ginsenoside-rg3 and Neoplasms

Panax ginseng, an ancient herb, belonging to Chinese traditional medicine, is an important herb that has a remarkable impact on various diseases. Ginsenoside Rg3, one of the most abundant ginsenosides, exerts significant functions in the prevention of various types of cancers with few side effects. In the present review, its functional molecular mechanisms are explored, including the improvement of antioxidant and anti-inflammation properties, immune regulation, induction of tumor apoptosis, prevention of tumor invasion and metastasis, tumor proliferation and angiogenesis, and reduction of chemoresistance and radioresistance. On the other hand, metabolism, pharmacokinetics and clinical indications of Rg3 are also discussed. The biological functional role of ginsenoside Rg3 may be associated with that it is a steroid glycoside with diverse biological activities and many signaling pathway can be regulated. Many clinical trials are highly needed to confirm the functions of ginsenoside Rg3.

Topics: Animals; Antineoplastic Agents; Apoptosis; Drug Resistance, Neoplasm; Ginsenosides; Humans; Neoplasms; Neovascularization, Pathologic

Cancer is a life-threatening disease with an alarmingly increased annual mortality rate globally. Although various therapies are employed for cancer, the final effect is not satisfactory. Chemotherapy is currently the most commonly used treatment option. However, the unsatisfactory efficacy, severe side-effects and drug resistance hinder the therapeutic efficacy of chemotherapeutic drugs. There is increasing evidence indicating that ginsenoside Rg3, a naturally occurring phytochemical, plays an important role in the prevention and treatment of cancer. The suggested mechanisms mainly include the induction of apoptosis, and the inhibition of proliferation, metastasis and angiogenesis, as well as the promotion of immunity. In addition, ginsenoside Rg3 can be used as an adjuvant to conventional cancer therapies, improving the efficacy and/or reducing adverse effects via synergistic activities. Ginsenoside Rg3 may be a widely applied natural medicine against cancer. To date however, there is no systematic summary available of the anticancer effects of ginsenoside Rg3. Therefore, in this review, all available literature over the past 10 years was reviewed and discussed in order to facilitate further research of ginsenoside Rg3.

Topics: Animals; Antineoplastic Agents, Phytogenic; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Gene Expression Regulation, Neoplastic; Ginsenosides; Humans; Molecular Structure; Neoplasms; Signal Transduction; Treatment Outcome

Topics: Angiogenesis Inhibitors; Animals; Bufanolides; Drugs, Chinese Herbal; Ginsenosides; Glucans; Humans; Neoplasms; Neovascularization, Pathologic; Pentacyclic Triterpenes; Phytotherapy; Plants, Medicinal; Polysaccharides; Triterpenes

Inherent or acquired resistance to paclitaxel (PTX) is a pivotal challenge for chemotherapy treatment of multidrug-resistant (MDR) breast cancer. Although various targeted drug-delivery systems, including nanoparticles and liposomes, are effective for MDR cancer treatment, their efficacy is restricted by immunosuppressive tumor microenvironment (TME).. Ginsenosides Rg3 was used to formulate unique Rg3-based liposomes loaded with PTX to establish Rg3-PTX-LPs, which were prepared by the thin-film hydration method. The stability of the Rg3-PTX-LPs was evaluated by particle size analysis through dynamic light scattering. The active targeting effect of Rg3-based liposomes was examined in an MCF-7/T xenograft model by an in a vivo imaging system. To evaluate the antitumor activity and mechanism of Rg3-PTX-LP, MTT, apoptosis assays, TAM regulation, and TME remodeling were performed in MCF-7/T cells in vitro and in vivo.. Rg3-PTX-LPs could specifically distribute to MCF7/T cancer cells and TME simultaneously, mainly through the recognition of GLUT-1. The drug resistance reversing capability and in vivo antitumor effect of Rg3-PTX-LPs were significantly improved compared with conventional cholesterol liposomes. The TME remodeling mechanisms of Rg3-PTX-LPs included inhibiting IL-6/STAT3/p-STAT3 pathway activation to repolarize protumor M2 macrophages to antitumor M1 phenotype, suppressing myeloid-derived suppressor cells (MDSCs), decreasing tumor-associated fibroblasts (TAFs) and collagen fibers in TME, and promoting apoptosis of tumor cells. Hence, through the dual effects of targeting tumor cells and TME remodeling, Rg3-PTX-LPs achieved a high tumor inhibition rate of 90.3%.. Our multifunctional Rg3-based liposome developed in the present study offered a promising strategy for rescuing the drug resistance tumor treatment.

Topics: Ginsenosides; Humans; Lipopolysaccharides; Liposomes; Neoplasms; Paclitaxel; Tumor Microenvironment

Topics: Animals; Ginsenosides; Mice; Nanoparticles; Neoplasms

This study aimed to develop hyaluronic acid (HA)-coated nanostructured lipid carriers (NLC) loaded simultaneously with oleanolic acid (OA), ursolic acid (UA) and Ginsenoside Rg3 (Rg3), prepared by electrostatic attraction for delivering OA, UA and Rg3 (OUR), termed HA-OUR-NLC, to tumors over expressing cluster determinant 44(CD44). The dialysis method was used to assess the in vitro release of OUR. Parameters such as pharmacokinetics, biodistribution, fluorescence in vivo endo-microscopy (FIVE), optical in vivo imaging (OIVI) data, and in vivo antitumor effects were evaluated. The results showed a total drug loading rate of 8.76±0.95% for the optimized HA-OUR-NLC; total encapsulation efficiency was 45.67±1.14%; particle size was 165.15±3.84%; polydispersity index was 0.227±0.01; zeta potential was -22.87±0.97 mV. Drug release followed the Higuchi kinetics. Pharmacokinetics and tissue distribution, as well as antitumor effects were evaluated in nude mice in vivo. HA-OUR-NLC were better tolerated, with increased antitumor activity compared with 5-Fu. In in vivo optical imaging, we use 1,1'-dioctadecyl-3,3,3',3'-tetramethy(DiR) as a fluorescent dye to label the NLC. The DiR-OUR-NLC group showed bright systemic signals, while the tumor site was weak. The present findings indicated that HA-OUR-NLC accumulated in the tumor site, prolonging OUR duration in the circulation and enhancing tumoral concentrations. Therefore, NLC prepared by electrostatic attraction constitute a good system for delivering OUR to tumors.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Drug Carriers; Drug Liberation; Female; Ginsenosides; Hyaluronic Acid; Lipids; Mice; Nanostructures; Neoplasms; Oleanolic Acid; Particle Size; Static Electricity; Tissue Distribution; Triterpenes; Ursolic Acid

Elevated production of reactive oxygen species (ROS) is observed in various cancer types and pathophysiological conditions. In cancer cells, ROS induce cell proliferation, genetic instability, and a malignant phenotype. Ginsenoside Rg3 is the main pharmacologically active component in ginseng and has been reported to have an antioxidant effect. To overcome lung cancer by regulating the ROS level, we investigated the antitumor effect and mechanism of Rg3 and its antioxidative property on Lewis lung carcinoma (LLC) cells.. Inhibition of ROS was suppressed in LLC cells by Rg3 treatment, and these cells were used to investigate the antioxidant, antiproliferative, and antitumor effects in LLC cells.. ROS production was increased in cells grown in serum-containing media (conditioned media) compared to those grown in serum-free media. The high level of ROS induced LLC cell proliferation, but treatment with Rg3 (200 ng/ml) resulted in reduction of ROS, leading to inhibition of cell proliferation. Treatment with Rg3 significantly reduced cyclin and cyclin-dependent kinase expression in LLC cells. Additionally, Rg3 treatment significantly suppressed activation of mitogen-activated protein kinases and induced LLC cell apoptosis through activation of pro-apoptotic proteins and suppression of anti-apoptotic proteins.. Taken together, these findings demonstrate the role of Rg3 in reduction of the intracellular ROS level, attenuation of proliferation via augmentation of cell cycle- and cell proliferation-associated proteins, and activation of apoptosis through regulation of apoptosis-associated proteins in LLC. These findings suggest that Rg3 could be used as a therapeutic agent in lung cancer.

Topics: Animals; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Carcinoma, Lewis Lung; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Culture Media, Conditioned; Culture Media, Serum-Free; Flow Cytometry; Ginsenosides; Mice; Neoplasms; Reactive Oxygen Species

The Ginsenoside Rg3 has been shown to possess antiangiogenic and anticancer properties. Because of its limited water solubility, we decided to design and synthesize liposomal Rg3 (L-Rg3), to optimize preparation conditions, and to investigate further whether liposome could enhance the anticancer activity of Rg3. L-Rg3 was prepared using a film-dispersion method and the preparation conditions were optimized with response surface methodology (RSM). The mean encapsulation efficiency (EE) of 82.47% was close to the predicted value of 89.69%. Therefore, the optimized preparation condition was predicted correctly. We evaluated the cytotoxicity, pharmacokinetics, biodistribution and antitumor activities of L-Rg3. HepG2 and A549 cells were treated with Rg3 or L-Rg3 at different concentrations in vitro. Pharmacokinetics and biodistribution studies were carried out in Wistar rats. Tumor model was established by inoculating a suspension of A549 cells into BALB/c nude mice. The mice were divided into Saline, Rg3 solution, and L-Rg3 groups with the drug given by i.p. injection. Survival of the mice and tumor volume were monitored. In addition, CD34 immunohistochemical analysis was used for measuring microvessel density (MVD) of the tumor tissues. The cytotoxicity and ratio of tumor inhibition of L-Rg3 group were significantly higher than the Rg3 solution group. MVD values in the Rg3 solution and L-Rg3 groups decreased, especially in the L-Rg3 group. Compared to Rg3 solution, the L-Rg3 showed increased Cmax and AUC of Rg3 by 1.19- and 1.52-fold, respectively. This liposomal formulation could potentially produce a viable clinical agent for improving the anticancer activity of Rg3.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Survival; Chemistry, Pharmaceutical; Female; Ginsenosides; Humans; Liposomes; Male; Mice; Mice, Nude; Neoplasms; Phosphatidylcholines; Rats; Rats, Wistar; Tumor Burden

The purpose of this study was to investigate the effect of paclitaxel in combination with 20(s)-ginsenoside Rg3 on its anti-tumour effect in nude mice. In the Caco-2 transport assay, the apparent permeability from the apical side to the basal side (P(app)) (A-B) and P(app) (B-A) of paclitaxel were measured when co-incubated with different concentrations of 20(s)-ginsenoside Rg3. The results indicated that the penetration of paclitaxel through the Caco-2 monolayer from the apical side to the basal side was facilitated by 20(s)-ginsenoside Rg3 in a concentration-dependent manner. Meanwhile, 20(s)-ginsenoside Rg3 inhibited P-glycoprotein (P-gp), and the maximum inhibition was achieved at 80 µM (p < 0.05). The pharmacokinetic parameters of paclitaxel after oral co-administration of paclitaxel (40 mg/kg) with various doses of 20(s)-ginsenoside Rg3 in rats were investigated by an in vivo pharmacokinetic experiment. The results showed that the AUC of paclitaxel co-administered with 20(s)-ginsenoside Rg3 was significantly higher (p < 0.001 at 10 mg/kg) compared with the control. The relative bioavailability (RB) % of paclitaxel with 20(s)-ginsenoside Rg3 was 3.4-fold (10 mg/kg) higher than that of the control. The effect of paclitaxel orally co-administered with 20(s)-ginsenoside Rg3 against human tumour MCF-7 xenografts in nude mice was also evaluated. Paclitaxel (20 mg/kg) co-administered with 20(s)-ginsenoside Rg3 (10 mg/kg) exhibited an effective anti-tumour activity with the relative tumor growth rate (T/C) values of 39.36% (p <0.05). The results showed that 20(s)-ginsenoside Rg3 enhanced the oral bioavailability of paclitaxel in rats and improved the anti-tumour activity in nude mice, indicating that oral co-administration of paclitaxel with 20(s)-ginsenoside Rg3 could provide an effective strategy in addition to the established i.v. route.

Topics: Animals; Antineoplastic Agents, Phytogenic; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Caco-2 Cells; Cell Line, Tumor; Cell Survival; Female; Ginsenosides; Humans; Male; Mice; Mice, Inbred BALB C; Neoplasms; Paclitaxel; Permeability; Rats; Rats, Sprague-Dawley; Tumor Burden; Xenograft Model Antitumor Assays

The ginsenoside Rg3 (Rg3) inhibits xenograft growth and angiogenesis in tumors mainly via down-regulates VEGF expression. This study was designed to investigate the mechanisms by which Rg3 down-regulates VEGF expression.. MTT assay was performed to investigate the effect of Rg3 on the growth of human esophageal carcinoma cell line Eca-109 and 786-0 cells under normoxic and hypoxic conditions. ELISA was used to detect VEGF protein secreted by the cells under normoxic and hypoxic conditions. Real-time quantitative reverse transcriptase polymerase chain reaction and Western blotting were used to detect gene expression and protein synthesis.. Rg3 inhibited Eca-109 and 786-0 cell proliferation and induced a significant reduction in VEGF mRNA under hypoxia conditions. Rg3 treatment inhibited hypoxia-induced expression HIF-1α, COX-2 and NF-κB under normoxic and hypoxic conditions. Treatment with Rg3 reduced the hypoxia-induced phosphorylation of STAT3 in a dose-dependent manner in the both cell lines. Rg3 treatment also inhibited the phosphorylation of ERK1/2 and JNK induced by hypoxia.. Rg3 targets hypoxia-induced multiple signaling pathways to down-regulate VEGF expression in cancer cells. These actions may contribute to the overall efficacy of Rg3 against tumor angiogenesis and growth.

Topics: Angiogenesis Inhibitors; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase 2; Ginsenosides; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; JNK Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasms; NF-kappa B; Phosphorylation; RNA, Messenger; STAT3 Transcription Factor; Vascular Endothelial Growth Factor A

The goal of this study was the application of a novel, fully automatic column-switching approach in a metabonomics study combining the orthogonal selectivities of hydrophilic interaction chromatography (HILIC) and reversed-phase chromatography. The temporal, pharmacodynamic effects of the ginsenoside Rg3 on the metabonome in urine of healthy and liver-tumor-bearing rats have been investigated. Within a total analysis time of 52 min we detected 5686 polar, and on the second column an additional 1808 apolar, urinary metabolite ions. The administration of a single, high dose of Rg3 in a beta-cyclodextrin-based formulation led to a considerable change of the metabolic pattern in cancer rats during 3 days studied. Seventeen biomarker candidates including three apolar metabolites, which were not retained on the HILIC column, were detected. Overall, the results suggest that the developed liquid chromatography-mass spectrometry strategy is a promising tool in metabonomics studies for global analysis of highly complex biosamples. It may not only increase the number of discovered biomarkers but consequently improve the comprehensive information on metabolic changes in a fully automatic manner.

Topics: Animals; beta-Cyclodextrins; Biomarkers; Cell Line, Tumor; Chromatography, High Pressure Liquid; Ginsenosides; Glycomics; Health; Hydrophobic and Hydrophilic Interactions; Male; Molecular Structure; Neoplasms; Rats; Rats, Sprague-Dawley; Spectrometry, Mass, Electrospray Ionization