iridoids and Liver-Neoplasms

Benign and malignant liver tumors are prevalent worldwide. However, there is no effective and comprehensive treatment option for many patients with malignant tumors. Thus, it is critical to prevent benign tumors from worsening, increasing the number of treatment options and effective medications against malignant liver tumors. Oleuropein is a natural and non-toxic product and inhibits tumor growth in various ways.. We employed bioinformatics analysis and molecular docking to identify potential targets of oleuropein. Surface plasmon resonance (SPR) was used to determine the direct binding strength of the target and compounds. Essential functionalities of the targets were analyzed using gene interference approaches. Transcriptomic studies were performed to observe the global genomic alterations occurring inside cells. Changes in glycolytic metabolites and gene and protein expressions were also detected. The anti-tumor benefits of oleuropein in vivo were determined using a tumor-bearing mouse model.. Glucose-6-phosphate isomerase (GPI) was found to be a direct target of oleuropein. GPI discontinuation in liver tumor cells altered the expression of many genes, causing glycogenolysis. GPI interference was associated with PYGM and PFKFB4 inhibitors to inhibit glycolysis in liver tumors. Oleuropein inhibited glycolysis and showed good anti-tumor activity in vivo without adverse side effects.. GPI is a crucial enzyme in glycolysis and the immediate target of oleuropein. GPI expression inside tumor cells affects different physiological functions and signal transduction. Oleuropein has depicted anti-tumor action in vivo without harmful side effects. Moreover, it can control tumor glycolysis through GPI.

Topics: Animals; Carcinoma, Hepatocellular; Glycolysis; Iridoid Glucosides; Iridoids; Liver Neoplasms; Mice; Molecular Docking Simulation

Liver cancer is distinguished as an irredeemable disease. We detected the geniposide (GEN) in HepG2 and Huh7 cell lines.. HepG2 and Huh7 cells were individually induced with GEN dilutions, and then they were transfected with microRNA (miR)-224 overproduction vector (miR-224 mimic) as well as the corresponding negative control (NC). Cell viability was detected with the CCK-8. The apoptotic rate was determined by the Annexin V-FITC/PI with flow cytometer. The migration or invasion rates were separately determined by migration assay or millicell hanging cell culture. The expression of miR-224 was quantified depending on qRT-PCR. Relative proteins were individually determined via western blot.. GEN treatment induced inhibition of HepG2 and Huh7 cells proliferation, migration and invasion but promotion of apoptosis. miR-224 was down-regulated by GEN. Transfection of miR-224 mimic led to high expression of miR-224, which partly rescued cancer cells survival by prohibiting cell apoptosis. Moreover, the production of Wnt/β-catenin and AKT proteins was notably reduced by GEN but increased by overexpressed miR-224.. GEN played anti-tumor roles by targeting miR-224 via blocking the Wnt/β-catenin and AKT cascades in the HepG2 and Huh7 cells.

Topics: Apoptosis; beta Catenin; Cell Movement; Cell Proliferation; Cell Survival; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Iridoids; Liver Neoplasms; MicroRNAs; Neoplasm Invasiveness; Proto-Oncogene Proteins c-akt

As a typical hypervascular tumour, hepatocellular carcinoma (HCC) is predominantly grown through angiogenesis. Geniposide is a promising anti-inflammatory compound found in Gardenia jasminoides, but its effects on the progression of HCC remain untested.. The anti-HCC effects of geniposide was investigated in cellular models and orthotopic HCC mice. Transcriptional regulation of the VEGF promoter was measured by dual-luciferase reporter assay. The anti-angiogenic action of geniposide was measured by tube formation assay. Both surface plasmon resonance techniques and human phospho-kinase array analysis were utilized to validate the relationship between targets of geniposide and hepatocarcinogenesis.. Geniposide exhibited significant disruption of HCC proliferation, invasion, angiogenesis and lung metastasis in orthotopic HCC mice. Geniposide inhibited secretion of VEGF by HCC and suppressed the migration of endothelial cells and the formation of intra-tumour blood vessels, without cytotoxicity and independently of the transcription factor HIF-1α. Direct inhibition of TLR4 by geniposide led to the shutdown of the TLR4/MyD88 pathway and STAT3/Sp1-dependent VEGF production. However, LPS, an agonist of TLR4, restored STAT3/Sp1-related VEGF production in geniposide-inhibited HCC angiogenesis.. The direct inhibitory effect of geniposide on TLR4/MyD88 activation contributes to the suppression of STAT3/Sp1-dependent VEGF overexpression in HCC angiogenesis and pulmonary metastasis. This action of geniposide was not affected by stabilization of HIF-1α. Our study offers a novel anti-VEGF mechanism for the inhibition of HCC.

Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Endothelial Cells; Hypoxia-Inducible Factor 1, alpha Subunit; Iridoids; Liver Neoplasms; Mice; Myeloid Differentiation Factor 88; Neovascularization, Pathologic; Toll-Like Receptor 4; Vascular Endothelial Growth Factor A

The signal transducer and activator of transcription-3 (STAT-3) can facilitate cancer progression and metastasis by being constitutively active via various signaling. Abundant evidence has indicated that STAT-3 may be a promising molecular target for cancer treatment.. In this study, a dual-luciferase assay-based screening of 537 compounds for STAT-3 inhibitors of hepatocellular carcinoma (HCC) cells was conducted, leading to the identification of genipin. Effects of genipin on HCC were assessed in a patient-derived xenograft nude mice model. Western blotting assay, chromatin immunoprecipitation (ChIP) assay, molecular docking study, tube formation assay, three-dimensional top culture assay, histological examination, and immunofluorescence were utilized to evaluate the regulatory signaling pathway.. Our research demonstrated that genipin suppresses STAT-3 phosphorylation and nuclear translocation, which may be attributed to the binding capacity of this compound to the Src homology-2 (SH2) domain of STAT-3. In addition, the therapeutic effects of genipin in a patient-derived HCC xenograft nude mice model were also demonstrated.. In conclusion, genipin showed therapeutic potential for HCC treatment by interacting with the SH2-STAT-3 domain and suppressing the activity of STAT-3. In the future, further research is planned to explore the potential role of genipin in combination with chemotherapy or radiotherapy for HCC.

Topics: Animals; Apoptosis; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Movement; Cell Proliferation; Cholagogues and Choleretics; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Iridoids; Liver Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Neovascularization, Pathologic; Phosphorylation; Signal Transduction; STAT3 Transcription Factor; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Whether and how amarogentin suppresses the angiogenesis effect in liver cancer cells after insufficient radiofrequency ablation (iRFA) are still poorly studied.. The number of liver cancer stem cells (LCSCs) and the level of vascular endothelial growth factor A (VEGFA) were assessed in liver cancer tissue after iRFA. Then, CD133-positive cells were detected in iRFA models of HepG2 and Huh7 cell lines treated with amarogentin. Tube formation assays were applied to observe the antiangiogenesis effects of amarogentin. In addition, the angiogenesis-related molecules p53, delta-like ligand 4 (Dll4), and Notch1 were detected in the iRFA cells and mouse models treated with amarogentin.. The mRNA and protein expression levels of CD133 and VEGFA were significantly higher in the residual liver cancer tissue than in the liver cancer tissues treated by hepatectomy. Amarogentin then markedly decreased the percentage of CD133-positive cells in the iRFA model in both HepG2 and Huh7 cell lines. The number of tubules formed by human umbilical vein endothelial cells (HUVECs) was significantly decreased by amarogentin. Inversely, the antiangiogenesis effect of amarogentin was counteracted after p53 silencing in the iRFA cell models.. Amarogentin prevents the malignant transformation of liver cancer after iRFA via affecting stemness and the p53-dependent VEGFA/Dll4/Notch1 pathway to inhibit cancer cell angiogenesis.

Topics: AC133 Antigen; Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Agents, Phytogenic; Calcium-Binding Proteins; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Hepatectomy; Human Umbilical Vein Endothelial Cells; Humans; Iridoids; Liver Neoplasms; Male; Mice; Neoplastic Stem Cells; Neovascularization, Pathologic; Platelet Endothelial Cell Adhesion Molecule-1; Radiofrequency Ablation; Receptor, Notch1; Signal Transduction; Tumor Burden; Tumor Suppressor Protein p53; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Oleuropein is considered as a new chemotherapeutic agent in human hepatocellular carcinoma (HCC) while, its exact underlying molecular mechanism still not yet explored. In addition, cisplatin is a standard anticancer drug against solid tumors with toxic side effects. Therefore, we conducted this study to assess antitumor activity of oleuropein either alone or in combination with cisplatin against HepG2, human HCC cell lines, via targeting pro-NGF/NGF signaling pathway.. HepG2 cells were treated with cisplatin (20, 50, 100 μM) and oleuropein (100, 200, 300 and 400 μM) as well as some of the cells were treated with 50 μM cisplatin and different concentrations of oleuropein. Gene expressions of nerve growth factor (NGF), matrix metalloproteinase-7 (MMP-7) and caspase-3 were evaluated by real time-PCR. In addition, protein levels of NGF and pro-form of NGF (pro-NGF) were measured by ELISA while, nitric oxide (NO) content was determined colorimetrically.. Cisplatin treatment showed a significant elevation of NO content and pro-NGF protein level with a marked reduction of NGF protein level in addition to the upregulation of caspase-3 along with downregulation of MMP-7 gene expressions in a dose-dependent manner. However, the combination of 50 μM cisplatin and 200 μM oleuropein showed the most potent effect on the molecular level when compared with oleuropein or cisplatin alone.. Our results showed for the first time that the anti-tumor activity of oleuropein against HCC could be attributed to influencing the pro-NGF/NGF balance via affecting MMP-7 activity without affecting the gene expression of NGF. Concurrent treatment with both oleuropein and cisplatin could lead to more effective chemotherapeutic combination against HCC.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Hepatocellular; Caspase 3; Cell Line, Tumor; Cell Proliferation; Cisplatin; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Hep G2 Cells; Humans; Iridoid Glucosides; Iridoids; L-Lactate Dehydrogenase; Liver Neoplasms; Matrix Metalloproteinase 7; Nerve Growth Factor; Oxidative Stress; Signal Transduction

Valjatrate E is an iridoid compound extracted from Valeriana jatamansi Jones herb and is the active ingredient in antitumor activity. Here, we reported its action on tumor invasion and metastasis in the human hepatocellular carcinoma HepG2, aiming at a better understanding of the potential mechanism of action of Valjatrate E. HepG2 cells were treated with Valjatrate E at different concentrations. Wound healing assay and transwell chamber assay were used to determine the effects of Valjatrate E on the migration and invasiveness of HepG2 cells, respectively. Moreover, homogeneity and heterotypic adhesion experiments evaluated the adhesion property of HepG2 cells. The molecular mechanisms by which Valjatrate E inhibited the invasion and migration of HepG2 cells were investigated by gelatin zymography experiment and western blot. Treatment with Valjatrate E inhibited the migration and invasion of HepG2 cells. It achieved this by reducing the expression of matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9), by inhibition of heterogeneous adhesion ability, by blocking mitogen-activated protein kinase (MAPK) signaling via inhibiting the phosphorylation of extracellular signal-regulated kinases (p-ERK). Taken together, these findings provide new evidence that mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) signaling pathway plays an important role in promoting invasion and metastasis in HepG2 cells through p-ERK, and MAPK/ERK signaling pathway may be a therapeutic target for tumor.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Adhesion; Cell Line, Tumor; Cell Movement; Extracellular Signal-Regulated MAP Kinases; Hep G2 Cells; Humans; Iridoids; Liver Neoplasms; MAP Kinase Signaling System; Matrix Metalloproteinases; Neoplasm Invasiveness; Neoplasm Metastasis; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Plants, Medicinal; Protein Kinase Inhibitors; Signal Transduction; Valerian

Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cell Survival; Hep G2 Cells; Humans; Iridoids; Liver Neoplasms; Molecular Structure; Plant Extracts; Plant Stems; Rubiaceae

Metastasis of hepatocellular carcinoma (HCC) is usually unrecognized before any pathological examination, resulting in time-taking treatment and poor prognosis. As a consequence, HCC patients usually show symptoms of depression. In order to suppress such psychiatric disorders and to facilitate better treatment outcome, antidepressants are prescribed. Up to present, information about the effect of antidepressants on HCC is still lacking. Therefore, we chose fluoxetine (FXT), one of the top five psychiatric prescriptions in the United States, together with the HepG2 cell model to explore its effect on HCC. Our study found that FXT (5 µM) increased the migratory distance of HepG2 cells by a factor of nearly 1.7 compared to control. In addition, our study also investigated the effect of genipin (GNP), which is an active compound from Gardenia jasminoides Ellis fruit (family Rubiaceae), on the FXT-induced HepG2 cells. Our study found that 30 and 60 µM GNP reduced the migratory distance by 42% and 74% respectively, compared to FXT treatment alone. Furthermore, we also found that FXT upregulated matrix metalloproteinases (MMPs) genes, increased the protein expression of MMPs, urokinase-type plasminogen activator (uPA), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), activator protein 1 (AP-1), phosphorylated mitogen-activated protein kinase (P-p38), phosphorylated protein kinase B (P-Akt), downregulated tissue inhibitor metalloproteinases (TIMPs) genes and decreased the TIMPs proteins expression whereas, GNP fully counteracted the action of FXT. Conclusively, this study has provided valuable information regarding the possible molecular mechanisms through which FXT affects the metastatic invasiveness of HepG2 cells and evidences to support that GNP counteracts such effect via the same molecular mechanisms.

Topics: Carcinoma, Hepatocellular; Fluoxetine; Hep G2 Cells; Humans; Iridoids; Liver Neoplasms; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Transcription Factor AP-1

Amarogentin has been reported to have a preventive effect on liver cancer via inducing cancer cell apoptosis. We attempted to elucidate the roles of p53-associated apoptosis pathways in the chemopreventive mechanism of amarogentin. The findings of this study will facilitate the development of a novel supplementary strategy for the treatment of liver cancer.. The purity of amarogentin was assessed by high-performance liquid chromatography. The inhibitory ratios of the liver cell lines were determined using a Cell Counting Kit-8 following treatment with a gradient concentration of amarogentin. Cell apoptosis was detected by flow cytometry using annexin V-fluorescein isothiocyanate/propidium iodide kits. The gene and protein expression of p53-associated molecules, such as Akt, human telomerase reverse transcriptase, RelA, and p38, was detected by real-time quantitative polymerase chain reaction, Western blotting, and immunohistochemical staining in liver cancer cells and mouse tumor tissues after treatment with amarogentin.. The inhibitory effect of amarogentin on cell proliferation was more obvious in liver cancer cells, and amarogentin was more likely to induce the apoptosis of liver cancer cells than that of normal liver cells. The gene and protein expression levels of Akt, RelA, and human telomerase reverse transcriptase were markedly higher in the control group than in the preventive group and treatment groups. Only the expression of human telomerase reverse transcriptase was downregulated, accompanied by the upregulation of p53.. The results of our study suggest that amarogentin promotes apoptosis of liver cancer cells by the upregulation of p53 and downregulation of human telomerase reverse transcriptase and prevents the malignant transformation of these cells.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Iridoids; Liver Neoplasms; Male; Mice; Signal Transduction; Telomerase; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Amarogentin, a secoiridoid glycoside isolated from medicinal plant Swertia chirata, was found to restrict CCl4 /N-nitrosodiethyl amine (NDEA) induced mouse liver carcinogenesis by modulating G1/S cell cycle check point and inducing apoptosis. To understand its therapeutic efficacy on stem cell self renewal pathways, prevalence of CD44 positive cancer stem cell (CSC) population, expressions (mRNA/protein) of some key regulatory genes of self renewal Wnt and Hedgehog pathways along with expressions of E-cadherin and EGFR were analyzed during the liver carcinogenesis and in liver cancer cell line HepG2. It was observed that amarogentin could significantly reduce CD44 positive CSCs in both pre and post initiation stages of carcinogenesis than carcinogen control mice. In Wnt pathway, amarogentin could inhibit expressions of β-catenin, phospho β-catenin (Y-654) and activate expressions of antagonists sFRP1/2 and APC in the liver lesions. In Hedgehog pathway, decreased expressions of Gli1, sonic hedgehog ligand, and SMO along with up-regulation of PTCH1 were seen in the liver lesions due to amarogentin treatment. Moreover, amarogentin could up-regulate E-cadherin expression and down-regulate expression of EGFR in the liver lesions. Similarly, amarogentin could inhibit HepG2 cell growth along with expression and prevalence of CD44 positive CSCs. Similar to in vivo analysis, amarogentin could modulate the expressions of the key regulatory genes of the Wnt and hedgehog pathways and EGFR in HepG2 cells. Thus, our data suggests that the restriction of liver carcinogenesis by amarogentin might be due to reduction of CD44 positive CSCs and modulation of the self renewal pathways. © 2015 Wiley Periodicals, Inc.

Topics: Animals; Carbon Tetrachloride; Cell Proliferation; Cell Survival; Female; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Hep G2 Cells; Humans; Hyaluronan Receptors; Iridoids; Liver Neoplasms; Mice; Neoplastic Stem Cells; Wnt Signaling Pathway

Accumulating evidences postulated the influential roles of macrophages in mediating hepatocellular carcinoma (HCC) initiation and progression. In this study, we demonstrate that a small molecule, genipin reduced HCC growth through suppressing IRE1α-mediated infiltration and priming of tumour associated macrophages (TAMs). Oral administration of genipin (30mg/kg/2days) suppressed orthotopic HCC tumour growth without challenging the viability and proliferation of HCC cells. Genipin reduced infiltration of inflammatory monocytes into liver and tumour thereby suppressed TAMs presence in HCC microenvironment. Suppression of HCC growth was diminished in HCC-implanted mice with depletion of TAMs by liposome clodronate. Genipin inhibited the TAMs migration, and reduced expression of TAMs-derived inflammatory cytokines that favors HCC proliferation. This is revealed by the in vivo deletion of IRE1α on TAMs in genipin-treated HCC-implanted mice. Diminishing IRE1α neutralised the inhibitory effect of genipin on TAMs. Silencing the expression of IRE1α greatly reduced TAMs migration and expression of inflammatory cytokines that prime HCC proliferation. Suppression of IRE1α led to reduced XBP-1 splicing and NF-κB activation. The reduced association of IRE1α with TRAF2 and IKK complex may be responsible for the genipin-mediated inactivation of NF-κB. The findings show the important role of TAMs in inhibitory effect of genipin on HCC, and TAMs-expressing IRE1α as a promising target for disrupting the tumour environment that favor of HCC development.

Topics: Animals; Carcinoma, Hepatocellular; Cell Proliferation; Endoribonucleases; Iridoids; Liver Neoplasms; Macrophages; Mice; Protein Serine-Threonine Kinases; Tumor Microenvironment

Oleuropein is a polyphenol, that is found in extra‑virgin olive oil. Previous studies have shown that oleuropein inhibits cell proliferation and induces apoptosis in breast cancer, colorectal cancer and thyroid cancer. The aim of the present study was to investigate the effects of oleuropein in hepatocellular carcinoma (HCC) cells. The results of Cell Counting Kit 8 and flow cytometric analysis indicated that oleuropein effectively inhibited cell viability and induced apoptosis in HepG2 human hepatoma cells in a dose‑dependent manner, through activation of the caspase pathway. Proapoptotic Bcl‑2 family members, BAX and Bcl‑2, were involved in oleuropein‑induced apoptosis. The phosphatidylinositol 3‑kinase/protein kinase B (PI3K/AKT) signaling pathway was also shown to be involved in this process. Oleuropein was demonstrated to suppress the expression of activated AKT. In addition, AKT overexpression promoted cell survival following treatment with oleuropein, while inhibition of AKT promoted cell death. Furthermore, the data demonstrated that oleuropein induces the production of reactive oxygen species (ROS) and that the function of oleuropein is, at least partially, ROS‑dependent. These results suggest that oleuropein may be a promising novel chemotherapeutic agent in hepatocellular carcinoma.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Carcinoma, Hepatocellular; Caspases; Cell Line, Tumor; Glutathione; Hep G2 Cells; Humans; Iridoid Glucosides; Iridoids; Liver Neoplasms; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction

An oriental medicinal formulation, Huanglian Jiedu Decoction (HLJDD), has been well documented in few Traditional Chinese Medicine Classics 1300 years ago for treatment of heat and dampness-related diseases. Its effect is well accepted in Asian community, including China, Japan and Korea. Recent studies have postulated HLJDD as a regimen for cancer treatment, especially liver cancer, but the underlying mechanism is unknown. The aim of this study was to examine the suppressive effect of HLJDD on the growth of hepatocellular carcinoma (HCC) and its possible underlying mechanism.. Chemical composition of HLJDD was analyzed by high performance liquid chromatography. The tumor suppressive effect of HLJDD was determined on both HCC cells and xenograft model. Nascent protein synthesis was detected with Click-IT protein labeling technology; protein expression was determined by immunoblotting and imunnohistochemical analysis.. Quality analysis revealed that HLJDD of different batches is consistent in both chemical composition and bioactivities. HLJDD inhibited HCC cell proliferation at its non-toxic doses, and suppressed growth and angiogenesis in xenografted murine model. HLJDD suppressed the synthesis of nascent protein via inactivation of eEF2 without deregulating the translation initiation factors. The major components in HLJDD, geniposide, berberine and baicalin, additively act on eEF2, and contributed to the responsible activity. HLJDD-activated eEF2 kinase (eEF2K) led to eEF2 inactivation, and activation of AMPK signaling may be responsible for the eEF2K induction. Blocked AMPK activity in HLJDD-treated HCC cells attenuated eEF2K activation as well as the inhibitory effect of the formula. In nutrient deprived HCC cells with inactivated eEF2, the inhibitory effect of HLJDD in tumor cell expansion was interfered.. Our results indicate that HLJDD has potential in blocking HCC progression with involvement of eEF2 inhibition.

Topics: Animals; Antineoplastic Agents; Berberine; Carcinoma, Hepatocellular; Cell Line, Tumor; Drugs, Chinese Herbal; Elongation Factor 2 Kinase; Female; Flavonoids; Humans; Iridoids; Liver Neoplasms; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Phytotherapy; Xenograft Model Antitumor Assays

Nyctanthes arbortristis Linn (Oleaceae) is widely distributed in sub-Himalayan regions and southwards to Godavari, India commonly known as Harsingar and Night Jasmine. In continuation of our drug discovery programme on Indian medicinal plants, we isolated arbortristoside-A (1) and 7-O-trans-cinnamoyl 6β-hydroxyloganin (2) from the seeds of N. Arbortristis, which exhibited moderate in vitro anticancer activity. Chemical transformation of 2 led to significant improvement in the activity in derivative 8 and 15 against HepG2 (human hepatocellular carcinoma), MCF-7 (breast adenocarcinoma) cell lines. The compounds 8 and 15 were also capable of cell cycle arrest and caspase dependent apoptosis in HepG2 cell lines. These iridoid derivatives hold promise for developing safer alternatives to the marketed drugs.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Breast Neoplasms; Carcinoma, Hepatocellular; Caspases; Cell Cycle Checkpoints; Cinnamates; Hep G2 Cells; Humans; India; Iridoid Glucosides; Iridoids; Liver Neoplasms; MCF-7 Cells; Neoplasms; Oleaceae; Phytotherapy; Plant Extracts; Seeds

Mitochondrial uncoupling protein 2 (UCP2) is suggested to have a role in the development of nonalcoholic steatohepatitis (NASH). However, the mechanism remains unclear. Autophagy is an important mediator of many pathological responses. This study aims to investigate the relationship between UCP2 and hepatoma cells autophagy in palmitic acid- (PA-) induced lipotoxicity. H4IIE cells were treated with palmitic acid (PA), and cell autophagy and apoptosis were examined. UCP2 expression, in association with LC3-II and caspase-3, which are indicators of cell autophagy and apoptosis, respectively,was measured. Results demonstrated that UCP2 was associated with autophagy during PA-induced hepatic carcinoma cells injury. Tests on reactive oxygen species (ROS) showed that UCP2 overexpression strongly decreases PA-induced ROS production and apoptosis. Conversely, UCP2 inhibition by genipin or UCP2 mRNA silencing enhances PA-induced ROS production and apoptosis. Autophagy partially participates in this progress. Moreover, UCP2 was associated with ATP synthesis during PA-induced autophagy. In conclusion, increasing UCP2 expression in hepatoma cells may contribute to cell autophagy and antiapoptotic as result of fatty acid injury. Our results may bring new insights for potential NASH therapies.

Topics: Apoptosis; Autophagy; Carcinoma, Hepatocellular; Caspase 3; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Ion Channels; Iridoids; Liver Neoplasms; Microtubule-Associated Proteins; Mitochondrial Proteins; Non-alcoholic Fatty Liver Disease; Palmitic Acid; Reactive Oxygen Species; RNA, Messenger; Uncoupling Protein 2

Hepatocellular carcinoma is one of the most malignant human cancers with high metastatic potential. The aim of this study is to investigate the anti-metastatic effect of genipin and its underlying mechanism.. The anti-metastatic potential of genipin was evaluated by both cell and animal model. Wound healing and invasion chamber assays were introduced to examine the anti-migration and anti-invasion action of genipin in human hepatocellular carcinoma cell HepG2 and MHCC97L; orthotopical implantation model was used for in vivo evaluation. Gelatin Zymography, Immunoblotting, quantitative real-time polymerase chain reaction and ELISA assays were used to study the mechanisms underlying genipin's anti-metastatic effect.. Genipin suppresses the motility and invasiveness of HepG2 and MHCC97L at non-toxic doses, which may be correlated to the inhibition of genipin on MMP-2 activities in the cells. No significant reduced expression of MMP-2 was observed either at mRNA or at protein level. Furthermore, genipin could specifically up-regulate the expression of TIMP-1, the endogenous inhibitor of MMP-2 activities. Silencing of TIMP-1 by RNA interference abolishes genipin's anti-metastaic effect. Activation of p38 MAPK signaling was observed in genipin-treated cells, which is responsible for the TIMP-1 overexpression and MMP-2 inhibition. Presence of SB202190, the p38 MAPK inhibitor, attenuates the anti-metastatic potential of genipin in hepatocellular carcinoma. Orthotopical implantation model showed that genipin could suppress the intrahepatic metastatic as well as tumor expansion in liver without exhibiting potent toxicity.. Our findings demonstrated the potential of genipin in suppressing hepatocellular carcinoma metastasis, and p38/TIMP-1/MMP-2 pathway may be involved as the key mechanism of its anti-metastasis effect.

Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cholagogues and Choleretics; Down-Regulation; Gene Silencing; Humans; Imidazoles; Iridoids; Liver Neoplasms; Matrix Metalloproteinase 2; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Second Primary; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; Pyridines; RNA, Small Interfering; Signal Transduction; Tissue Inhibitor of Metalloproteinase-1; Up-Regulation

Pedicularioside G is a new compound of phenylpropanoid glycosides, isolated from Pedicularis striata in our laboratory. Pedicularioside G inhibited two major angiogenic responses, human umbilical vein endothelial cell proliferation and migration, as well as neovascularization in a chicken embryo chorioallantoic membrane model. In addition, pedicularioside G inhibited human hepatoma cells proliferation and migration in vitro along with transplanting tumour formation and growth in a chicken embryo chorioallantoic membrane model. So pedicularioside G has anti-angiogenic, antitumour growth, antimetastatic and antitumoural effects. Pedicularioside G also remarkably reduced reactive oxygen species level in both vein endothelial cells and hepatoma cells in a concentration-dependent manner. These results suggest that the anti-angiogenic and antitumoural effects of pedicularioside G might partially attribute to its antioxidative activity.

Topics: Angiogenesis Inhibitors; Animals; Antioxidants; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chick Embryo; Chorioallantoic Membrane; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drugs, Chinese Herbal; Endothelium, Vascular; Glucosides; Humans; In Vitro Techniques; Iridoid Glucosides; Iridoids; Liver Neoplasms; Neovascularization, Pathologic; Pedicularis; Plant Extracts; Reactive Oxygen Species