficient (ADC), rBV, and rBF were correlated with ex vivo microangiographic and histopathologic findings.. CA4P-treated tumors (n = 18) grew slower than those (n = 12) of controls (P < 0.05), with vascular shutdown evident on CE-T1WI at 1 hour but more prominent at 6 hours. However, enhanced rim occurred in the periphery 48 hours after treatment, indicating neovascularization. ADC map enabled distinction between necrotic and viable tumors. DSI-derived tumoral rBV and rBF decreased significantly at 1 hour through 6 hours and partly recovered at 48 hours. SI-time curve reflected diverse therapeutic responses between tumor and liver. MRI findings were verified by ex vivo techniques.. Clinical MRI allowed monitoring of CA4P-related vascular shutdown, necrosis, and neovascularization of liver tumors in rats. Single dose of CA4P seemed insufficient for tumor eradication because of evident peripheral residue and recurrence.

    Topics: Algorithms; Angiography; Animals; Antineoplastic Agents, Phytogenic; Contrast Media; Image Enhancement; Image Interpretation, Computer-Assisted; Liver Neoplasms; Magnetic Resonance Angiography; Male; Neovascularization, Pathologic; Rats; Reproducibility of Results; Rhabdomyosarcoma; Sensitivity and Specificity; Statistics as Topic; Stilbenes; Treatment Outcome

2009
Caveolin-1 enhances resveratrol-mediated cytotoxicity and transport in a hepatocellular carcinoma model.
    Journal of translational medicine, 2009, Mar-25, Volume: 7

    Resveratrol (RES), an estrogen analog, is considered as a potential cancer chemo-preventive agent. However, it remains unclear how RES is transported into cells. In this study, we observed that Caveolin-1(CAV1) expression can increase the cytotoxic and pro-apoptotic activity of RES in a dose- and time-dependent manner both in vitro and in vivo in a Hepatocellular Carcinoma animal model.. High performance liquid chromatography (HPLC) demonstrated that RES intra-cellular concentration is increased about 2-fold in cells stably expressing CAV1 or CAVM1 (a scaffolding domain (81-101AA)-defective CAV1 mutant) compared to the untransduced human Hepatoblastoma cell line (HepG2) or after transduction with the green fluorescent protein (GFP) control vector. The increased intra-cellular transport of RES was abolished in cells stably expressing CAVM2 (a cholesterol shuttle domain (143-156AA)-defective CAV1 mutant) or CAVRNAi. In order to further characterize CAV1-dependent RES transport, we synthesized RES-dansyl chloride derivatives as fluorescent probes to visualize the transport process, which demonstrated a distribution consistent with that of CAV1 in HepG2 cells.. In addition, RES endocytosis was not mediated by estrogen receptor (ER) alpha and beta, as suggested by lack of competitive inhibition by estrogen or Tamoxifen. Pathway analysis showed that RES can up-regulate the expression of endogenous CAV1; this activates further the MAPK pathway and caspase-3 expression.. This study provides novel insights about the role played by CAV1 in modulating cellular sensitivity to RES through enhancement of its internalization and trafficking.

    Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Carcinoma, Hepatocellular; Caveolin 1; Cell Death; Cell Line, Tumor; Cell Survival; Chromatography, High Pressure Liquid; Drug Synergism; Endocytosis; Genes, Reporter; Humans; Liver Neoplasms; Mice; Mice, Nude; Resveratrol; Sequence Deletion; Stilbenes; Transfection

2009
Pterostilbene inhibited tumor invasion via suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells.
    Carcinogenesis, 2009, Volume: 30, Issue:7

    Pterostilbene, a natural dimethylated analog of resveratrol, is known to have diverse pharmacologic activities including anticancer, anti-inflammation, antioxidant, apoptosis, anti-proliferation and analgesic potential. However, the effects of pterostilbene in preventing invasion of cancer cells have not been studied. Here, we report our finding that pterostilbene significantly suppressed 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced invasion, migration and metastasis of human hepatoma cells (HepG(2) cells). Increase in the enzyme activity, protein and messenger RNA levels of matrix metalloproteinase (MMP)-9 were observed in TPA-treated HepG(2) cells, and these were blocked by pterostilbene. In addition, pterostilbene can inhibit TPA-induced expression of vascular endothelial growth factor, epidermal growth factor and epidermal growth factor receptor. Transient transfection experiments also showed that pterostilbene strongly inhibited TPA-stimulated nuclear factor kappa B (NF-kappaB) and activator protein-1 (AP-1)-dependent transcriptional activity in HepG(2) cells. Moreover, pterostilbene can suppress TPA-induced activation of extracellular signal-regulated kinase 1/2, p38 mitogen-activated protein kinase, c-Jun N-terminal kinases 1/2 and phosphatidylinositol 3-kinase/Akt and protein kinase C that are upstream of NF-kappaB and AP-1. Significant therapeutic effects were further demonstrated in vivo by treating nude mice with pterostilbene (50 and 250 mg/kg intraperitoneally) after inoculation with HepG(2) cells into the tail vein. Presented data reveal that pterostilbene is a novel, effective, anti-metastatic agent that functions by downregulating MMP-9 gene expression.

    Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Movement; Gene Expression Regulation, Neoplastic; Humans; JNK Mitogen-Activated Protein Kinases; Liver Neoplasms; Lung Neoplasms; Matrix Metalloproteinase 9; Mice; Mitogen-Activated Protein Kinase 3; Neoplasm Invasiveness; Neoplasm Transplantation; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Signal Transduction; Stilbenes; Tetradecanoylphorbol Acetate; Transcription Factor AP-1; Transplantation, Heterologous

2009
Induction of a reversible, non-cytotoxic S-phase delay by resveratrol: implications for a mechanism of lifespan prolongation and cancer protection.
    British journal of pharmacology, 2009, Volume: 158, Issue:2

    Resveratrol (RES) has been shown to prolong lifespan and prevent cancer formation. At present, the precise cellular mechanisms of RES actions are still not clearly understood, and this is the focus of this study.. Using human hepatocellular carcinoma-derived HepG2 cells as a model, we studied RES-induced changes in cell growth, cell cycle progression and apoptosis.. RES at lower concentrations induced a strong but reversible S-phase delay and mild DNA synthesis inhibition, yet without causing apoptotic or necrotic cell death. At high concentrations, RES induced apoptosis, which is mainly mediated by the mitochondrial pathway. Overall, RES was a relatively weak apoptotic agent. Mechanistically, MEK inhibition was identified as an important early signalling event for RES-induced apoptosis. In comparison, activation of CDK2 and checkpoint kinase 2, and inhibition of phosphatidylinositol 3'-kinase/Akt signalling pathway contributed to the induction by RES of a reversible, non-cytotoxic S-phase delay.. It is hypothesized that the induction of a non-cytotoxic S-phase delay may represent a useful mechanistic strategy for lifespan prolongation and cancer prevention. When cell cycles are selectively slowed down in the S phase, it would cumulatively increase the total lifespan of an organism if the total numbers of cell divisions of a given organism are assumed to remain basically constant. Likewise, when cells proceed through the cell cycles at a reduced pace during DNA replication, it may allow cells more time to repair the damaged DNA, and thereby reduce the chances for mutagenesis and tumour initiation.

    Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Hepatocellular; Cell Cycle; Cell Line, Tumor; DNA; Dose-Response Relationship, Drug; Humans; Liver Neoplasms; Membrane Potential, Mitochondrial; Resveratrol; S Phase; Signal Transduction; Stilbenes

2009
XN05, a novel synthesized microtubule inhibitor, exhibits potent activity against human carcinoma cells in vitro.
    Cancer letters, 2009, Nov-18, Volume: 285, Issue:1

    The present data showed that a novel synthesized compound, N-acetyl-N-(4-(4-methoxyphenyl-3-(3,4,5-trimethoxyphenyl)isoxazol-5-yl)acetamide (XN05), exhibited potent antitumor activity against various cancer cells in vitro. XN05-treatment in human hepatocellular carcinoma cells resulted in the accumulation of G2/M phase cells and finally induced apoptosis assessed by flow cytometry analysis. Western blot and immunofluorescence experiments indicated that XN05 depolymerized microtubules similar to the effect of combretastatin-A4. In addition, XN05-treatment influenced the expression of cell cycle and apoptosis related proteins in BEL-7402 cells, which was associated with the appearance of phosphorylated Bcl-2. Taken together, all the data demonstrated that XN05 exhibited its antitumor activity through disrupting the microtubule assembly, causing cell cycle arrest and consequently inducing apoptosis in BEL-7402 cells. Therefore, the novel compound XN05 is a promising microtubule inhibitor that has great potentials for therapeutic treatment of various malignancies.

    Topics: Acetamides; Apoptosis; Carcinoma, Hepatocellular; Caspases; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Enzyme Activation; Humans; Inhibitory Concentration 50; Isoxazoles; Liver Neoplasms; Microtubules; Phosphorylation; Protein Multimerization; Proto-Oncogene Proteins c-bcl-2; Stilbenes; Time Factors; Tubulin; Tubulin Modulators

2009
[The mechanism of resveratrol on anti-hepatoma Bel-7402 and modulating IL-8 in tumor model mice].
    Zhong yao cai = Zhongyaocai = Journal of Chinese medicinal materials, 2008, Volume: 31, Issue:5

    To explore the anti-tumor effect of resveratrol on the hepatocellular carcinoma cell line Bel-7402 both in vitro and in vivo.. MTT colorimetry was used to measure the tumor cell growth repression rate. The level of Bcl-2 was measured by Western blotting. The cell cycle of Bel-7402 and intracellular IL-8 were analyzed by flow cytometry. The expression of IL-8 mRNA was determined by semiquantitative RT-PCR and quantification assay of IL-8 was determined by ELISA.. Our findings indicated that resveratrol inhibited proliferation, induced apoptosis, and influenced cell cycle of Bel-7402 cells at a dose-and time-dependent manner in vitro. Furthermore, resveratrol could exert a dose-related down-regulatory effect on IL-8 in Bel-7402 bearing mice.. It suggestes resveratrol might have chemotherapeutic potential and immunomodulation action to Bel-7402 to cellular carcinoma both in vitro and in vivo.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Hepatocellular; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Flow Cytometry; Interleukin-8; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Proto-Oncogene Proteins c-bcl-2; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes

2008
Alterations in vascular architecture and permeability following OXi4503 treatment.
    Anti-cancer drugs, 2008, Volume: 19, Issue:1

    OXi4503 retards tumor growth in a dose-dependent manner and improves survival in a murine model of colorectal liver metastases. This agent causes extensive vascular shutdown by selectively altering the tubulin cytoskeleton within the endothelial cells of tumor vessels. The destruction of tumor vessels is incomplete, however, and tumor revascularization occurs after the treatment. This study evaluates the pattern of microcirculatory changes and alterations to the ultrastructural properties of the tumor vasculature that result from OXi4503 treatment. Male CBA mice were induced with liver metastases via an intrasplenic injection of a murine-derived colorectal cell line. After administering a single intraperitoneal dose of OXi4503, changes in tumor perfusion, microvascular architecture and permeability were assessed at various time points. One hour after a 100-mg/kg dose of OXi4503, a significant decrease in the percentage of tumor perfusion (63.96+/-1.98 in controls versus 43.77+/-2.71 in treated mice, P<0.001) was observed, which was still evident 5 days after the treatment. Substantial tumor microvascular damage and minimal normal liver injury were observed. Tumor vascular permeability was significantly elevated 45 min after the OXi4503 treatment (67.5+/-3.60 in controls versus 80.5+/-2.24 microg/g, P<0.05). The findings suggest that OXi4503 selectively targets tumor vessels and causes immediate microvascular destruction. Even at the maximum tolerated dose, however, residual patent tumor vessels were still present after treatment, implying incomplete tumor destruction. A combination of OXi4503 with other chemotherapeutic modalities might achieve complete tumor eradication and improve long-term survival.

    Topics: Angiogenesis Inhibitors; Animals; Blood Vessels; Capillaries; Capillary Permeability; Carcinogens; Colorectal Neoplasms; Dimethylhydrazines; Diphosphates; Evans Blue; Laser-Doppler Flowmetry; Liver Neoplasms; Male; Mice; Mice, Inbred CBA; Microscopy, Confocal; Microscopy, Electron, Scanning; Regional Blood Flow; Stilbenes; Tissue Fixation

2008
p38 MAPK, but not ERK1/2, is critically involved in the cytotoxicity of the novel vascular disrupting agent combretastatin A4.
    International journal of cancer, 2008, Apr-15, Volume: 122, Issue:8

    Combretastatin A4 (CA4) is a novel vascular disrupting agent that has promising clinical efficacy because of its ability to inhibit microtubule assembly and subsequently disrupt tumor blood flow. In this study, we demonstrate that mitogen-activated protein kinases (MAPKs) are critically involved in the cytotoxicity of CA4. CA4 stimulates both extracellular signal-regulated kinases (ERK1/2) and p38 MAPK in the BEL-7402 hepatocellular carcinoma cell line in a time- and dose-dependent manner. This stimulation is a result of CA4-induced microtubule disassembly, which is a reversible process. Reversibility of microtubule disassembly is evidenced by the ability of disassembled microtubules to reassemble just a few hours after CA4 treatment. p38 MAPK, but not ERK1/2, contributes to this microtubule reassembly following CA4 exposure, and only inhibition of p38 MAPK, but not ERK1/2, synergistically enhances CA4-induced G(2)/M cell cycle arrest. Consistent with this, p38 MAPK inhibitors such as SB203580 and SB202190 also synergistically enhance the cytotoxicity of CA4 in cells where p38 MAPK is activated by CA4. This enhancement appears to be specific for CA4 because the cytotoxicity of other microtubule-targeted agents such as paclitaxel, vinorelbine and colchicine was not affected by p38 MAPK inhibitors. These data indicate that p38 MAPK is a potential anticancer target and that the combination of CA4 with p38 MAPK inhibitors may be a novel and promising strategy for cancer therapy.

    Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Phytogenic; Blotting, Western; Carcinoma, Hepatocellular; Cell Line, Tumor; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Fluorescent Antibody Technique; Humans; Imidazoles; Liver Neoplasms; Male; Microtubules; Ovarian Neoplasms; p38 Mitogen-Activated Protein Kinases; Pyridines; Stilbenes; Time Factors

2008
[Effects of resveratrol on matrix metalloproteinase-9 expression in hepatoma cells].
    Zhong xi yi jie he xue bao = Journal of Chinese integrative medicine, 2008, Volume: 6, Issue:3

    To observe the effects of resveratrol on proliferation of human hepatocellular carcinoma cell line SMMC-7721 cells and expression of matrix metalloproteinase-9 (MMP-9) in vitro.. SMMC-7721 cells were treated with different concentrations of resveratrol for 24, 48 and 72 h, respectively. The effect of resveratrol on proliferation of SMMC-7721 cells was assessed with methyl thiazolyl tetrazolium (MTT). The expression of MMP-9 mRNA was determined by reverse transcription polymerase chain reaction (RT-PCR). MMP-9 protein was identified by Western blot analysis.. Resveratrol could inhibit the proliferation of SMMC-7721 cells with dose- and time-dependent effects. Moreover, both MMP-9 mRNA expression and MMP-9 protein production were markedly reduced after resveratrol treatment.. Resveratrol can inhibit the proliferation of SMMC-7721 cells and down-regulate MMP-9 expression. It is presumed that resveratrol may suppress the invasion and metastasis of hepatocellular carcinoma.

    Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cell Proliferation; Dose-Response Relationship, Drug; Down-Regulation; Humans; Liver Neoplasms; Matrix Metalloproteinase 9; Resveratrol; RNA, Messenger; Stilbenes; Tumor Cells, Cultured

2008
Resveratrol in human hepatoma HepG2 cells: metabolism and inducibility of detoxifying enzymes.
    Drug metabolism and disposition: the biological fate of chemicals, 2007, Volume: 35, Issue:5

    trans-Resveratrol is a polyphenol present in several plant species. Its chemopreventive properties against several diseases have been largely documented. To validate a model for the study of the factors influencing its biological fate at the hepatic level, the metabolism and the efflux of resveratrol were studied in the human hepatoblastoma cell line, HepG2. Comparative high-performance liquid chromatography analysis of cell culture media before and after deconjugation showed that resveratrol was rapidly conjugated; at the concentration of 10 microM, it was entirely metabolized at 8 h of incubation. Two main resveratrol metabolites, monosulfate and disulfate, were identified by atmospheric pressure chemical ionization-mass spectrometry, thanks to their quasi-molecular ion and their characteristic fragmentation. To correlate with the auto-induction of resveratrol metabolism evidenced in HepG2 cells after a pretreatment for 48 h with 10 microM resveratrol, the inducibility of phase II enzymes by resveratrol was studied by real-time quantitative reverse transcriptase-polymerase chain reaction and flow cytometry. Observed, in particular, were an increase in mRNA expression levels of three metabolizing enzymes, two isoforms of UDP-glucuronosyltransferases, UGT1A1 and UGT2B7 (5-fold increased), and a sulfotransferase, ST1E1, in cells pretreated for 24 h with 10 microM resveratrol. These results were correlated with an increase in protein expression, especially after 48 h of treatment. On the other hand, the intracellular resveratrol retention in cells treated with MK571 (3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid), a multidrug resistance-associated protein inhibitor, strongly suggests the involvement of this ABC transporter family in the efflux of resveratrol conjugates from human liver.

    Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cell Line, Tumor; Chromatography, High Pressure Liquid; Enzyme Induction; Enzymes; Flow Cytometry; Glucuronosyltransferase; Humans; Liver Neoplasms; Mass Spectrometry; Metabolic Detoxication, Phase II; Multidrug Resistance-Associated Proteins; Propionates; Quinolines; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes; Sulfotransferases; Time Factors; Tritium

2007
Effect of formaldehyde and resveratrol on the viability of Vero, HepG2 and MCF-7 cells.
    Cell biology international, 2007, Volume: 31, Issue:10

    A non-transformed (Vero) and two tumor cell lines (HepG2 and MCF-7) were treated with 10nM to 100 microM formaldehyde. Lower doses (10nM to 10 microM) enhanced the viability of the cultured cells, measured by MTT assay. Higher doses (75-100 microM) decreased viability of the cells by 50% or more. The 100 microM concentration of HCHO has been chosen for combination treatment of the three cell lines with a series of concentrations (0.2-100 microM) of resveratrol, a phytoestrogen occurring in various fruits. Resveratrol decreased the cytotoxicity of formaldehyde depending on cell line and point of time, especially in case of MCF-7 cells at 24 and 72 h, Vero cells at 24h and HepG2 cells at 48 h after treatment. Possible modes of interactions are discussed, considering the role of resveratrol in formaldehyde metabolism and also the estrogen receptor positivity of MCF-7 cells.

    Topics: Angiogenesis Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Breast Neoplasms; Carcinoma, Hepatocellular; Cell Survival; Cells, Cultured; Chlorocebus aethiops; Disinfectants; Formaldehyde; Liver Neoplasms; Receptors, Estrogen; Resveratrol; Stilbenes; Vero Cells

2007
[Resveratrol induces HepG2 cell apoptosis by depolarizing mitochondrial membrane].
    Nan fang yi ke da xue xue bao = Journal of Southern Medical University, 2006, Volume: 26, Issue:4

    To investigate the effects of resveratrol on the proliferation, apoptosis, mitochondrial membrane potential and cell morphology of human liver cancer cell line HepG2.. The changes in HepG2 cell growth and proliferation in response to resveratrol treatment were evaluated by MTT assay, and resveratrol-induced apoptosis of HepG2 cells was investigated by flow cytometry. Inverted microscope and electron microscope were employed for observing morphological changes of the treated cells. The whole-cell mitochondrial membrane potential was measured in separate experiments using two fluorimetric probes, rhodamine123 and TMRE, respectively. HepG2 cells treated with rhodamine123 were analyzed by flow cytometry and cells treated with TMRE by confocal microscope.. MTT assay showed that low concentrations of resveratrol produced no significant effect on the growth of HepG2 cells, whereas at high concentrations, resveratrol could obviously inhibit the cell growth in a time- and dose-dependent manner. Resveratrol also induced apoptosis of HepG2 cells, and after a 24-hour treatment, resveratrol caused sharp increment of the mitochondria membrane potential.. Resveratrol is capable of inhibiting the proliferation of HepG2 cells and inducing cell apoptosis by depolarizing mitochondrial membrane potential.

    Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Liver Neoplasms; Membrane Potentials; Mitochondrial Membranes; Resveratrol; Stilbenes

2006
[Effects of resveratrol on growth inhibition and gap-junctional intercellular communication of HepG2 cells].
    Nan fang yi ke da xue xue bao = Journal of Southern Medical University, 2006, Volume: 26, Issue:7

    To investigate the effects of the resveratrol on proliferation and gap-junctional intercellular communication (GJIC) in human liver cancer cell line HepG2.. MTT assay was used to observe the effects of resveratrol on HepG2 cell growth, and the distribution of cell cycles was detected with flow cytometry (FCM). The effects of resveratrol on GJIC of HepG2 cells labeled with 5'-CFDA/AM was examined with fluorescence redistribution after photobleaching (FRAP) and confocal microscope.. The results of MTT assay indicated that the proliferation of HepG2 cells was significantly inhibited by resveratrol in a time- and dose-dependent manner. Resveratrol could arrest HepG2 cell growth in S phase, inhibit DNA synthesis and induce cell apoptosis. Furthermore, the levels of GJIC increased sharply after resveratrol treatment of the cells.. Resveratrol is capable of inhibiting HepG2 cell proliferation, causing cell growth arrest at S phase and inducing cell apoptosis. Increased GJIC level contributes to the effect of resveratrol in HepG2 cell proliferation inhibition and its cancer chemopreventive activity.

    Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cell Communication; Cell Line, Tumor; Cell Proliferation; Cell Survival; Gap Junctions; Humans; Liver Neoplasms; Resveratrol; S Phase; Stilbenes

2006
Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice.
    Diabetes, 2006, Volume: 55, Issue:8

    Because polyphenols may have beneficial effects on dyslipidemia, which accelerates atherosclerosis in diabetes, we examined the effect of polyphenols on hepatocellular AMP-activated protein kinase (AMPK) activity and lipid levels, as well as hyperlipidemia and atherogenesis in type 1 diabetic LDL receptor-deficient mice (DMLDLR(-/-)). In HepG2 hepatocytes, polyphenols, including resveratrol (a major polyphenol in red wine), apigenin, and S17834 (a synthetic polyphenol), increased phosphorylation of AMPK and its downstream target, acetyl-CoA carboxylase (ACC), and they increased activity of AMPK with 200 times the potency of metformin. The polyphenols also prevented the lipid accumulation that occurred in HepG2 cells exposed to high glucose, and their ability to do so was mimicked and abrogated, respectively, by overexpression of constitutively active and dominant-negative AMPK mutants. Furthermore, treatment of DMLDLR(-/-) mice with S17834 prevented the decrease in AMPK and ACC phosphorylation and the lipid accumulation in the liver, and it also inhibited hyperlipidemia and the acceleration of aortic lesion development. These studies 1) reveal that inactivation of hepatic AMPK is a key event in the pathogenesis of hyperlipidemia in diabetes, 2) point to a novel mechanism of action of polyphenols to lower lipids by activating AMPK, and 3) emphasize a new therapeutic avenue to benefit hyperlipidemia and atherosclerosis specifically in diabetes via activating AMPK.

    Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Animals; Apigenin; Atherosclerosis; Benzopyrans; Carcinoma, Hepatocellular; Cell Line, Tumor; Diabetes Mellitus, Experimental; Enzyme Activation; Flavonoids; Glucose; Humans; Hypolipidemic Agents; Lipid Metabolism; Lipids; Liver; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Multienzyme Complexes; Phenols; Phosphorylation; Polyphenols; Protein Serine-Threonine Kinases; Receptors, LDL; Resveratrol; Stilbenes

2006
Resveratrol exerts its antiproliferative effect on HepG2 hepatocellular carcinoma cells, by inducing cell cycle arrest, and NOS activation.
    Biochimica et biophysica acta, 2006, Volume: 1760, Issue:11

    The stilbene resveratrol exerts antiproliferative and proapoptotic actions on a number of different cancer cell lines, through diverse mechanisms, including antioxidant effects, enzyme, growth factor and hormone receptor binding, and nucleic acid direct or indirect interactions. Although resveratrol accumulates in the liver, its effect on hepatocellular carcinoma has not been extensively studied. We have used the human hepatocyte-derived cancer cell line HepG2 to address the possible action of resveratrol on cell growth and to examine some possible mechanisms of action. Our results indicate that the stilbene inhibits potently cell proliferation, reduces the production of reactive oxygen species and induces apoptosis, through cell cycle arrest in G1 and G2/M phases. Furthermore it modulates the NO/NOS system, by increasing iNOS and eNOS expression, NOS activity and NO production. Inhibition of NOS enzymes attenuates its antiproliferative effect. These data could be of value in possible prevention or adjuvant treatment of hepatocellular carcinoma, through an increased consumption of resveratrol-rich foods and beverages.

    Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Hepatocellular; Cell Cycle; Cell Proliferation; G1 Phase; G2 Phase; Humans; Liver Neoplasms; Nitric Oxide; Nitric Oxide Synthase; Reactive Oxygen Species; Resveratrol; Stilbenes; Time Factors; Transcription, Genetic; Tumor Cells, Cultured

2006
[Studies on active substance of anticancer effect in Polygonum cuspidatum].
    Zhong yao cai = Zhongyaocai = Journal of Chinese medicinal materials, 2006, Volume: 29, Issue:7

    To supply the scientific basis of research and development of the medicinal value of Polygonum cuspidatum.. One composition was isolated from the roots of Polygonum cuspidatum by cytotoxicity based fractionation and identified by HPLC-MS, UV scanning and IR. The inhibition and morphology of L-02, Hep G2, SHZ-888, MCF-7, MCF-7/ADM cells growth caused by this composition was determined by MTT assay and HE dyeing.. This composition was identified as trans-and cis-resveratrol. It could specifically inhibit proliferation of many cancer cells but not human normal liver cell. We investigated the cytotoxicity of resveratrol to adriamycin-resistant MCF-7 cell in virtro.. Resveratrol is a new anticancer composition which is less toxicity and higher efficiency in Polygonum cuspidatum.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Epithelial Cells; Fallopia japonica; Female; Humans; Liver Neoplasms; Plants, Medicinal; Rats; Resveratrol; Rhizome; Stilbenes

2006
Time- and concentration-dependent effects of resveratrol in HL-60 and HepG2 cells.
    Cell proliferation, 2006, Volume: 39, Issue:6

    Resveratrol, a phytochemical present in grapes, has been demonstrated to inhibit tumourigenesis in animal models. However, the specific mechanism by which resveratrol exerts its anticarcinogenic effect has yet to be elucidated. In the present study, the inhibitory effects of resveratrol on cell proliferation and apoptosis were evaluated in the human leukaemia cell line HL-60 and the human hepatoma derived cell line HepG2. We found that after a 2 h incubation period, resveratrol inhibited DNA synthesis in a concentration-dependent manner. The IC50 value was 15 microm in both HL-60 and HepG2 cells. When the time of treatment was extended, an increase in IC50 value was observed; for example, at 24 h the IC50 value was 30 microm for HL-60 cells and 60 microm for HepG2 cells. Flow cytometry revealed that cells accumulated in different phases of the cell cycle depending on the resveratrol concentration. Furthermore, an increase in nuclear size and granularity was observed in the G1 and S phases of HL-60 treated and HepG2-treated cells. Apoptosis was also stimulated by resveratrol in a concentration-dependent manner in HL-60 and HepG2 cells. In conclusion, resveratrol inhibits cell proliferation in a concentration- and time-dependent manner by interfering with different stages of the cell cycle. Furthermore, resveratrol treatment causes stimulation of apoptosis as well as an increase in nuclear size and granularity.

    Topics: Annexin A5; Anticarcinogenic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Cycle; Cell Nucleus Size; DNA Fragmentation; Dose-Response Relationship, Drug; Flow Cytometry; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Liver Neoplasms; Resveratrol; Stilbenes; Thymidine; Tritium

2006
Association between pterostilbene and quercetin inhibits metastatic activity of B16 melanoma.
    Neoplasia (New York, N.Y.), 2005, Volume: 7, Issue:1

    Inhibition of cancer growth by resveratrol (trans-3,5,4'-trihydroxystilbene; RESV), a phytoalexin present in many plant species, is limited by its low bioavailability. Pterostilbene (3,5-dimethoxy-4'-hydroxystilbene; PTER) and quercetin (3,3',4',5,6-pentahydroxyflavone; QUER), two structurally related and naturally occurring small polyphenols, show longer half-life in vivo. In vitro growth of highly malignant B16 melanoma F10 cells (B16M-F10) is inhibited (56%) by short-time exposure (60 min/day) to PTER (40 microm) and QUER (20 microm) (approximate mean values of plasma concentrations measured within the first hour after intravenous administration of 20 mg/kg each polyphenol). Intravenous administration of PTER and QUER (20 mg/kg per day) to mice inhibits (73%) metastatic growth of B16M-F10 cell in the liver, a common site for metastasis development. The anti-metastatic mechanism involves: 1) a PTER-induced inhibition of vascular adhesion molecule 1 expression in the hepatic sinusoidal endothelium, which consequently decreases B16M-F10 cell adhesion to the endothelium through very late activation antigen 4; and 2) a QUER- and PTER-induced inhibition of Bcl-2 expression in metastatic cells, which sensitizes them to vascular endothelium-induced cytotoxicity. Our findings demonstrate that the association of PTER and QUER inhibits metastatic melanoma growth and extends host survival.

    Topics: Animals; Cell Adhesion; Endothelium, Vascular; Hydrogen Peroxide; Integrin alpha4beta1; Liver Neoplasms; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Nitrates; Nitrites; Phenols; Proto-Oncogene Proteins c-bcl-2; Quercetin; Stilbenes; Tumor Cells, Cultured; Vascular Cell Adhesion Molecule-1

2005
Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1alpha and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells.
    Molecular cancer therapeutics, 2005, Volume: 4, Issue:10

    Hypoxia-inducible factor-1alpha (HIF-1alpha) is overexpressed in many human tumors and their metastases, and is closely associated with a more aggressive tumor phenotype. In this study, we investigated the effect of resveratrol, a natural product commonly found in grapes and various other fruits, on hypoxia-induced HIF-1alpha protein accumulation and vascular endothelial growth factor (VEGF) expression in human tongue squamous cell carcinomas and hepatoma cells. Our results showed that resveratrol significantly inhibited both basal level and hypoxia-induced HIF-1alpha protein accumulation in cancer cells, but did not affect HIF-1alpha mRNA levels. Pretreatment of cells with resveratrol significantly reduced hypoxia-induced VEGF promoter activities and VEGF expression at both mRNA and protein levels. The mechanism of resveratrol inhibition of hypoxia-induced HIF-1alpha accumulation seems to involve a gradually shortened half-life of HIF-1alpha protein caused by an enhanced protein degradation through the 26S proteasome system. In addition, resveratrol remarkably inhibited hypoxia-mediated activation of extracellular signal-regulated kinase 1/2 and Akt, leading to a marked decrease in hypoxia-induced HIF-1alpha protein accumulation and VEGF transcriptional activation. Functionally, we observed that resveratrol also significantly inhibited the hypoxia-stimulated invasiveness of cancer cells. These data suggested that HIF-1alpha/VEGF could be a promising drug target for resveratrol in the development of an effective chemopreventive and anticancer therapy in human cancers.

    Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Carcinoma, Squamous Cell; Cell Hypoxia; Cell Line, Tumor; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Neoplasm Invasiveness; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Resveratrol; RNA, Messenger; Stilbenes; Tongue Neoplasms; Transcriptional Activation; Vascular Endothelial Growth Factors

2005
Effect of resveratrol and in combination with 5-FU on murine liver cancer.
    World journal of gastroenterology, 2004, Oct-15, Volume: 10, Issue:20

    To study the anti-tumor effect of resveratrol and in combination with 5-FU on murine liver cancer.. Transplantable murine hepatoma22 model was used to evaluate the anti-tumor activity of resveratrol (RES) alone or in combination with 5-FU in vivo. H22 cell cycles were analyzed with flow cytometry.. Resveratrol could inhibit the growth of murine hepatoma22, after the mice bearing H22 tumor were treated with 10 mg/kg or 15 mg/kg resveratrol for ten days, and the inhibition rates were 36.3% (n = 10) and 49.3% (n = 9), respectively, which increased obviously compared with that in control group (85+/-22 vs 68+/-17, P<0.01). RES could induce the S phase arrest of H22 cells, and increase the percentage of cells in S phase from 59.1% (n = 9) to 73.5% (n = 9) in a dose-dependent manner (P<0.05). The enhanced inhibition of tumor growth by 5-FU was also observed in hepatoma22 bearing mice when 5-FU was administered in combination with 10 mg/kg resveratrol. The inhibition rates for 20 mg/kg or 10 mg/kg 5-FU in combination with 10 mg/kg resveratrol were 77.4% and 72.4%, respectively, compared with the group of 20 mg/kg or 10 mg/kg 5-FU alone, in which the inhibition rates were 53.4% and 43.8%, respectively (n = 8). There was a statistical significance between the combination group and 5-FU group.. RES could induce the S phase arrest of H22 cells and enhance the anti-tumor effect of 5-FU on murine hepatoma22 and antagonize its toxicity markedly. These results suggest that resveratrol, as a biochemical modulator to enhance the therapeutic effects of 5-FU, may be potentially useful in cancer chemotherapy.

    Topics: Animals; Anticarcinogenic Agents; Antimetabolites, Antineoplastic; Carcinoma, Hepatocellular; Cell Cycle Proteins; Drug Synergism; Drug Therapy, Combination; Fluorouracil; Liver Neoplasms; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Resveratrol; Stilbenes; Survival Rate

2004
Induction of the paraoxonase-1 gene expression by resveratrol.
    Arteriosclerosis, thrombosis, and vascular biology, 2004, Volume: 24, Issue:12

    The human paraoxonase-1 (PON-1) is a high-density lipoprotein-associated enzyme, mainly secreted by the liver, that displays protective properties toward cardiovascular disease and organophosphate intoxication. Resveratrol is a polyphenolic phytoalexin found in grapes and wine and is thought to display cardioprotective effects. It is able to interact with transcriptional modulators such as the estrogen receptor alpha (ERalpha). We investigated the effect of resveratrol on the PON-1 gene expression.. PON-1 activity assays, Northern blot, and transfection experiments showed that resveratrol increased the PON-1 gene expression in human hepatocyte primary cultures and in the HuH7 hepatoma cell line involving a transcriptional mechanism. The resveratrol effect was not ERalpha-dependent and was surprisingly mediated by the aryl hydrocarbon receptor (AhR) and an unconventional AhR responsive element in the PON-1 gene promoter. This agonist effect of resveratrol was specific for this DNA motif and was not observed on classical AhR responsive elements.. These observations suggest that the PON-1 gene induction may be involved in the cardioprotective properties of resveratrol. They also highlight a ligand-dependent differential modulation of AhR-sensitive genes.

    Topics: Aryldialkylphosphatase; Carcinoma, Hepatocellular; Cell Line; Cell Line, Tumor; Chromosome Mapping; Enzyme Induction; Estrogen Receptor alpha; Gene Expression Regulation, Enzymologic; Hepatocytes; Humans; Liver Neoplasms; Promoter Regions, Genetic; Receptors, Aryl Hydrocarbon; Response Elements; Resveratrol; Stilbenes; Transcriptional Activation; Transfection; Xenobiotics

2004
Potent inhibition of recombinant human cytochrome p-450 1A1 by pentamethoxystilbene.
    Journal of toxicology and environmental health. Part A, 2004, Volume: 67, Issue:23-24

    Previously it was reported that various hydroxystilbene compounds strongly inhibit human cytochrome P-450 1 enzymes and were postulated as candidate chemopreventive agents. In this study, the inhibitory potential of P-450 1 enzyme activities by 3,5,3,4,5-pentamethoxystilbene (PMS), a synthetic stilbene compound, was evaluated with the Escherichia coli (E. coil) membranes of recombinant human cytochrome P-450 1A1, 1A2, or 1B1 coexpressed with human NADPH-P-450 reductase. PMS produced a significant inhibition of ethoxyresorufin O-deethylation (EROD) activities with IC50 values of 0.14, 934, and 3.2 M for 1A1, 1A2, and 1B1, respectively. PMS did not significantly inhibit EROD activities in human liver microsomes. To elucidate the mechanism of inhibition by PMS, kinetic studies were performed. Analysis of the mode of inhibition indicated a mixed-type inhibition of P-450 1A1. The inhibition of P-450 1A1-mediated EROD activity by PMS was not irreversible-mechanism based. The loss of EROD activity of P-450 1A1 with PMS was blocked by trapping agents such as glutathione, N-acetylcysteine, or dithiothreitol. Moreover, PMS significantly suppressed P-450 1A1-mediated EROD activity and P-450 1A1 gene expression in HepG2 cells induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Taken together, the results suggested that PMS is a potent and selective inhibitor of human P-450 1A1 and may be considered for use as a cancer chemopreventive agent in humans.

    Topics: Carcinoma, Hepatocellular; Cell Membrane; Cytochrome P-450 CYP1A1; Enzyme Inhibitors; Escherichia coli; Gene Expression Regulation; Humans; Liver Neoplasms; Microsomes, Liver; Stilbenes; Tumor Cells, Cultured

2004
Resveratrol inhibits hepatoma cell invasion by suppressing gene expression of hepatocyte growth factor via its reactive oxygen species-scavenging property.
    Clinical & experimental metastasis, 2004, Volume: 21, Issue:5

    Resveratrol, present in grapes and other plants, is a polyphenolic compound with strong antioxidative activity. In our previous studies, we found that reactive oxygen species (ROS) accelerated the invasive capacity of a rat ascites hepatoma cell line of AH109A in culture and that resveratrol and resveratrol-loaded rat sera suppressed the ROS-potentiated invasion of the hepatoma cells. To study mechanisms by which resveratrol and its in vivo metabolite(s) suppress the invasion, we estimated intracellular peroxide level and expression of hepatocyte growth factor (HGF), a known cell motility factor, in AH109A cells. Exogenously added ROS promoted the intracellular peroxide level and the expression of HGF. Resveratrol and resveratrol-loaded rat sera canceled the rise in the peroxide level and HGF expression in ROS-stimulated tumor cells. These results suggest an involvement of the antioxidative property of resveratrol and sera from rats orally given resveratrol in their suppressive effects on ROS-potentiated invasion of AH109A cells.

    Topics: Animals; Carcinoma, Hepatocellular; Free Radical Scavengers; Gene Expression; Hepatocyte Growth Factor; Hypoxanthine; Liver Neoplasms; Male; Neoplasm Invasiveness; Rats; Reactive Oxygen Species; Resveratrol; Stilbenes; Tumor Cells, Cultured; Xanthine Oxidase

2004
Effect of resveratrol on cell cycle proteins in murine transplantable liver cancer.
    World journal of gastroenterology, 2003, Volume: 9, Issue:10

    To study the antitumour activity of resveratrol and its effect on the expression of cell cycle proteins including cyclin D1, cyclin B1 and p34cdc2 in transplanted liver cancer of murine.. Murine transplanted hepatoma H22 model was used to evaluate the in vivo antitumor activity of resveratrol. Following abdominal administration of resveratrol, the change in tumour size was recorded and the protein expression of cyclin D1, cyclin B1 and p34cdc2 in the tumor and adjacent noncancerous liver tissues were measured by immunohistochemistry.. Following treatment of H22 tumour bearing mice with resveratrol at 10 or 15 mg/kg bodyweight for 10 days, the growth of murine transplantable liver cancer was inhibited by 36.3% or 49.3%, respectively. The inhibitory effect was significant compared to that in control group (P<0.05). The level of expression of cyclin B1 and p34cdc2 protein was decreased in the transplantable murine hepatoma 22 treated with resveratrol whereas the expression of cyclin D1 protein did not change.. Resveratrol exhibits anti-tumour activities on murine hepatoma H22. The underlying anti-tumour mechanism of resveratrol might involve the inhibition of the cell cycle progression by decreasing the expression of cyclinB1 and p34cdc2 protein.

    Topics: Animals; Antineoplastic Agents, Phytogenic; CDC2 Protein Kinase; Cell Cycle Proteins; Cyclin B; Cyclin B1; Cyclin D1; Liver Neoplasms; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Resveratrol; Stilbenes

2003
Resveratrol- induced apoptosis is mediated by p53-dependent pathway in Hep G2 cells.
    Life sciences, 2002, Nov-22, Volume: 72, Issue:1

    Resveratrol, a phytoalexin found in many plants, has been reported to possess a wide range of pharmacological properties and is one of the promising chemopreventive agents for cancer. Here, we examined the antiproliferation effect of resveratrol in two human liver cancer cell lines, Hep G2 and Hep 3B. Our results showed that resveratrol inhibited cell growth in p53-positive Hep G2 cells only. This anticancer effect was a result of cellular apoptotic death induced by resveratrol via the p53-dependent pathway. Here we demonstrated that the resveratrol-treated cells were arrested in G1 phase and were associated with the increase of p21 expression. In addition, we also illustrated that the resveratrol-treated cells had enhanced Bax expression but they were not involved in Fas/APO-1 apoptotic signal pathway. In contrast, the p53-negative Hep 3B cells treated with resveratrol did not show the antiproliferation effect neither did they show significant changes in p21 nor Fas/APO-1 levels. In summary, our study demonstrated that the resveratrol effectively inhibited cell growth and induced programmed cell death in Hepatoma cells on a molecular basis. Furthermore, these results implied that resveratrol might also be a new potent chemopreventive drug candidate for liver cancer as it played an important role to trigger p53-mediated molecules involved in the mechanism of p53-dependent apoptotic signal pathway.

    Topics: Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Carcinoma, Hepatocellular; Cell Cycle; Cell Division; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; fas Receptor; Growth Inhibitors; Humans; Kinetics; Liver Neoplasms; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Resveratrol; Stilbenes; Tumor Cells, Cultured; Tumor Suppressor Protein p53

2002
Anti-hepatoma activity of resveratrol in vitro.
    World journal of gastroenterology, 2002, Volume: 8, Issue:1

    To study the anti-tumor effect of resveratrol alone and the synergistic effects of resveratrol with 5-FU on the growth of H22 cells line in vitro.. The number of cells was measured by MTT method the morphological changes of H22 cells were investigated under microscopy and electron microscopy examination.. Resveratrol inhibited the growth of hepatoma cells line H22 in a dose- and time-dependent manner, IC50 of the resveratrol on H22 cells was 6.57mg x L(-1),The synergistic anti-tumor effects of resveratrol with 5-FU increased to a greater extent than for H22 cells treated with 5-FU alone (70.2% vs 28.4%) P<0.05 .Under microscope and electron microscope, characteristics of apoptosis such as typical apoptotic bodies were commonly found in tumor cells in the drug-treated groups.. Resveratrol can suppresses the growth of H22 cells in vitro,its anti-tumor activity may occur through the induction of apoptosis.

    Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Hepatocellular; Cell Division; Humans; In Vitro Techniques; Liver Neoplasms; Resveratrol; Stilbenes; Tumor Cells, Cultured

2002
Combretastatin A4 prodrug study of effect on the growth and the microvasculature of colorectal liver metastases in a murine model.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2001, Volume: 7, Issue:4

    Combretastatin A4P (CA4P) is a prodrug that, in active form, binds to tubulin microtubules of capillary endothelial cells. Studies to date indicate it has significant activity as a specific tumor vascular targeting agent. The goals were to assess the effects of CA4P on tumor growth and microvasculature of colorectal liver metastases in the mouse model, using stereological and histological methods to measure tumor growth, and vascular corrosion casting and laser doppler flowmetry to assess effect on the microvasculature. Continuous s.c. infusion of CA4P produced a major reduction in tumor growth. The percentage of the liver occupied by metastases decreased from 20.55 +/- 13.3% in controls to 7.46 +/- 5.99% in treated animals (P = 0.03). Ultrastructural study of tumor microvasculature after a single dose of CA4P revealed marked effects 1 h after treatment. There was loss of patent microvessels at the normal liver-tumor interface. Central microvascular density was reduced, with constriction and tapering of vessels. CA4P appeared to cause no damage to normal liver tissue or vasculature. Tumor blood flow decreased from 37.6 +/- 13.9% in controls to 24.4 +/- 6.1% in tumors >5 mm in diameter, 1 h after treatment with CA4P (P < 0.03). Quantitative histology of tissue at 6 and 24 h after CA4P treatment showed a significant increase in tumor necrosis (48.7 +/- 21% and 55.5 +/- 19% compared with controls, 20.6 +/- 8%; P = 0.01). Continuous infusion with CA4P causes marked reduction in tumor volume. A single dose of CA4P causes major changes of the tumor microvasculature, reduction of tumor blood flow, and increase in tumor necrosis. CA4P has a potential role in the management of patients with liver metastases.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Division; Colorectal Neoplasms; Disease Models, Animal; Laser-Doppler Flowmetry; Liver Neoplasms; Male; Mice; Mice, Inbred CBA; Neovascularization, Pathologic; Stilbenes

2001
Resveratrol suppresses hepatoma cell invasion independently of its anti-proliferative action.
    Cancer letters, 2001, Jun-26, Volume: 167, Issue:2

    Resveratrol, found in grapes, is a phytoalexin with antioxidative activity. The compound (100 and 200 microM) inhibited the proliferation of hepatoma cells, although this phytoalexin exerted little influence up to 50 microM. Resveratrol, however, suppressed the invasion of the hepatoma cells even at a concentration of 25 microM. Sera from rats orally given resveratrol restrained only the invasion of AH109A cells. Resveratrol and resveratrol-loaded rat serum suppressed reactive oxygen species-potentiated invasive capacity. These results suggest that the anti-invasive activity of resveratrol is independent of the anti-proliferative activity, and that the antioxidative property of resveratrol may be involved in its anti-invasive action.

    Topics: Animals; Antineoplastic Agents; Antioxidants; Carcinoma, Hepatocellular; Cell Division; Hypoxanthine; Liver Neoplasms; Neoplasm Invasiveness; Rats; Resveratrol; Stilbenes; Tumor Cells, Cultured; Xanthine Oxidase

2001
Trans-resveratrol, a grapevine-derived polyphenol, blocks hepatocyte growth factor-induced invasion of hepatocellular carcinoma cells.
    International journal of oncology, 2001, Volume: 19, Issue:1

    We have shown that liver myofibroblasts stimulate in vitro invasion of hepatocellular carcinoma cell lines through a hepatocyte growth factor/urokinase-dependent mechanism. Resveratrol, a grapevine-derived polyphenol, has been shown to inhibit cellular events associated with tumor initiation, promotion and progression. The aim of this study was to evaluate the effects of trans-resveratrol on invasion of the human hepatoma cell line HepG2. Cell invasion was assessed using a Boyden chamber assay. Activation of the HGF signal transduction pathways was evaluated by Western blot with phospho-specific antibodies. Urokinase expression was measured by RT-PCR and zymography. Trans-resveratrol decreased hepatocyte growth factor-induced cell scattering and invasion. It also decreased cell proliferation without evidence for cytotoxicity or apoptosis. Trans-resveratrol did not decrease the level of the hepatocyte growth factor receptor c-met and did not impede the hepatocyte growth factor-induced increase in c-met precursor synthesis. Moreover, trans-resveratrol did not decrease hepatocyte growth factor-induced c-met autophosphorylation, or Akt-1 or extracellular-regulated kinases-1 and -2 activation. Finally, it did not decrease urokinase expression and did not block the catalytic activity of urokinase. In conclusion, our results demonstrate that trans-resveratrol decreases hepatocyte growth factor-induced HepG2 cell invasion by an as yet unidentified post-receptor mechanism.

    Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cell Division; Cell Survival; Flavonoids; Hepatocyte Growth Factor; Humans; Liver Neoplasms; Mitogen-Activated Protein Kinase Kinases; Neoplasm Invasiveness; Phenols; Phosphorylation; Poly(ADP-ribose) Polymerases; Polymers; Polyphenols; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Receptors, Cell Surface; Receptors, Urokinase Plasminogen Activator; Resveratrol; RNA, Messenger; Stilbenes; Tetrazolium Salts; Thiazoles; Tumor Cells, Cultured; Urokinase-Type Plasminogen Activator

2001
Positron emission tomography of murine liver metastases and the effects of treatment by combretastatin A-4.
    European journal of nuclear medicine, 1999, Volume: 26, Issue:3

    There are major potential advantages in non-invasive measurement of preclinical tumour biology and therapeutic response in clinically relevant, internal body sites, notably the ability to follow outcome in individual animals rather than averaging results from groups. We have exploited positron emission tomography (PET) to determine the feasibility of detecting liver metastases in B6D2F1 mice using fluorine-18 fluorodeoxyglucose ([18F]FDG) both before and after treatment by the novel cytotoxic agent, combretastatin A-4. The normal distribution of [18F]FDG in the absence of disease was characterised, with the clear delineation of the brain, the heart and the urinary bladder in all studies. In untreated mice with liver metastases, a strong correlation (r2 = 0.98) was found between the quantitative estimates of [18F]FDG uptake obtained by analysis of PET images, and those obtained from ex vivo assay of liver plus metastases excised immediately after imaging. In this first series, the effective limit of resolution was in livers containing a number of small metastases (range 8-14) with a single volume equivalent of approximately 200 mm3. PET image analysis was concordant with histological measurements in showing that single intraperitoneal doses of combretastatin A-4 resulted in an average 30% volume destruction of metastatic mass by 24 h following administration.

    Topics: Animals; Antineoplastic Agents, Phytogenic; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Liver Neoplasms; Male; Mammary Neoplasms, Experimental; Mice; Neoplasm Transplantation; Radiopharmaceuticals; Stilbenes; Tomography, Emission-Computed

1999
Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor.
    Cancer research, 1998, Dec-15, Volume: 58, Issue:24

    Resveratrol, a compound present in a variety of plants, was recently shown to have potent chemopreventive activity against aryl hydrocarbon-induced tumorigenesis in mice. Therefore, in the present study, we examined the effect of resveratrol on the function of the aryl hydrocarbon receptor (AHR) and the transcription of CYP1A1 in human HepG2 hepatoma cells. Resveratrol inhibited the increase in cytochrome P450 (CYP) 1A1 mRNA caused by the AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in a concentration-dependent manner. The induction of transcription of an aryl hydrocarbon-responsive reporter vector containing the CYP1A1 promoter by TCDD was likewise inhibited by resveratrol. Resveratrol also inhibited the constitutive level of CYP1A1 mRNA and reporter vector transcription in HepG2 cells. The increase in CYP1A1 enzyme activity induced by TCDD was inhibited by resveratrol. Resveratrol prevented the TCDD-induced transformation of the cytosolic AHR to its nuclear DNA-binding form. However, resveratrol had no effect on the binding of TCDD to the cytosolic AHR. These data demonstrate that resveratrol inhibits CYP1A1 expression in vitro, and that it does this by preventing the binding of the AHR to promoter sequences that regulate CYP1A1 transcription. This activity may be an important part of the chemopreventive activity of resveratrol.

    Topics: Anticarcinogenic Agents; Carcinoma, Hepatocellular; Cytochrome P-450 CYP1A1; Cytosol; Humans; Liver Neoplasms; Polychlorinated Dibenzodioxins; Promoter Regions, Genetic; Receptors, Aryl Hydrocarbon; Resveratrol; RNA, Messenger; Stilbenes; Tumor Cells, Cultured

1998
The dual role of 2-acetylaminofluorene in hepatocarcinogenesis: specific targets for initiation and promotion.
    Mutation research, 1997, May-12, Volume: 376, Issue:1-2

    2-Acetylaminofluorene (AAF) is one of the most widely studied model carcinogens. It produces liver tumors in rats. Comparison with other arylamides shows that promutagenic DNA lesions are necessary but not sufficient to explain this tissue-specific effect. Mutagenicity of AAF was studied in AS52 cells and compared with that of 2-acetylaminophenanthrene and trans-4-acetylaminostilbene which are incomplete carcinogens in rat liver. The major mutations were G to T transversions in all cases. All three acetamides acted as initiators in an initiation-promotion experiment with phenobarbital as a promoter. Chronic toxic effects of AAF were attributed to specific effects of AAF metabolites on mitochondrial respiration. Electron drainage by 2-nitrosofluorene causes an uncoupling effect on oxidative phosphorylation in vitro. Corresponding compensatory effects were observed in vivo. Initiating as well as promoting properties of AAF are therefore considered responsible for the generation of rat liver tumors. The results support the hypothesis that genotoxic effects generate initiated cells which begin to proliferate only when microcirculation is disturbed due to cirrhotic alterations. These are triggered by non-genotoxic interference with mitochondrial respiration and oxidative phosphorylation.

    Topics: 2-Acetylaminofluorene; Animals; Cell Survival; Liver Neoplasms; Mitochondria, Liver; Mutagens; NAD; Oxidation-Reduction; Phenanthrenes; Rats; Rats, Wistar; Stilbenes

1997
Synergistic effects of trans-4-acetylaminostilbene and 2-acetylaminofluorene at the level of tumor initiation.
    Chemico-biological interactions, 1994, Volume: 93, Issue:1

    The synergism of two carcinogenic aromatic amines with different tissue specificities was studied at the level of initiation in Wistar rats. Gamma-glutamyl transpeptidase and glutathione S-transferase P were used as markers for preneoplastic foci in liver. 2-Acetylaminofluorene (AAF) is a complete rat liver carcinogen, whereas trans-4-acetylaminostilbene (AAS) produces ear duct tumors quite selectively, but also acts as a strong initiator in rat liver. When these carcinogens were administered sequentially as two doses of each or simultaneously as four doses of a mixture to neonate animals, which then were treated with phenobarbital in the drinking water for promotion, the initiating activity was additive. When these chemicals were given to young adult animals within 4 weeks in two series of four doses, followed by partial hepatectomy and phenobarbital in the drinking water, the number of preneoplastic foci was greater in groups which had received AAS in both series or in the second series after AAF than in those groups which had received only AAF or AAF in the second series. The average size of foci depended clearly on the sequence in which the two carcinogens were administered. The foci were larger when AAF was given after AAS. The results support the notion that AAS is a strong initiator in rat liver, and that AAF, which is a complete liver carcinogen, has promoting properties under certain circumstances in addition to its initiating properties. The two carcinogens seem to produce the initiating lesions independently but the extent of initiation is additive in this model situation. The simplified neonatal rat liver model appears to be particularly suitable for investigating initiating properties and is proposed for studies of synergistic effects of genotoxic chemicals on the initiation stage, independent of organotropism. It avoids a number of complicating factors related to treatment schedule, forced proliferation rate and toxicity in other models.

    Topics: 2-Acetylaminofluorene; Aging; Animals; Biomarkers, Tumor; Carcinogens; Drug Synergism; Female; gamma-Glutamyltransferase; Glutathione Transferase; Hepatectomy; Liver; Liver Neoplasms; Male; Phenobarbital; Precancerous Conditions; Rats; Rats, Wistar; Sex Factors; Stilbenes; Time Factors

1994
Glutathione S-transferase mu in human lymphocyte and liver: role in modulating formation of carcinogen-derived DNA adducts.
    Carcinogenesis, 1991, Volume: 12, Issue:12

    Glutathione transferase (GT) activity towards trans-stilbene oxide (tSBO), benzo[a]pyrene-4,5-oxide (B[a]PO) and 1-chloro-2,4-dinitrobenzene (CDNB) was measured in human liver and lymphocytes. GT-tSBO activity is catalyzed by GT mu which has polymorphic expression in human lymphocytes. Our results show that activity of GT-tSBO in lymphocytes correlates with its activity in liver (r = 0.7, P less than 0.001). GT activity towards BPO (GT-BPO) also correlated with GT-tSBO in lymphocytes and liver. However, interindividual variation of GT-BPO is less than that of GT-tSBO, suggesting that BPO may not be as specific a substrate for GT mu and therefore other GT isozymes may contribute to BPO conjugation. Conjugation of CDNB by GT was not different using cytosols from either high or low GT mu individuals. The functional significance of the GT-mu polymorphism was evaluated by measuring its effect on benzo[a]pyrene (B[a]P)- and aflatoxin B1 (AFB1)-DNA adduct formation in vitro. Human liver cytosols prepared from persons having low or high GT-tSBO activity were incubated with human liver microsomes, calf thymus DNA and B[a]P or AFB1. HPLC analysis revealed that the major B[a]P adduct was dG(N2)-7 beta, 8 alpha-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE-dG). BPDE-dG adducts were decreased equally by cytosols from either low or high conjugators. In contrast, AFB1-DNA binding was inhibited to a greater extent in high conjugators than low conjugators. HPLC analysis demonstrates that adducts formed were AFB1-FAPyr and AFB1-N7-Gua. The correlation between AFB1-DNA adduct concentrations and GT mu activity was highly significant with a correlation coefficient of r = 0.88 at P less than 0.001. These results suggest that GT mu plays an important role in detoxifying DNA reactive metabolites of AFB1 and this enzyme may be a susceptibility marker for AFB1 related liver cancer. Moreover, our data demonstrate that lymphocytes are a reliable surrogate tissue for detecting liver GT mu polymorphisms.

    Topics: Adolescent; Adult; Aflatoxin B1; Aged; Aged, 80 and over; Benzo(a)pyrene; Benzopyrenes; Carcinogens; Chromatography, High Pressure Liquid; Cytosol; Dinitrochlorobenzene; DNA; Female; Glutathione Transferase; Humans; Liver; Liver Neoplasms; Lymphocytes; Male; Middle Aged; Polymorphism, Genetic; Pyrimidines; Stilbenes

1991
A methodology for the analysis of the preneoplastic antigen.
    Carcinogenesis, 1984, Volume: 5, Issue:11

    A highly sensitive assay for the epoxide hydrolase activity associated with the preneoplastic antigen (PNA) has been developed based on the synthesis of cis-stilbene oxide labeled with tritium at approximately 15 Ci/mmol. This assay allows the detection of elevated epoxide hydrolase activity in the serum of humans and rodents as well as in the culture medium bathing isolated hepatocytes. The integrity of the enzymatic assay was confirmed in rodents by precipitating the serum PNA activity using an antibody raised against the rat microsomal epoxide hydrolase. Methodology for the detection of PNA in serum will facilitate evaluation of this antigen as a marker for hepatic neoplasia in man and in experimental animals.

    Topics: Acetaminophen; Adult; Animals; Antigens, Neoplasm; Epoxide Hydrolases; Female; Humans; Liver Neoplasms; Male; Middle Aged; Precancerous Conditions; Rabbits; Rats; Rats, Inbred Strains; Stilbenes

1984
Role of tissue exposure and DNA lesions for organ-specific effects of carcinogenic trans-4-acetylaminostilbene in rats.
    Environmental health perspectives, 1983, Volume: 49

    trans-4-Acetylaminostilbene is acutely toxic to the glandular stomach and produces sebaceous gland tumors in rats quite specifically. Metabolism, tissue exposure to reactive metabolites, DNA binding and persistence of DNA lesions are implicated in tissue susceptibility, but nothing indicates that one of these parameters determines the biological effect. All tissues are exposed to reactive metabolites, liver as a nontarget tissue ranking highest. DNA binding in this tissue, however, is not irrelevant to tumor formation, but rather indicates the presence of initiating lesions. They can be amplified by partial hepatectomy and/or promoters, such as phenobarbital, DDT and diethylstilbestrol. Liver tumors are formed in high yields with these treatments, and mammary tumors also occur. trans-4-Acetylaminostilbene is therefore considered to be an incomplete carcinogen in these tissues and may initiate cells in other tissues as well. Apparently it lacks promoting properties which are supposed to be unrelated to reactive metabolites. It is concluded that DNA lesions do not reflect tissue risk, but rather secondary effects ultimately determine where the process of tumor formation starts and how fast it develops.

    Topics: Animals; Binding Sites; Carcinogens; DNA; DNA Repair; Hepatectomy; Liver Neoplasms; Neoplasms, Experimental; Rats; Stilbenes

1983
Microsomal and cytosolic epoxide hydrolases in rhesus monkey liver, and in normal and neoplastic human liver.
    Life sciences, 1983, Jun-06, Volume: 32, Issue:23

    The cytosolic epoxide hydrolase (EH-LC) was observed in rhesus monkey liver cytosol, and in both normal and neoplastic human liver. Microsomal epoxide hydrolase (EH-LM) was detected not only in the microsomes of normal and neoplastic human liver and normal rhesus monkey liver, but also in the cytosol of these tissues. No apparent differences were observed between the EH-LM in liver cytosol and that in microsomes. No major differences were observed between the levels of EH-LM in the cytosol of normal and that in neoplastic human liver.

    Topics: Animals; Cytosol; Epoxide Hydrolases; Female; Humans; Infant; Liver; Liver Neoplasms; Macaca mulatta; Male; Microsomes, Liver; Middle Aged; Species Specificity; Stilbenes; Styrenes; Tissue Distribution

1983
Enhancing and inhibitory effects of some stilbene and steroid compounds on induction of hepatoma in rats fed 3'-methyl-4-(dimethylamino)azobenzene.
    Gan, 1978, Volume: 69, Issue:3

    Examinations were made on substances that enhance or inhibit the induction of hepatoma in rats previously fed 3'-methyl-4-(dimethylamino)azobenzene (3'-Me-DAB) for a brief period. The substances tested were stilbene, 4-nitrostilbene, 4,4'-dihydroxystilbene, diethylstilbestrol, 17beta-estradiol, and methyltestosterone. Male Donryu rats were fed 0.5 g of 3'-Me-DAB by being maintained on a diet containing 0.06% 3'-Me-DAB, and then they were fed 0.25 or 0.5 g of a test substance with the basal diet. Comparison of the development and yield of hepatomas indicated that 4-nitrostilbene and methyltestosterone had an activity of enhancing 3'-Me-DAB carcinogenesis, whereas diethylstilbestrol and 17beta-estradiol had an activity to retard it. Other substances showed no such activities. The enhancement by 4-nitrostilbene and inhibition by diethylstilbestrol of 3'-Me-DAB carcinogenesis was correlated with their effect on liver nucleic acid metabolism. Feeding of 4-nitrostilbene caused a selective inhibition of Mn2+-(NH4)2SO4-activated RNA polymerase activity of liver nuclei and reduced liver RNA content. The deleterious alteration of liver RNA metabolism was followed by the enhancement in the incorporation of ip-injected 3H-thymidine into DNA of liver nuclei. On the other hand, feeding of diethylstilbestrol increased tissue RNA content without effect on RNA polymerase activity of liver nuclei, and had an activity of increasing the incorporation of 3H-thymidine into DNA. The possible implication of these results with regard to the enhancement and inhibition of hepatocarcinogenesis is discussed.

    Topics: Animals; Azo Compounds; Carcinoma, Hepatocellular; DNA; Drug Synergism; Estradiol; Female; Liver; Liver Neoplasms; Male; Methyltestosterone; Neoplasms, Experimental; Rats; Stilbenes

1978
Effect of TC-17, a triazinylstilbene derivative, on the dissemination of mouse tumors.
    Gan, 1970, Volume: 61, Issue:6

    Topics: Animals; Antibody Formation; Antineoplastic Agents; Blood Coagulation; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Chemical Phenomena; Chemistry; Cyclophosphamide; Depression, Chemical; Drug Synergism; Female; Fibrinolysis; Fluorescent Dyes; Hemolysin Proteins; Hyaluronoglucosaminidase; Liver Neoplasms; Lymphatic Metastasis; Male; Mice; Mitomycins; Mononuclear Phagocyte System; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Neuraminidase; Phagocytosis; Rats; Sarcoma, Yoshida; Skin Transplantation; Stilbenes; Transplantation, Heterologous; Triazines

1970
[Experimental investigation of "syncarcinogenesis". 4. Studies of the induction of cancer in rats with the simultaneous oral administration of diethylnitrosamine and 4-dimethylaminostilbene].
    Zeitschrift fur Krebsforschung, 1965, Volume: 67, Issue:2

    Topics: Animals; Drug Synergism; Ear Canal; Liver Neoplasms; Neoplasms, Experimental; Nitrosamines; Rats; Stilbenes

1965
COMBINED EFFECT OF CARCINOGENS AND CO-CARCINOGENS ON METABOLIC PROCESS.
    Acta - Unio Internationalis Contra Cancrum, 1964, Volume: 20

    Topics: Carcinogens; Liver; Liver Neoplasms; Methylcholanthrene; Neoplasms; Neoplasms, Experimental; p-Dimethylaminoazobenzene; Pharmacology; Rats; Research; Skin Neoplasms; Stilbenes

1964
Combined effect of carcinogens with different actions. I. Development of liver cancer in the rat by the feeding of 4-dimethylaminostilbene following initial feeding of 4-dimethyiaminoazobenzene.
    Gan, 1962, Volume: 53

    Topics: Animals; Bile Ducts, Intrahepatic; Carcinogens; Liver Neoplasms; Neoplasms, Experimental; p-Dimethylaminoazobenzene; Rats; Stilbenes; Stomach Neoplasms

1962
Combine effect of carcinogens with different actions. II. Effect of pretreatment of painting with 20-methylcholanthrene or feeding of 4-dimethylaminostilbene upon carcinogenesis of 4-dimethylaminoazobenzene in the rat.
    Gan, 1962, Volume: 53

    Topics: Animals; Carcinogenesis; Carcinogens; Liver Neoplasms; Methylcholanthrene; Neoplasms; Neoplasms, Experimental; p-Dimethylaminoazobenzene; Paintings; Rats; Stilbenes

1962
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