Stereoisomer-Specific Anticancer Activities of Ginsenoside Rg3 and Rh2 in HepG2 Cells: Disparity in Cytotoxicity and Autophagy-Inducing Effects Due to 20(S)-Epimers

Cheong, Jong Hye; Kim, Hyeryung; Hong, Mei; Yang, Min; Kim, Jung Wha; Yoo, Han‐Ill; Yang, Heejung; Park, Jeong Hill; Sung, Sang Hyun; Kim, Hong Pyo; Kim, Jinwoong

doi:10.1248/bpb.b14-00603

Cited by 49 publications

(32 citation statements)

References 27 publications

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“…Park et al (20) reported that 20(S)-ginsenoside Rg3 reduced human gastric cancer cellular proliferation, whereas 20(R)-ginsenoside Rg3 had no effect. Cheong et al (21) showed that 20(S)-ginsenoside Rg3 had higher cytotoxic potency, compared with the 20(R) epimer in HepG2 cells.…”

Section: Resultsmentioning

confidence: 99%

Effects of R type and S type ginsenoside Rg3 on DNA methylation in human hepatocarcinoma cells

Teng

Wang

et al. 2017

Molecular Medicine Reports

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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.

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Section: Resultsmentioning

confidence: 99%

Effects of R type and S type ginsenoside Rg3 on DNA methylation in human hepatocarcinoma cells

Teng

Wang

et al. 2017

Molecular Medicine Reports

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“…GRg3 may be metabolized to GRh2 by human fecal microflora (24). It has been reported that GRh2 and GRg3 have anticancer effects on numerous strains of human tumor cells (6,25,26), and GRh2 has a more potent anticancer activity than GRg3 (6,27,28). The present study investigated the underlying mechanisms of GRh2- and GRg3-induced toxicity, and examined whether mitochondrial ROS contributes to apoptosis via mitochondrial damage in Jurkat cells.…”

Section: Discussionmentioning

confidence: 99%

Ginsenoside Rh2 and Rg3 inhibit cell proliferation and induce apoptosis by increasing mitochondrial reactive oxygen species in human leukemia Jurkat cells

Xia

Wang

Zhou

et al. 2017

Molecular Medicine Reports

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Ginsenoside Rh2 (GRh2) and ginsenoside Rg3 (GRg3) are primary bioactive components in Panax ginseng. The present study aimed to investigate the underlying mechanisms of apoptotic cell-death induced by GRh2 and GRg3 in human leukemia Jurkat cells. The Cell Counting kit-8 assay was used to determine cell proliferation. Apoptosis was detected by nuclear morphologic observation by Hoechst 33342 staining and Annexin V-allophycocyanin and 7-amino-actinomycin D assay. mitoTEMPO, a mitochondrial reactive oxygen species (ROS) scavenger, was used to examine the effects of mitochondrial ROS on cell viability and mitochondrial membrane potential (MMP). Finally, the expression levels of numerous mitochondrial-associated apoptosis proteins were assessed by western blot analysis. These results demonstrated that GRh2 and GRg3 inhibited cell growth and induced apoptosis, and that GRh2 had greater cytotoxicity than GRg3. GRh2 induced generation of more mitochondrial ROS compared with GRg3 in Jurkat cells; however, this effect was ameliorated by subsequent treatment with mitoTEMPO. Furthermore, excess mitochondrial ROS induced by GRh2 was more potent than GRg3 in inhibiting cell proliferation and reducing MMP. In addition, expression levels of apoptosis-associated proteins were significantly increased in Jurkat cells treated with GRh2 than GRg3. In conclusion, these findings suggested that GRh2 and GRg3 induce mitochondrial-associated apoptosis by increasing mitochondrial ROS in human leukemia Jurkat cells. GRh2 may more effectively inhibit cell growth and accelerate apoptosis than GRg3. This study provides a potential novel strategy for the treatment of acute lymphoblastic leukemia.

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“…[20] recently reported that Rg3, one of the active components in KG-135, induced autophagy in HepG2 hepatoma cells evidenced by the increase of LC-3-II. Controversially, the study by Kim et al.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to apoptosis, autophagy induction was also observed in cancer cells treated with ginsenoside Rg3 [20] or microwave-irradiated P. ginseng extract containing higher content of Rk1, Rg3, and Rg5 [9]. How autophagy affects the anticancer activity of ginsenoside-rich fractions such as KG-135 has not been reported.…”

Section: Introductionmentioning

confidence: 99%

Induction of Forkhead Class box O3a and apoptosis by a standardized ginsenoside formulation, KG-135, is potentiated by autophagy blockade in A549 human lung cancer cells

Yao

Chow

Chuang

et al. 2017

Journal of Ginseng Research

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BackgroundKG-135, a standardized formulation enriched with Rk1, Rg3, and Rg5 ginsenosides, has been shown to inhibit various types of cancer cells; however, the underlying mechanisms are not fully understood. In this study, we explored its effects in A549 human lung cancer cells to investigate the induction of Forkhead Class box O3a (FOXO3a) and autophagy.MethodsCell viability was determined by sulforhodamine B staining. Apoptosis and cell cycle distribution were analyzed using flow cytometry. The changes of protein levels were determined using Western blot analysis. Autophagy induction was monitored by the formation of acidic vesicular organelles stained with acridine orange.ResultsKG-135 effectively arrested the cells in G1 phase with limited apoptosis. Accordingly, a decrease of cyclin-dependent kinase-4, cyclin-dependent kinase-6, cyclin D1, and phospho-retinoblastoma protein, and an increase of p27 and p18 proteins were observed. Intriguingly, KG-135 increased the tumor suppressor FOXO3a and induced the accumulation of autophagy hallmark LC3-II and acidic vesicular organelles without an increase of the upstream marker Beclin-1. Unconventionally, the autophagy adaptor protein p62 (sequestosome 1) was increased rather than decreased. Blockade of autophagy by hydroxychloroquine dramatically potentiated KG-135-induced FOXO3a and its downstream (FasL) ligand accompanied by the cleavage of caspase-8. Meanwhile, the decrease of Bcl-2 and survivin, as well as the cleavage of caspase-9, were also drastically enhanced, resulting in massive apoptosis.ConclusionBesides arresting the cells in G1 phase, KG-135 increased FOXO3a and induced an unconventional autophagy in A549 cells. Both the KG-135-activated extrinsic FOXO3a/FasL/caspase-8 and intrinsic caspase-9 apoptotic pathways were potentiated by blockade of autophagy. Combination of KG-135 and autophagy inhibitor may be a novel strategy as an integrative treatment for cancers.

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Stereoisomer-Specific Anticancer Activities of Ginsenoside Rg3 and Rh2 in HepG2 Cells: Disparity in Cytotoxicity and Autophagy-Inducing Effects Due to 20(S)-Epimers

Cited by 49 publications

References 27 publications

Effects of R type and S type ginsenoside Rg3 on DNA methylation in human hepatocarcinoma cells

Effects of R type and S type ginsenoside Rg3 on DNA methylation in human hepatocarcinoma cells

Ginsenoside Rh2 and Rg3 inhibit cell proliferation and induce apoptosis by increasing mitochondrial reactive oxygen species in human leukemia Jurkat cells

Induction of Forkhead Class box O3a and apoptosis by a standardized ginsenoside formulation, KG-135, is potentiated by autophagy blockade in A549 human lung cancer cells

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