Ginsenoside Rg3, one of the major ingredients of heat-processed ginseng, has been reported to inhibit the growth of various cancer cells. We previously reported that Rg3 inhibited the proliferation and induced apoptosis of breast cancer (MDA-MB-231) cells. In the present study, we have explored the mechanism underlying the anti-proliferative and proapoptotic effects of Rg3 in MDA-MB-231 cells, which have constitutively activated NF-κB and the mutant form of p53. Rg3 inhibited DNA binding and transcriptional activity of NF-κB and these effects were attributable to its suppression of IKKβ activity, degradation of IκBα and subsequent nuclear translocation of the p65 subunit of NF-κB. Similarly, the constitutive activation of ERK and Akt through phosphorylation was gradually reduced in MDA-MB-231 cells treated with Rg3. The pharmacological inhibitors of these kinases both U0126 (MEK1/2 inhibitor) and LY294002 (PI3K inhibitor) abrogated the NF-κB DNA binding activity in MDA-MB-231 cells. In addition, Rg3 treatment lowered the levels of the mutant p53 in concentration- and time-dependent manners. Rg3 also increased the association between p53 and its negative regulator Mdm2 in MDA-MB-231 cells. These findings suggest that Rg3 induced apoptosis in MDA-MB-231 cells, which is mediated by blocking NF-κB signaling via inactivation of ERK and Akt as well as destabilization of mutant p53.
Background:Rg3, a major ginsenoside derived from heat-processed ginseng, has been reported to have anti-inflammatory and anti-proliferative activities. In our previous studies, Rg3 inhibited phorbol ester-induced cyclooxygenase-2 expression and NF-κB activation in cultured human mammary epithelial (MCF-10A) cells and in mouse skin in vivo. In this study, we investigated Rg3-induced apoptosis in human breast cancer (MDA-MB-231) cells and underlying molecular mechanisms.Methods:After Rg3 treatment, apoptotic cell death of MDA-MB-231 cell was investigated by the MTT reduction assay and measurement of the mitochondrial membrane depolarization. Flow cytometry was used for cell cycle analysis and detection of apoptotic cells as well as measurement of reactive oxygen species. Expression of apoptotic-related proteins was determined by immunoblot analysis.Results:MDA-MB-231 cells treated with Rg3 (30μM) exhibited the increased proportion of hypodiploid or apoptotic cells. Rg3 treatment resulted in an increase in the ratio of proapoptotic Bax to antiapoptotic Bcl-2, depolarization of the mitochondria membrane potential and the release of cytochrome c from mitochondria. Rg3 also induced the proteolytic cleavage of caspase-3 and poly (ADP-ribose) polymerase, which was attenuated by a caspase-3 inhibitor, z-VAD-fmk.Conclusions:Based on these findings, it is likely that Rg3 induces apoptosis in MDA-MB-231 cells via classical mitochondria-dependent caspase activation. These data suggest that Rg3 might be a potential candidate as a breast cancer chemopreventive agent.
Anxiety affects one-eighth of the total population worldwide and has become a very important area of research interest in psychopharmacology during this decade.1) Benzodiazepines are still the most frequently used drugs for the treatment of generalized anxiety disorder despite their undesirable side effects such as muscle relaxation, sedation, physical dependence, memory disturbance, and interaction with other drugs. 2)In recent years, the development of new anxiolytics has been an area of interest. Various types of herbal medicines have been used as anxiolytic agents in different parts of the world.3) The root of the kava plant from the tropical Pacific region, St. John's wort extract from Europe, and the saponincontaining fraction of the leaves of Albizzia lebbeck from India are known to have anxiolytic effects. [4][5][6] Panax ginseng, as a folk medicine, is one of the most commonly and widely used herbal medicines in Oriental countries such as Korea, China, and Japan. Ginseng has also long been used traditionally for the treatment of psychiatric disorders such as anxiety and depression. It was reported that Panax ginseng extract stabilized sleeping in food-deprived rats.7) Ginseng saponins prolonged pentobarbital sleeping time and delayed the onset of convulsions when administered at high doses, effects that appear to be due to the GABA-benzodiazepinechloride channel complex. On the other hand, we reported that ginseng produced anxiolytic-like effects and the saponin fraction played an important role in the plus-maze model in mice.10) The present study was to know the anxiolytic potential of ginsenosides Rb 1 , Rg 1 , Rg 3 -R, Rg 3 -S, and the Rg 5 and Rk mixture in the elevated plus-maze, a behavioral test for anxiolytic drugs. Furthermore, the anxiolytic effects of ginsenosides and diazepam in the elevated plus-maze were compared to determine whether the behavioral profile of ginsenosides differed from that of the established anxiolytic diazepam. MATERIALS AND METHODS AnimalsMale ICR mice (Samtako, Korea) weighing 20-28 g, in groups of 10-15, were used in all experiments. Groups of 10 mice were housed in acrylic cages (45ϫ 60ϫ25 cm) with water and food available ad libitum under an artificial 12-h light/dark cycle (lights on at 07:00) and at a constant temperature (22Ϯ2°C). To ensure adaptation to the new environment, the mice were housed in the departmental holding room for 1 week before experiments.Experimental Compounds and Drug Ginsenosides Rb 1 , Rg 1 , Rg 3 ,-S, and Rg 3 ,-R, and the Rg 5 and Rk mixture were kindly provided by the Ginseng Science Inc. Rg 3 ,-S, Rg 3 ,-R, and the Rg 5 . and Rk mixture, which are not usually found in white ginseng, were isolated in ginseng steamed at high temperature. Those compounds are unique constituents of red and sun ginseng, and more abundant in sun ginseng than in red ginseng.11-13) Mice were given a single oral administration of each ginsenoside 60 min being placed on the elevated plus-maze. Diazepam (2 mg/kg, Dae-Won Pharmaceutical Co.) was administered orally...
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