ginsenoside-rg3 and Liver-Neoplasms

Purpose To conduct a single-center, open-label, randomized, controlled trial to compare the effectiveness and safety of (a) ginsenoside Rg3 combined with transcatheter arterial chemoembolization (TACE) and (b) TACE alone in patients with advanced hepatocellular carcinoma (HCC). Materials and Methods This trial was approved by the Fudan University Zhongshan Hospital ethics committee and was registered with the Chinese Clinical Trial Registry (ChiCTR-TRC-11001643). After informed consent was obtained, 228 patients with advanced HCC (Barcelona Clinic Liver Cancer stage C) were randomly assigned to receive an Rg3 capsule and undergo TACE (n = 152; mean age ± standard deviation, 52.4 years ± 11.8; 84.2% men) or undergo TACE alone (n = 76; mean age, 52.4 years ± 10.4; 82.9% men). TACE was performed by using iodized oil with epirubicin and gelatin sponge after oxaliplatin and 5-fluorouracil were infused. The primary end point was overall survival. Secondary end points included time to progression, time to untreatable progression, disease control rate, and safety. Data were compared with the log-rank test, and survival curves were generated with the Kaplan-Meier method. Results Median overall survival was 13.2 months (95% confidence interval [CI]: 11.15, 15.26) in the TACE with Rg3 group and 10.1 months (95% CI: 9.14, 11.06) in the control group (hazard ratio, 0.63 [95% CI: 0.46, 0.85]; P = .002). Median time to progression (4.3 vs 3.2 months, respectively; P = .151) and median time to untreatable progression (8.3 vs 7.3 months, respectively; P = .063) were similar in the two groups. Disease control rate was 69.7% in the TACE with Rg3 group versus 51.3% in the control group (P = .012). Constipation and epistaxis were more frequent in the Rg3 with TACE group (P < .05). Importantly, Rg3 alleviated some TACE-related adverse syndromes and blood anomalies. Conclusion In patients with advanced HCC and adequate liver function, the combination of TACE and ginsenoside Rg3 may prolong overall survival when compared with TACE alone. (©) RSNA, 2016.

Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Combined Modality Therapy; Female; Ginsenosides; Humans; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Survival Rate

Hepatocellular carcinoma (HCC) is the most common pathological type of primary hepatic carcinoma. This study investigated the effects of ginsenoside Rg3 (Rg3) and sorafenib (SFN) combination therapy on HCC progression. The HCC-related data were obtained from TCGA database, and the data of HK2 mRNA, clinicopathological features, and survival outcomes were extracted using R Programming 4.0. The human hepatoma cell lines HepG2 and Bel7404 were used. Cell viability was tested using the MTT assay. Glucose consumption and lactate levels of HCC cells were detected using the corresponding kits. Western blotting was used to determine the protein expression of HK2, PI3K, and Akt. HK2 was overexpressed in patients with HCC. Compared with patients with overexpressed HK2, those with low levels of HK2 achieved a longer survival time. In addition, the Rg3 and SFN combination therapy significantly reduced cell viability, glucose consumption, lactate levels, and protein expression of HK2, PI3K, and Akt in HCC cells. Additionally, the Rg3 and SFN combination therapy exhibited a better effect than the single drug group. Inhibition of the PI3K/Akt signaling pathway or exogenous lactate intervention reversed the effects of Rg3 and SFN combination therapy in HCC cells. In conclusion, Rg3 has a synergistic effect on the sensitivity of HepG2 and Bel7404 hepatoma cells to SFN, which is related to HK2-mediated glycolysis and the PI3K/Akt signaling pathway.

Topics: Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Ginsenosides; Glucose; Glycolysis; Humans; Lactates; Liver Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Sorafenib

Liposomes co-loaded with ursolic acid and ginsenoside Rg3 (UA+Rg3-LIP) were prepared to study their effects on the proliferation, apoptosis and cell cycle of hepatocellular carcinoma (HCC) cells.. Liposomes were prepared by reverse evaporation, and then UA+Rg3-LIP were prepared by the pH gradient method, and followed by liposome characterization. Next, the effects of UA+Rg3-LIP on the proliferation, apoptosis and cell cycle of HepG2 cells were investigated by MTT method and flow cytometry at the cell level.. The entrapment efficiency of UA in UA+Rg3-LIP was 78.52% and that of Rg3 was 71.68%, as assayed by low-temperature ultracentrifugation. The in vitro release rates of UA+Rg3-LIP and UA+Rg3 detected by the dialysis membrane method were 1-10 h. The release rate of UA+Rg3 was close to 100%; that of UA+Rg3-LIP was decreased after 10 h and approached 100% after 24 h. It was further confirmed by cell experiments that UA+Rg3-LIP could significantly reduce cells viability while at the same time increase their apoptosis rate and raise the proportion of cells in the G0/G1 phase.. Liposomes co-loaded with ursolic acid and ginsenoside Rg3 could affect cell proliferation, apoptosis and cell cycle, thus slowing down the in vitro drug release ability of HCC.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Cycle; Cell Proliferation; Cell Survival; Ginsenosides; Hep G2 Cells; Humans; Liposomes; Liver Neoplasms; Triterpenes; Ursolic Acid

Ginsenoside Rg3, a natural compound, has been reported to function as an anticancer agent for hepatoma carcinoma, while the mechanisms underlying the anticancer effects are not clear. Therefore, the objective of our study was to explore the impact of RG3 on cell migration and invasion by regulating the lncRNA HOX antisense intergenic (HOTAIR) expression involving PI3K/AKT signaling pathway. qRT-PCR was utilized to measure the mRNA expression of HOTAIR. Furthermore, HOTAIR overexpression plasmids were transfected to SMMC-7721 and SK-Hep-1 cells. Additionally, MTT assay was used to evaluate the proliferation of transfected cells. The scratch and transwell assays were used to determine the migration and invasion ability of the cell. The protein levels were determined with Western blot. lncRNA HOTAIR was overexpressed in SMMC-7721 and SK-Hep-1 cells. Ginsenoside-Rg3 reduced the level of lncRNA HOTAIR. Overexpressed lncRNA HOTAIR offset ginsenoside-Rg3 inhibited proliferation, migration and invasion of HCC cells. Furthermore, ginsenoside-Rg3 decreased the expression of p-AKT, p-PI3K, matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (MMP9), which was reversed after the treatment of HOTAIR. LncRNA HOTAIR was overexpressed in SMMC-7721 cells. Ginsenoside-Rg3 could reduce the expression of lncRNA HOTAIR, resulting in the inhibited cell proliferation, migration and invasion. Furthermore, ginsenoside-Rg3 inhibited cell proliferation and invasion ability through the PI3k/AKT pathway. Thus, ginsenoside-Rg3 might be a potential and effective treatment for HCC.

Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Gene Expression Regulation, Neoplastic; Ginsenosides; HEK293 Cells; Humans; Liver Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; RNA, Long Noncoding

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. The prognosis of HCC remains very poor; thus, an effective treatment remains urgent. Herein, a type of nanomedicine is developed by conjugating Fe@Fe

Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Ginsenosides; Humans; Liver Neoplasms; Mice; Nanoparticles; Neoplasm Metastasis

The overexpression of sialic acids and sialyltransferases (STs) during malignant transformation and progression could result in the aberrant sialylation of cancer cells. Therefore, interfering the sialic acid synthesis might be an effective pathway in cancer therapy. In this study, we assessed that the antitumor inhibitors of 20(S)-ginsenosides Rg3, 20(R)-ginsenosides Rg3, 20(S)-ginsenosides Rh2, and 20(R)-ginsenosides Rh2 could block the sialoglycans in liver cancer cells HepG2. The results showed that these four compounds could inhibit the expressions of the total and free sialic acid at different levels in HepG2, respectively; also, it showed dose dependence. In addition, the results of the enzyme-linked immunosorbent assay showed that the above four compounds can inhibit the expression of STs significantly. We also found that these compounds could mediate the block of sialylation of α2,3- and α2,6-linked sialic acids in HepG2 cells by flow cytometry. Meanwhile, the results of the molecular docking investigation showed that these compounds showed strong interaction with ST6GalI and ST3GalI. These results verified that the ginsenosides have a powerful inhibiting aberrant sialylation, and it laid a theoretical foundation for further research on the investigation of ginsenosides as the target inhibitors on STs.

Topics: Gene Expression Regulation, Neoplastic; Ginsenosides; Hep G2 Cells; Humans; Liver Neoplasms; Molecular Docking Simulation; Sialic Acids; Sialyltransferases

Microvessel density is a marker of tumor angiogenesis activity for development and metastasis. Our preliminary study showed that ginsenoside Rg3 (Rg3) induces apoptosis in hepatocellular carcinoma (HCC). The murine HCC cells Hep1-6 were implanted in the liver of mouse. With oral feeding of Rg3 (10 mg/kg once a day for 30 days), the quantitative analysis of apoptosis was performed by using pathology and a transmission electron microscope and microvessel density was quantitatively measured by immunohistochemical staining of the CD105 antibody. The mice treated with Rg3 (. With oral feeding of Rg3 daily in the first 30 days on tumor implantation, Rg3 significantly decreased the orthotopic tumor growth and increased the survival of animals (. Rg3 inhibited the activation of microtumor vessel formation

Topics: Animals; Apoptosis; Body Weight; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Female; Ginsenosides; Kaplan-Meier Estimate; Liver Neoplasms; Mice, Inbred C57BL; Microvessels; Models, Biological; Neovascularization, Pathologic

The present study aims to investigate the effects of ginsenoside Rg3 combined with oxaliplatin on the proliferation and apoptosis of hepatocellular carcinoma cells and the related mechanism. In this study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was applied to examine the proliferation rate of hepatocellular carcinoma cell SMMC-7721 with different treatment. Flow cytometry was performed to examine apoptosis rate of hepatocellular carcinoma cells with different treatment. Immunofluorescence and Western blot methods were used to evaluate the expressions of proliferating cell nuclear antigen (PCNA) and cyclin D1 in different groups. We found that ginsenoside Rg3, oxaliplatin or ginsenoside Rg3 + oxaliplatin significantly suppressed the proliferation and promoted the apoptosis of SMMC-7721. Meanwhile, ginsenoside Rg3, oxaliplatin or ginsenoside Rg3 + oxaliplatin also significantly inhibited the expressions of PCNA and cyclin D1. Moreover, compared with ginsenoside Rg3 group and oxaliplatin group, the effect of ginsenoside Rg3 + oxaliplatin was more remarkable. Taken together, cells treated with oxaliplatin+ ginsenoside enhanced the anti-tumor effect and may inhibit the proliferation and promoted apoptosis of hepatocellular carcinoma via regulating the expression of PCNA and cyclin D1.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Down-Regulation; Drug Synergism; Ginsenosides; Humans; Liver Neoplasms; Oxaliplatin; Proliferating Cell Nuclear Antigen

Sorafenib, a multikinase inhibitor for hepatocellular carcinoma treatment, inhibits the Raf/MAPK/ERK signaling pathway. However, PI3K/Akt signaling pathway is activated by Sorafenib and cross-talks with the Raf/MAPK/ERK signaling pathway, leading to drug resistance. 20(S)-Ginsenoside Rg3 has been reported with significant anticancer effect to numerous carcinomas by inhibition of PI3K-Akt signaling pathway. Hence, we aim to examine the synergistic anticancer activity of 20(S)-Ginsenoside Rg3 and Sorafenib via modulation of PTEN/Akt signaling pathway. Human hepatocellular carcinoma cell lines HepG2 and Huh7 were used. Cell viability, clonogenic assay, apoptosis assay, western blot analysis, xenograft treatment and immunohistochemistry were carried out. The viability of hepatocellular carcinoma cells significantly decreased by the treatment of Sorafenib combined with 20(S)-Ginsenoside Rg3, as well as the enhanced apoptotic rates. The levels of PTEN, Bax and cleaved caspase-3 expression increased, while the levels of phospho-PDK1 and phospho-Akt expression decreased by the treatment of Sorafenib combined with 20(S)-Ginsenoside Rg3. In vivo, the tumor volumes and weight decreased in the Sorafenib combined with 20(S)-Ginsenoside Rg3 group. The results demonstrated the synergistic anticancer activity of 20(S)-Ginsenoside Rg3 and Sorafenib in HCC by modulating PTEN/Akt signaling pathway. These findings suggest a promising strategy for HCC treatment, which could be performed in a sufficiently frequent manner.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Survival; Drug Synergism; Gene Expression Regulation, Neoplastic; Ginsenosides; Hep G2 Cells; Humans; Liver Neoplasms; Niacinamide; Phenylurea Compounds; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Signal Transduction; Sorafenib

Ginsenoside Rg3, a bioactive constituent isolated from Panax ginseng, exhibits antitumorigenic, antioxidative, antiangiogenic, neuroprotective and other biological activities are associated with the regulation of multiple genes. DNA methylation patterns, particularly those in the promoter region, affect gene expression, and DNA methylation is catalyzed by DNA methylases. However, whether ginsenoside Rg3 affects DNA methylation is unknown. High performance liquid chromatography assay, MspI/HpaII polymerase chain reaction (PCR) and reverse transcription‑quantitative PCR were performed to assess DNA methylation. It was demonstrated that 20(S)‑ginsenoside Rg3 treatment resulted in increased inhibition of cell growth, compared with treatment with 20(R)‑ginsenoside Rg3 in the human HepG2 hepatocarcinoma cell line. It was additionally revealed that treatment with 20(S)‑ginsenoside Rg3 reduced global genomic DNA methylation, altered cystosine methylation of the promoter regions of P53, B cell lymphoma 2 and vascular endothelial growth factor, and downregulated the expression of DNA methyltransferase (DNMT) 3a and DNMT3b more than treatment with 20(R)‑ginsenoside Rg3 in HepG2 cells. These results revealed that the modulation of DNA methylation may be important in the pharmaceutical activities of ginsenoside Rg3.

Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cell Proliferation; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; DNA Methyltransferase 3A; DNA Methyltransferase 3B; Gene Expression Regulation, Neoplastic; Ginsenosides; Hep G2 Cells; Humans; Liver Neoplasms; Panax

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. High mortality from HCC is mainly due to widespread prevalence and the lack of effective treatment, since systemic chemotherapy is ineffective, while the targeted agent Sorafenib extends median survival only briefly. The steroidal saponin 20(S)-ginsenoside Rg3 from Panax ginseng C.A. Meyer is proposed to chemosensitize to various therapeutic drugs through an unknown mechanism. Since autophagy often serves as cell survival mechanism in cancer cells exposed to chemotherapeutic agents, we examined the ability of Rg3 to inhibit autophagy and chemosensitize HCC cell lines to doxorubicin in vitro. We show that Rg3 inhibits late stage autophagy, possibly through changes in gene expression. Doxorubicin-induced autophagy plays a protective role in HCC cells, and therefore Rg3 treatment synergizes with doxorubicin to kill HCC cell lines, but the combination is relatively nontoxic in normal liver cells. In addition, Rg3 was well-tolerated in mice and synergized with doxorubicin to inhibit tumor growth in HCC xenografts in vivo. Since novel in vivo inhibitors of autophagy are desirable for clinical use, we propose that Rg3 is such a compound, and that combination therapy with classical chemotherapeutic drugs may represent an effective therapeutic strategy for HCC treatment.

Topics: Antibiotics, Antineoplastic; Autophagy; Carcinoma, Hepatocellular; Doxorubicin; Female; Ginsenosides; Humans; Liver Neoplasms; Male

Previous investigations have demonstrated that ginsenoside Rg3 (Rg3) has many actions including antitumor, antioxidative, and immunomodulatory effects. However, Rg3 exists as 2 stereoisomeric pairs, 20(S)-ginsenoside Rg3 [20(S)-Rg3] and 20(R)-ginsenoside Rg3 [20(R)-Rg3], which have disparate pharmacological actions because of their different chemical structures. In this study, the 2 epimers were compared for their effects on the growth of hepatocellular carcinoma H22 transplanted tumors and the immune function of H22-bearing mice. In vivo efficacy study showed that the growth of H22 transplanted tumors was significantly inhibited when treated with 20(S)-Rg3 and 20(R)-Rg3 (P < 0.05), and the inhibition rate of tumor growth was 23.6% and 40.9%, respectively. Furthermore, the cellular immunity of H22-bearing mice was remarkably enhanced after Rg3 treatment (P < 0.05), which may be due to stimulation of ConA-induced lymphocyte proliferation and augmentation of Th1-type cytokines interleukin-2 and interferon-γ levels in mice. Interestingly, the effects of 20(R)-Rg3 were significantly greater than those of the S-form (P < 0.05). Taken together, these results indicate that Rg3 inhibits H22 tumor growth in vivo at least partly by improving the host's cellular immunity in a stereospecific manner, and 20(R)-Rg3 is more potent for treating cancers or other immune-mediated diseases clinically.

Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cell Proliferation; Ginsenosides; Immunity, Cellular; Liver Neoplasms; Mice; Neoplasms, Experimental

The TRAIL pathway is a potential therapeutic target for anticancer drugs due to selective cytotoxicity in cancer cells. Despite considerable promise, TRAIL or TRAIL receptor agonists have been used thus far with limited success in multiple clinical trials, in part due to acquired TRAIL resistance during chemotherapeutic treatment. Hepatocellular carcinoma (HCC) is a common solid tumor and the third leading cause of cancer-related death worldwide. Classical chemotherapy is not effective for HCC treatment and targeted therapy is limited to sorafenib. Isolated from Panax ginseng CA Meyer, 20(S)-ginsenoside Rg3 is a steroidal saponin with high pharmacologic activity that has been shown to sensitize cells to some chemotherapeutic agents. We investigated the sensitizing effect of Rg3 on TRAIL-induced cell death in HCC cells. We show Rg3 is capable of promoting TRAIL-induced apoptosis in a number of HCC cell lines, including HepG2, SK-Hep1, Huh-7, and Hep3B, but not in normal HL-7702 hepatocytes, indicating that Rg3 sensitization to TRAIL may be specific to cancer cells. Mechanistically, we found that Rg3 upregulates DR5 expression at the transcriptional level. DR5 upregulation in this case is mediated by C/EBP homology protein (CHOP), an important endoplasmic reticulum stress responsive protein. Furthermore, Rg3 is well tolerated and enhances the therapeutic efficacy of TRAIL in mouse xenograft models, suggesting that chemosensitization also occurs in vivo. Taken together, our study identifies Rg3 as a novel anticancer therapeutic agent and supports the further development of Rg3 as a chemosensitizer in combined therapy with TRAIL.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Endoplasmic Reticulum Stress; Gene Expression Regulation, Neoplastic; Ginsenosides; Hep G2 Cells; Humans; Liver Neoplasms; Mice; Reactive Oxygen Species; Receptors, TNF-Related Apoptosis-Inducing Ligand; TNF-Related Apoptosis-Inducing Ligand; Transcription Factor CHOP; Up-Regulation

Panax ginseng (P. ginseng) has anti-cancer effects in several cancer models. Ginsenosides are the main bioactive components in P. ginseng. Korean red ginseng (KRG) extract can potently kill various cancer cells and ginsenosides Rg3 (GRg3) and Rh2 (GRh2) are the primary ginsenosides in KRG. This study was carried out to examine whether KRG and its primary ginsenosides (GRg3 and GRh2) affect apoptosis of human hepatocellular carcinoma cells (Hep3B). KRG, GRg3 and GRh2 have obvious cytotoxic and apoptotic effects in Hep3B cells as evidenced by a decrease in cell viability and mitochondria membrane potential, but an increase in LDH release. In the mitochondria-mediated apoptosis pathway, KRG, GRg3 and GRh2 have the ability to stimulate the release of mitochondrial cytochrome c, activation of caspase-3 and Bax protein, inhibition of Bcl-2 protein and production of intracellular reactive oxygen species in Hep3B cells. These results suggest that KRG, GRg3 and GRh2 may induce apoptosis by direct activation of the mitochondrial pathway.

Topics: Apoptosis; Blotting, Western; Carcinoma, Hepatocellular; Cell Line, Tumor; Ginsenosides; Humans; Liver Neoplasms; Mitochondria, Liver; Reactive Oxygen Species; Signal Transduction

To investigate the anti-tumor function of ginsenoside Rg3 on hepatocellular carcinoma (HCC) in vitro and in vivo, and its mechanism.. Hep1-6 and HepG2 cells were treated by Rg3 in different concentrations (0, 50, 100 and 200 μg/mL) in vitro. After incubation for 0, 6, 12, 24 and 48 h, cell viability was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. Apoptosis was identified by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling. Caspase-3 activity was measured by chromophore p-nitroanilide and flow cytometry. Bcl-2 family proteins were ascertained by Western-blotting. Mitochondria membrane potential was detected by 5, 5', 6' 6' - tetrachloro-1, 1', 3, 3' - tetraethylbenzimidazolylcarbocyanine iodide. Forty liver tumor-bearing C57Bl6 mice were divided randomly into 4 groups for intra-tumor injection of saline, ginsenoside Rg3, cyclophosphamide (CTX) and ginsenoside Rg3 + CTX combination.. The survival time was followed up to 102 d. The mice in the Rg3 + CTX group showed significant increased survival time compared with those in the control group (P < 0.05). Rg3 could inhibit HCC cell proliferation and induce cell apoptosis in vitro in the concentration and time dependent manner. It also induced mitochondria membrane potential to decrease. Caspase-3 activation can be blocked by the inhibitor z-DEVD-FMK. Bax was up-regulated while Bcl-2 and Bcl-XL were down-regulated after Rg3 treatment.. Our data suggested that Rg3 alone or combined with CTX inhibited tumor growth in vivo and prolonged mouse survival time by inducing HCC cell apoptosis via intrinsic pathway by expression alterations of Bcl-2 family proteins.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Caspase 3; Cell Line, Tumor; Cell Survival; Cyclophosphamide; Cysteine Proteinase Inhibitors; Female; Ginsenosides; Humans; Liver Neoplasms; Mice; Mice, Inbred C57BL; Oligopeptides; Random Allocation; Survival Rate