The effects of ginsenoside Rb1 on JNK in oxidative injury in cardiomyocytes.

Reactive oxygen species (ROS) can induce oxidative injury via iron interactions (i.e. Fenton chemistry and hydroxyl radical formation). Our prior work suggested that American ginseng berry extract and ginsenoside Re were highly cardioprotective against oxidant stress. To extend this study, we evaluated the protective effect of protopanaxadiol-type ginsenoside Rb1 (gRb1) on H(2)O(2)-induced oxidative injury in cardiomyocytes and explored the ROS-mediated intracellular signaling mechanism. Cultured embryonic chick cardiomyocytes (4-5 day) were used. Cell death was assessed by propidium iodide and lactate dehydrogenase release. Pretreatment with gRb1 (0.01, 0.1, or 1 µM) for 2 h and concurrent treatment with H(2)O(2) (0.5 mM) for 2 h resulted in a dose-dependent reduction of cell death, 36.6 ± 2.9% (n = 12, p < 0.05), 30.5 ± 5.1% (n = 12, p < 0.05) and 28.6 ± 3.1% (n = 12, p < 0.01) respectively, compared to H(2)O(2)-exposed cells (48.2 ± 3.3%, n = 12). This cardioprotective effect of gRb1 was associated with attenuated intracellular ROS generation as measured by 6-carboxy-2', 7'-dichlorodihydrofluorescein diacetate, preserved the mitochondrial membrane potential as determined using JC-1. In the ESR study, gRb1 exhibited the scavenging DPPH and hydroxyl radical activities. Furthermore, our data showed the increased JNK phosphorylation (p-JNK) in H(2)O(2)-exposed cells was suppressed by the pretreatment with gRb 1 (1 µM) (p < 0.01). Co-treatment of gRb1 with a specific inhibitor of JNK SP600125 (10 µM) further reduced the p-JNK and enhanced the cell survival after H(2)O(2) exposure. Collectively, our results suggest that gRb1 conferred cardioprotection that was mediated via attenuating ROS and suppressing ROS-induced JNK activation.

Ginsenoside Re: Its chemistry, metabolism and pharmacokinetics.

Ginsenosides, the bioactive components of ginseng, can be divided into two major groups, namely 20(S)-protopanaxatriol (e.g. Re, Rg1, Rg2, and Rb3) and 20(S)-protopanaxadiol (e.g. Rb1, Rb2, Rc, and Rd). Biological and environmental factors may affect the content of ginsenosides in different parts of ginseng plant. Evidence from pharmacokinetic and metabolic studies of Re demonstrated that (1) the absorption of Re is fast in gastrointestinal tract; (2) Re may be metabolized mainly to Rh1 and F1 by intestinal microflora before absorption into blood; and (3) Re is quickly cleared from the body.

Ginsenoside Re: pharmacological effects on cardiovascular system.

Ginsenosides are the bioactive constituents of ginseng, a key herb in traditional Chinese medicine. As a single component of ginseng, ginsenoside Re (G-Re) belongs to the panaxatriol group. Many reports demonstrated that G-Re possesses the multifaceted beneficial pharmacological effects on cardiovascular system. G-Re has negative effect on cardiac contractility and autorhythmicity. It causes alternations in cardiac electrophysiological properties, which may account for its antiarrhythmic effect. In addition, G-Re also exerts antiischemic effect and induces angiogenic regeneration. In this review, we first outline the chemistry and the pharmacological effects of G-Re on the cardiovascular system.

The effect of diet on the response of low-density lipoprotein receptor knockout mice to the liver X receptor agonist T1317.

It has been previously observed that low-density lipoprotein receptor knockout (LDLR--/--) mice fed a Western-type diet without cholate and given the liver X receptor agonist T1317 develop a persistent and enhanced hypertriglyceridemia. In contrast, LDLR--/-- mice fed a Paigen diet with cholate exhibit only a transient increase in plasma triglycerides when given T1317. Cholate as an activator of farnesoid X receptor may attenuate T1317-induced triglyceridemia. To determine if cholate was responsible for this transient nature of the hypertriglyceridemia, we orally administered T1317 to LDLR--/-- mice fed a modified Paigen diet without cholate. T1317 transiently elevated plasma triglycerides by increasing plasma very-low-density lipoprotein. Cholesterol and triglyceride levels in plasma very-low-density lipoprotein in T1317-treated mice decreased from peak levels to levels found in vehicle-treated mice after 8 weeks of treatment. A gradual decline of hepatic cholesterol and a transient increase in hepatic triglycerides were also observed in T1317-treated mice. T1317 only transiently activated the expression of genes related to liver de novo lipogenesis, whereas genes related to lipid metabolism were induced in T1317-treated mice, including a gradual increase in plasma lipoprotein lipase activity. Atheroprotective effects of T1317 were observed in the innominate artery and aortic arch but not in the aortic sinus. This work indicates that some component(s) in the Paigen diet other than cholate affect the T1317-induced gene expression profile and ameliorate its effects on lipid synthesis, which lead to hypertriglyceridemia and fatty liver. These findings are important for liver X receptor-related pharmaceutical development for the treatment of cardiovascular disease.

Effects of Triterpenoid Glycosides from Fresh Ginseng Berry on SW480 Human Colorectal Cancer Cell Line.

PURPOSE: The pharmacological activities, notably the anticancer properties, of bioactive constituents fromfresh American ginseng berry have not yet been well studied. In this study, we investigated the antiproliferative effects of fresh American ginseng berry extract (AGBE) and its representative triterpenoid glycosides using the human colorectal cancer cell line SW480. MATERIALS AND METHODS: Using high performance liquid chromatography (HPLC), the contents of 8 ginsenosides in AGBE were determined. The cell growth inhibitory effects of AGBE and three triterpenoid glycosides (ginsenosides Rb3, Re, and Rg3) were evaluated by proliferation assay and (3)H-thymidine incorporation assay. Cell cycle and apoptotic effects were analyzed by using flow cytometry after staining with propidium iodide and annexin V. RESULTS: HPLC analysis data showed that AGBE has a distinct ginsenoside profile. AGBE inhibited SW480 cell growth significantly in a time-dependent (24-96 hours) and concentration-dependent (0.1-1.0 mg/mL) manner. Ginsenosides Rb3, Re, and Rg3 also possess significant antiproliferative activities on SW480 cells. (3)H-thymidine incorporation assay indicated that AGBE and ginsenosides Rb3, Re, and Rg3 might inhibit the transferring and duplication of DNA in SW480 cells. Flow cytometric assay data suggested that AGBE arrested SW480 cells in S and G2/M phases, and significantly induced cell apoptosis. CONCLUSION: AGBE and ginsenosides Rb3, Re, and Rg3 possessed significant antiproliferative effects and induced changes of morphological appearance on SW480 cells. The mechanisms of the antiproliferation of AGBE and tested ginsenosides involved could be cell cycle arrest and induction of apoptosis.

A novel potent synthetic steroidal liver X receptor agonist lowers plasma cholesterol and triglycerides and reduces atherosclerosis in LDLR(-/-) mice.

BACKGROUND AND PURPOSE: Potent synthetic nonsteroidal liver X receptor (LXR) agonists like T0901317 induce triglyceridaemia and fatty liver, effects not observed with some natural and synthetic steroidal, relatively weak agonists of LXR. To determine if potency is responsible for the lack of side effects with some steroidal agonists, we investigated the in vivo effects of a novel steroidal LXR agonist, ATI-111, that is more potent than T0901317. EXPERIMENTAL APPROACH: Eight week old male LDLR(-/-) mice fed an atherogenic diet were orally treated with vehicle or ATI-111 at 3 and 5 mg·kg(-1) ·day(-1) for 8 weeks, and effects on plasma and liver lipid levels, expression of genes involved in lipid metabolism and on atherogenesis were analysed. KEY RESULTS: ATI-111 increased the expression of genes involved in lipid transport, such as ABCA1, ABCG1 and ABCG5/G8, in intestine and macrophages; decreased ABCG1, apoE; and slightly increased ABCA1 and ABCG5/G8 expression in liver. ATI-111 markedly increased sterol regulatory element-binding protein (SREBP)-1c mRNA in some tissues, whereas acetyl-coenzyme A carboxylase and fatty acid synthase expression was unaffected or only slightly increased in intestine and liver. ATI-111 inhibited the conversion of SREBP-1c precursor form to its active form. Compared with vehicle-treated mice, the levels of hepatic lipids and liver-secreted nascent lipoproteins were not altered, while a significant decrease in plasma cholesterol and triglyceride levels was observed in ATI-111-treated mice. ATI-111 significantly inhibited atherogenesis in three separate vascular sites. CONCLUSIONS AND IMPLICATIONS: ATI-111 is a promising candidate for further development as a treatment of certain vascular diseases as it lacks the significant side effects associated with nonsteroidal LXR agonists, the induction of fatty liver and hypertriglyceridaemia.

Lack of significant association between TGF-ß1-590C/T polymorphism and breast cancer risk: a meta-analysis.

Transforming growth factor ß1 (TGF-ß1) is a cytokine that plays an important role in the control of cell proliferation and differentiation in breast cancer. The -509C/T polymorphism in the TGF-ß1 gene has been implicated in breast cancer risk. However, studies on the association between this polymorphism and breast cancer risk have produced conflicting results. To derive a more precise estimation of the relationship, a meta-analysis of the -509C/T polymorphism (5,825 cases and 7,953 controls) from seven published case-control studies was performed. Our analysis suggests that -509C/T has no association with breast cancer risk when using either dominant [odds ratio (OR) = 1.01, 95% confidence intervals (CI): 0.82-1.24], or recessive models (OR = 0.91, 95% CI: 0.66-1.27), or other genetic models to analyze the data. In ethnic subgroups analysis, -509C/T also did not appear to be a risk factor for breast cancer. However, larger scale primary studies are still required to further evaluate the interaction of TGF-ß1 -509C/T polymorphism and breast cancer risk in specific populations.

TGF-ß1 29T/C polymorphism and breast cancer risk: a meta-analysis involving 25,996 subjects.

Transforming growth factor ß1 (TGF-ß1) is a cytokine, playing an important role in controlling cell proliferation and differentiation involved in breast cancer. It was reported the 29T/C polymorphism in TGF-ß1 has been implicated in breast cancer risk. However, studies on the association between this polymorphism and breast cancer remain conflicting. To derive a more precise estimation of the relationship, a meta-analysis of 10,341 cases and 15,655 controls from fifty published case-control studies was performed. Our analysis suggested that 29T/C has no association with a trend of breast cancer risk when using both dominant [odds ratio (OR) = 1.01, 95% confidence intervals (CI) 0.96-1.07] and recessive models (OR = 0.98, 95% CI 0.89-1.08) to analyze the data. In ethnic subgroups analysis, 29T/C also did not appear to be risk factors for breast cancer. However, larger scale primary studies are required to further evaluate the interaction of TGF-ß1 29T/C polymorphism and breast cancer risk in specific populations.

Differential effects of activation of liver X receptor on plasma lipid homeostasis in wild-type and lipoprotein clearance-deficient mice.

The effects of liver X receptor (LXR) agonists on plasma lipid homeostasis, especially triglyceride metabolism are controversial. Here we examined the effect of long-term activation of LXR on plasma lipid homeostasis in wild-type C57BL/6 and LDL receptor deficient (LDLR-/-) mice given the LXR agonist T0901317 for 4 weeks. LXR agonist treatment of wild-type mice decreased plasma total triglycerides by 35% due to a significant reduction of plasma VLDL triglycerides. In contrast, in LDLR-/- mice T0901317 treatment increased plasma total cholesterol and triglycerides. An increase in the level of smaller VLDL particles was also observed in T0901317-treated LDLR-/- mice. The changes in circulating lipoprotein profiles in response to T0901317 treatment in these two animal models reflect the balance between synthesis and secretion on the one hand and lipolysis and clearance on the other. In both models there was both an increase in VLDL production and secretion and in an increase in LPL production and activity in T0901317-treated animals. In wild-type mice lipolysis and clearance predominates, while in the absence of the LDLR, which plays a major role in the clearance of apoB-containing lipoproteins, the increased output predominates. The generation of elevated levels of small VLDL particles due to increased lipolysis may represent an additional risk factor for atherosclerosis.

Ginseng leaf-stem: bioactive constituents and pharmacological functions.

Ginseng root is used more often than other parts such as leaf stem although extracts from ginseng leaf-stem also contain similar active ingredients with pharmacological functions. Ginseng's leaf-stems are more readily available at a lower cost than its root. This article reviews the pharmacological effects of ginseng leaf-stem on some diseases and adverse effects due to excessive consumption. Ginseng leaf-stem extract contains numerous active ingredients, such as ginsenosides, polysaccharides, triterpenoids, flavonoids, volatile oils, polyacetylenic alcohols, peptides, amino acids and fatty acids. The extract contains larger amounts of the same active ingredients than the root. These active ingredients produce multifaceted pharmacological effects on the central nervous system, as well as on the cardiovascular, reproductive and metabolic systems. Ginseng leaf-stem extract also has anti-fatigue, anti-hyperglycemic, anti-obesity, anti-cancer, anti-oxidant and anti-aging properties. In normal use, ginseng leaf-stem extract is quite safe; adverse effects occur only when it is over dosed or is of poor quality. Extracts from ginseng root and leaf-stem have similar multifaceted pharmacological activities (for example central nervous and cardiovascular systems). In terms of costs and source availability, however, ginseng leaf-stem has advantages over its root. Further research will facilitate a wider use of ginseng leaf-stem.

In vitro and in vivo anticancer effects of American ginseng berry: exploring representative compounds.

Panax ginseng roots, including the steamed roots, have been demonstrated to possess anticancer properties. However, there have been limited published studies on the cancer preventive effects of American ginseng. In this study, the in vitro and in vivo anti-colorectal cancer effects of American ginseng berry extracts, and their representative bioactive compounds were evaluated. The ginsenoside content in unsteamed American ginseng berry extract (AGE) and steamed berry extract (S-AGE) were determined by HPLC. In comparison to AGE, S-AGE showed significantly stronger antiproliferative effects on HCT-116, SW-480 and HT-29 human colorectal cancer cells. Antiproliferative effects of representative constituents in AGE and S-AGE, ginsenosides Rb3 and Rg3, were also evaluated, showing that Rg3 had a positive effect. Using flow cytometric analyses, we found that S-AGE arrests cancer cells in G1-phase and significantly induces cell apoptosis. Using xenograft mice, we conducted an in vivo antitumor study using S-AGE after HCT-116 cell inoculation. We observed that 50 mg/kg of S-AGE showed significant antitumor effects. Our results suggested that S-AGE inhibited the colorectal cancer growth both in vitro and in vivo, and this inhibition might be achieved through cell cycle arrest and induced apoptosis in the cells.

Methylnaltrexone, a peripherally acting opioid receptor antagonist, enhances tumoricidal effects of 5-Fu on human carcinoma cells.

BACKGROUND: Methylnaltrexone, a novel peripherally acting opioid receptor antagonist, is used to treat opiate-induced constipation in cancer patients. Its effects on the activities of chemotherapeutic agents, however, have not been evaluated. In this study, the effect of methylnaltrexone on the action of 5-fluorouracil (5-FU) was tested in three human cancer cell lines. MATERIALS AND METHODS: Treatment was for 72 h and the effects on cell proliferation were measured in human SW-480 colorectal cancer cells, MCF-7 breast cancer cells and non-small cell lung cancer cells in vitro. The apoptotic effect was analyzed by using flow cytometry. The cell cycle and expression of cyclin A were assayed after staining with propidium iodide and cyclin A-fluorescein isothiocyanate. RESULTS: 5-FU decreased the cancer cell growth significantly in all three cancer cell lines in a concentration-dependent manner and methylnaltrexone enhanced the actions of 5-FU. Compared to 5-FU 10 muM alone on SW-480 cells (63.5+/-1.1%), on MCF-7 cells (58.3+/-3.1%), or on non-small cell lung cancer cells (81.3+/-1.6%), 5-FU 10 muM plus methylnaltrexone 1.0 muM reduced cancer cell growth in all three cell lines to 50.2+/-2.9% for SW-480 cells (p<0.05), 50.0+/-1.7% for MCF-7 cells (p<0.05) and 68.7+/-2.2% for lung cancer cells (p<0.01). Methylnaltrexone alone also showed anti-proliferative activity in the three cell lines. Methylnaltrexone at 1.0 muM, reduced SW-480 cell growth to 81.9+/-3.7% (p<0.01), MCF-7 cell growth to 85.9+/-2.4% (p<0.01) and lung cancer cell growth to 85.5+/-2.2% (p<0.01). Apoptosis was not induced by treatment of SW-480 cells with 1.0 or 10 muM methylnaltrexone for 48 h. However, methylnaltrexone increased the number of cells in the G(1)-phase and decreased the expression of cyclin A. CONCLUSION: At its therapeutic concentrations for opioid-induced constipation, methylnaltrexone does not attenuate and in fact may enhance the tumoricidal activity of 5-FU. Enhanced 5-FU activity may be attributed to the distinct pathways of 5-FU and methylnaltrexone, an effect that could give methylnaltrexone a complementary role in the treatment of cancer with chemotherapeutic agents.

Anti-diabetic effect of American ginseng may not be linked to antioxidant activity: comparison between American ginseng and Scutellaria baicalensis using an ob/ob mice model.

Antioxidants have been considered as a useful remedy in diabetes therapeutics, and thus, herbal medicines with antioxidant properties may play major role in treating diabetes. In this report, we performed a comparative study using American ginseng and Scutellaria baicalensis to test whether the anti-diabetic effect of American ginseng is associated with its antioxidant activity. We used a simple water extraction procedure to prepare American ginseng root extract (AGE) and S. baicalensis extract (SbE), and utilized these two antioxidant herbs to evaluate their anti-diabetic effect in obese diabetic ob/ob mice. HPLC analysis was used to identify major constituents in the AGE and SbE. After 12 days of daily intraperitoneal injection, AGE at 300 mg/kg showed significant effects on fasting blood glucose levels (P<0.01) and glucose tolerance test (P<0.01) compared to vehicle-treated mice. Animal body weights also reduced significantly after 12-day treatment (P<0.01). However, SbE, a very strong antioxidant extract, administered at 5-50 mg/kg (based on our previous studies without adverse events) for 12 days did not show any significant effects on blood glucose and body weight changes. No effects were shown when baicalein, an effective antioxidant constituent in SbE, was administered at 1-5 mg/kg. It appears that the anti-diabetic effect of American ginseng may not be linked to its antioxidant actions. The mechanisms of American ginseng's effects on reducing high blood glucose levels and body weight remain to be investigated in future experiments.

Antiproliferative effects of different plant parts of Panax notoginseng on SW480 human colorectal cancer cells.

The chemical constituents and antiproliferative effects on SW480 human colorectal cancer cells of different plant parts of P. notoginseng were evaluated. The contents of saponins in extracts from root, rhizome, flower and berry of P. notoginseng were determined using high performance liquid chromatography. The contents and proportions of saponins were different among the four plant parts. Using the cell counting method, the antiproliferative effects were evaluated and the results indicated all four extracts, at 0.05-1.0 mg/mL, showed concentration-related antiproliferative effects on the cancer cells. The flower extract had stronger effects compared with the other three extracts; at 1.0 mg/mL, it inhibited the cell growth by 93.1% (p < 0.01). The antiproliferative effects of major saponins in notoginseng, notoginsenoside R1, ginsenosides Rb1, Rb3 and Rg1, were also evaluated, and the observed effects of major constituents support the pharmacological activities of extracts. The effects of notoginseng extracts on cell cycle and apoptosis of SW480 cells were determined using flow cytometry. Notoginseng extract can arrest the cells in S and G2/M phases. Remarkably apoptosis induction activities of notoginseng extracts were observed with the flower extract possessing the most potent effect, supporting the antiproliferative effect.

Antioxidant protection by American ginseng in pancreatic beta-cells.

Hyperglycemia in diabetic conditions may cause oxidative stress in pancreatic beta-cells, leading to their dysfunction and insulin resistance within peripheral tissues. Previous studies suggest that American ginseng berry extract may have hypoglycemic effects, as well as offer antioxidant protection. We examined effects of American ginseng berry extract and ginsenoside Re in a pancreatic beta-cell line, MIN-6, to determine if these two properties are related. Cells were exposed to oxidative stress via hydrogen peroxide incubation and oxidative stress was measured by oxidation of 2',7'-dichlorofluorescin diacetate. These cells showed a concentration-related response to hydrogen peroxide at 100-500 microM. In acute conditions where cells were treated with the extract for 10 min, we observed reduced oxidant injury suggesting direct scavenging effects. Chronic incubation of cells with the extract for 48 hours also demonstrated attenuation of oxidative stress. At high concentrations, Re showed a mild antioxidant effect in MIN-6 cells. Our insulin release observations also showed that the extract may help to increase insulin secretions from the cells. Our data suggest that the observed ability of ginseng to reduce blood glucose levels may be linked to its antioxidant effects on pancreatic beta-cells.

Chemopreventive effects of heat-processed Panax quinquefolius root on human breast cancer cells.

BACKGROUND: Former studies have shown that extract from American ginseng (Panax quinquefolius) may possess certain antiproliferative effects on cancer cells. In this study, the chemical constituents of both untreated and heat-processed American ginseng and their antiproliferative activities on human breast cancer cells were evaluated. MATERIALS AND METHODS: American ginseng roots were steamed at 120 degrees C for 1 h or 2 h. The major ginsenosides in the two steamed and in the unsteamed extracts were quantitatively determined using high performance liquid chromatography (HPLC). The antiproliferative activities of these extracts and individual ginsenosides on MCF-7 and MDA-MB-231 breast cancer cells were assayed using the MTS method. The effects of the extracts and the ginsenosides on the induction of cell apoptosis, the expression of cyclins A and D1, and cell cycle arrest were evaluated. RESULTS: Compared to the untreated extract, heat-processing reduced the content of ginsenosides Rb1, Re, Rc and Rd, and increased the content of Rg2 and Rg3. After 2 h steaming, the percent content of ginsenoside Rg3 was increased from 0.06% to 5.9%. Compared to the unsteamed extract, the 2 h steamed extract significantly increased the antiproliferative activity and significantly reduced the number of viable cells. The steamed extract also significantly reduced the expression of cyclin A and cyclin D1. The cell cycle assay showed that the steamed extract and ginsenoside Rg3 arrested cancer cells in G1-phase. CONCLUSION: Heat-processing of American ginseng root significantly increases antiproliferative activity and influences the cell cycle profile.

Scutellaria baicalensis and a constituent flavonoid, baicalein, attenuate ritonavir-induced gastrointestinal side-effects.

Ritonavir, a protease inhibitor drug, is commonly used in AIDS therapy. As with other chemotherapeutic drugs that cause gastrointestinal adverse effects, ritonavir treatment is associated with significant nausea and vomiting. This study investigated whether Scutellaria baicalensis, and its active flavonoid constituent, baicalein, attenuate the gastrointestinal effects of ritonavir. The effects of herb administration were evaluated in ritonavir-treated rats using a rat pica model, which simulates nausea and vomiting in humans. The effects of herb administration on gastric emptying in rats were also measured. Ritonavir treatment resulted in increased kaolin intake or severe pica, the intensity of which was reduced significantly with S. baicalensis administration (1 mg kg(-1); P<0.05). High-performance liquid chromatography analysis of S. baicalensis showed the presence of an extremely potent flavonoid constituent, baicalein. The study aimed to determine if baicalein contributed to the anti-pica effect of the extract. It was observed that baicalein dose-dependently decreased pica in ritonavir-treated rats (P<0.001). In addition to inducing pica, ritonavir also significantly delayed gastric emptying, which could contribute to ritonavir-induced gastrointestinal dysfunction. When S. baicalensis extract was administered to ritonavir-treated rats the delayed gastric emptying was significantly attenuated (P<0.05). The results suggest that S. baicalensis and the constituent baicalein reduce the gastrointestinal dysfunction caused by ritonavir. It is concluded that S. baicalensis may potentially have a role to play in reducing drug-induced adverse effects.

Chemopreventive effects of Panax notoginseng and its major constituents on SW480 human colorectal cancer cells.

In this study, we evaluated the effects of Panax notoginseng root extract (NGRE) and its major constituents on SW480 human colorectal cancer cells. We used high performance liquid chromatography to determine the contents of major saponins in NGRE. The anti-proliferative effects were evaluated by the cell counting method, and concentration-related anti-proliferative effects were observed. At 1.0 mg/ml, NGRE inhibited cell growth by 85.8% (P<0.01), probably linked to the higher concentration of ginsenosides Rb1 and Rg1. The pharmacologic activities of notoginsenoside R1 and ginsenosides Rg1 and Rb1 on the cells were antiproliferative. We tested the effects of NGRE on DNA synthesis by measuring [3H]-thymidine incorporation. NGRE induced cell apoptosis at 0.5 and 1 mg/ml. Two-day treatment with 300 microM of notoginsenoside R1, ginsenosides Rg1 and Rb1 increased cell apoptosis significantly. Cell cycle and cyclin A assay showed that NGRE arrested cells in the synthesis phase and increased the expression of cyclin A remarkably. NGRE also enhanced the actions of two chemotherapeutic agents, 5-fluorouracil and irinotecan. Cell growth decreased more with the combined treatment of NGRE and 5-fluorouracil (or irinotecan) than with the chemotherapy agent applied alone, suggesting that notoginseng can reduce the dose of 5-fluorouracil (or irinotecan) needed to achieve desired effects. Further in vivo and human trials are warranted to test whether notoginseng is a valuable chemo-adjuvant with clinical validity.

Notoginseng enhances anti-cancer effect of 5-fluorouracil on human colorectal cancer cells.

PURPOSE: Panax notoginseng is a commonly used Chinese herb. Although a few studies have found that notoginseng shows anti-tumor effects, the effect of this herb on colorectal cancer cells has not been investigated. 5-Fluorouracil (5-FU) is a chemotherapeutic agent for the treatment of colorectal cancer that interferes with the growth of cancer cells. However, this compound has serious side effects at high doses. In this study, using HCT-116 human colorectal cancer cell line, we investigated the possible synergistic anti-cancer effects between notoginseng flower extract (NGF) and 5-FU on colon cancer cells. METHODS: The anti-proliferation activity of these modes of treatment was evaluated by MTS cell proliferation assay. Apoptotic effects were analyzed by using Hoechst 33258 staining and Annexin-V/PI staining assays. The anti-proliferation effects of four major single compounds from NGF, ginsenosides Rb1, Rb3, Rc and Rg3 were also analyzed. RESULTS: Both 5-FU and NGF inhibited proliferation of HCT-116 cells. With increasing doses of 5-FU, the anti-proliferation effect was slowly increased. The combined usage of 5-FU 5 microM and NGF 0.25 mg/ml, significantly increased the anti-proliferation effect (59.4 +/- 3.3%) compared with using the two medicines separately (5-FU 5 microM, 31.1 +/- 0.4%; NGF 0.25 mg/ml, 25.3 +/- 3.6%). Apoptotic analysis showed that at this concentration, 5-FU did not exert an apoptotic effect, while apoptotic cells induced by NGF were observed, suggesting that the anti-proliferation target(s) of NGF may be different from that of 5-FU, which is known to inhibit thymidilate synthase. CONCLUSIONS: This study demonstrates that NGF can enhance the anti-proliferation effect of 5-FU on HCT-116 human colorectal cancer cells and may decrease the dosage of 5-FU needed for colorectal cancer treatment.

Cisplatin's tumoricidal effect on human breast carcinoma MCF-7 cells was not attenuated by American ginseng.

PURPOSE: We previously observed that American ginseng berry and ginsenoside Re attenuated cisplatin-induced emesis in a rat model, suggesting that the herb may have a value in treating chemotherapy-induced nausea/vomiting. However, it is not clear whether consuming ginseng concurrently with chemotherapy affects the efficacy of chemotherapeutic agents. In this study, we explored if the ginseng extract and its constituents, ginsenosides Rb1, Rb3, and Re, alter tumoricidal activity of cisplatin in human cancer cells. METHODS: Tumoricidal effects of cisplatin, and/or American ginseng berry extract (AGBE) and ginsenosides Rb1, Rb3, and Re, on human breast carcinoma MCF-7 cells were measured as cell proliferation in vitro. Cell counts were performed in MCF-7 cells pretreated with test agents for 72 h. RESULTS: Cisplatin decreased MCF-7 cell proliferation significantly in a concentration-dependent manner. Compared to control group, cisplatin reduced the cell proliferations to 56.5+/-3.3% at 1 microg/ml, to 36.6+/-2.4% at 5 microg/ml, and to 26.9+/-2.4% at 15 microg/ml (P<0.01). AGBE also inhibited the cell proliferation significantly, although in a less extended manner. When the berry extract at 0.5 mg/ml was used with cisplatin at 1 microg/ml, a significant enhancement of cisplatin's activity was observed (35.8+/-2.5%; P<0.05). We also observed that Rb1 did not change cisplatin's activity; Rb3, at a higher concentration, increased cisplatin's anti-proliferation activity (48.0+/-1.2%; P<0.05); Re increased cisplatin's activity (Re 0.1 mg/ml, 48.0+/-2.8%; Re 0.3 mg/ml, 31.9+/-2.2%, P<0.01). CONCLUSION: Our data suggest that AGBE and the tested ginsenosides do not attenuate cisplatin's tumoricidal activity in MCF-7 cells, but in fact may actually enhance it. Additionally, the ginseng extract and ginsenoside Re by themselves exerted anti-proliferative activity against MCF-7 cells. The herb might potentially serve a complementary role with the chemotherapeutic agents in treating cancer, in addition to decreasing chemotherapy-induced nausea/vomiting.