- Open Access
Ginsenoside compound K induces apoptosis in nasopharyngeal carcinoma cells via activation of apoptosis-inducing factor
© Law et al.; licensee BioMed Central Ltd. 2014
- Received: 27 August 2013
- Accepted: 31 March 2014
- Published: 2 April 2014
Nasopharyngeal carcinoma (NPC) has a high incidence rate in Southern China. Although there are conventional therapies, the side effects and toxicities are not always tolerable for patients. Recently, the tumoricidal effect of ginsenosides on different cancer cells has been studied. This study aims to investigate the anti-cancer effect of ginsenosides on NPC cells and their underlying mechanism.
The cytotoxicity of ginsenosides on NPC cell line HK-1 was measured by MTT assay. Apoptosis was detected by propidium iodide staining followed by flow cytometry. A xenograft tumor model was established by injecting nude mice with HK-1 cells. The activation of caspases and apoptosis-inducing factor (AIF) were evaluated by Western blot analysis. Nuclear translocation of AIF was also studied by immunofluorescence staining. Mitochondrial membrane potential was measured by JC-1 dye using flow cytometry.
Four ginsenosides, 20 (S)-Rh2, compound K (CK), panaxadiol (PD) and protopanaxadiol (PPD), induced apoptotic cell death in HK-1 cells in a concentration-dependent manner. CK inhibited HK-1 xenograft tumor growth most extensively and depleted mitochondrial membrane potential depolarization and induced translocation of AIF from cytoplasm to nucleus in HK-1 cells. In addition, depletion of AIF by siRNA abolished CK-induced HK-1 cell death.
Ginsenoside CK-induced apoptosis of HK-1 cells was mediated by the mitochondrial pathway and could significantly inhibit tumor growth in vivo.
- Mitochondrial Membrane Potential
- Human Astrocytoma Cell
- FV1000 Confocal Scanning Laser Microscope
- Nuclear Extraction Buffer
Nasopharyngeal carcinoma (NPC) is a head and neck cancer with a distinctive ethnic and geographic distribution. In Southern China, NPC has a high incidence of about 25–30 per 100,000 persons per year, in contrast to the low incidence of less than 1 per 100,000 persons per year was recorded in Western countries . The common treatment for NPC is radiotherapy. Besides the undesirable side effects of radiotherapy, the location of the tumor also leads to complications after treatment. Chemotherapy is an alternative in treating NPC but resistance to conventional drugs is a challenge. Therefore, new multiple regimens such as radiochemotherapy and combination treatments with adjuvant drugs are being studied .
Ginsenosides are a group of saponin glycosides, which contribute to the pharmacological effects of ginseng . More than 40 ginsenosides have been separated and identified from ginseng [4, 5] and can be classified into three groups: protopanaxadiols (PPD) (e.g., Rb2, Rc, Rd, Rg3, and Rh2), protopanaxatriols (PPT) (e.g., Re, Rf, Rg1, Rg2, and Rh1), and oleanolic acid derivatives [6, 7]. Structure-activity relationship studies on different ginsenosides and their anti-cancer effects have been demonstrated that ginsenosides with a sugar moiety at C-6 (PPT-type) exhibit less cytotoxicity than those without a sugar moiety at C-6 (PPD-type) . In the last few years, ginsenosides were reported to be responsible for the vasorelaxation, antioxidation, anti-inflammation, anti-angiogenesis and anti-cancer effects of ginseng [9, 10]. Ginsenosides PPD and Rh2 exhibited anti-proliferative effects on intestinal and glioma cell models [11–13]. Apoptosis induction by different ginsenosides was also demonstrated on human astrocytoma cells, human epidermal carcinoma cells, HeLa cells, and HT-29 colon cells [14–18]. Compound K (CK) is the major metabolite of PPD-type ginsenosides, and is transformed by intestinal bacteria . CK is rapidly absorbed in the gastrointestinal tract and is retained for a long time in rat plasma [20, 21]. The anti-angiogenic effect of CK was also reported [14, 16, 22]. Although the anti-cancer effects of ginsenosides have been studied extensively in other cancer models, the effect of ginsenosides on NPC is unknown. Several natural compounds extracted from plants could induce apoptosis in NPC through the mitochondria-dependent pathway. For example, capsaicin (EC50 ~ 300 μM) from hot chili peppers , aloe emodin (EC50 100 μM) , and rhein (EC50 180 μM)  isolated from the rhizome of rhubarb, induced depletion of mitochondrial membrane potential and subsequent AIF release in NPC-derived cell lines. However, ginsenosides and especially CK are more potent (EC50 15 μM) than these natural compounds. Although caspase-dependent apoptosis induced by CK was reported in other cancer cell-lines [26–28], cell type-specific intracellular signaling might account for the discrepancy observed. The adjuvant effect of ginsenosides has been demonstrated by increasing chemotherapy efficacy  and patient survival rates [29, 30].
This study aims to investigate the anti-cancer effects and action mechanism of ginsenosides on NPC cells.
High-performance liquid chromatography-purified ginsenosides as standard compounds (purity >98%) were purchased from Fleton Natural Products (Chengdu, China). Stock solutions of PPD (20 mM), CK (40 mM), and 20 (S)-Rh2 (40 mM) were prepared in dimethyl sulfoxide (DMSO) (Sigma Aldrich, St. Louise, MO, USA), while PD (20 mM) was prepared in absolute ethanol.
Cell culture and drug treatments
NPC cell line HK-1 was maintained in RPMI 1640 medium (Gibco, Grand Island , NY, USA) supplemented with 10% fetal bovine serum (FBS) (Gibco) and 1% penicillin and streptomycin (Gibco) at 37°C in a humidified incubator with 5% CO2. HK-1 cells were starved in medium with 1% FBS for 24 h before drug treatment. Cells were treated with indicated concentrations of ginsenosides for different times in medium supplemented with 1% FBS.
Cell viability assay
Cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Briefly, HK-1 cells (1 × 104 cells/well) were seeded onto 96-well plates and incubated overnight. Cells were starved in medium with 1% FBS for 24 h and then subjected to different treatments for another 24 h. After that, MTT solution (USB, Cleveland, OH, USA) was added into each well to a final concentration of 0.5 mg/mL and incubated for 3 h. The culture medium was then removed and DMSO was added to solubilize the purple formazan product. Absorbances at wavelengths of 540 and 690 nm were measured by a microplate reader (ELx800, Biotek, Winooski, VT, USA).
Cell cycle analysis
HK-1 cells (1.5 × 105 cells/well) were seeded onto 6-well plates and incubated overnight. Cells were starved in medium with 1% FBS for 24 h and then treated with different ginsenosides for 24 h. Cells were harvested, washed with PBS (Gibco) twice, and fixed in 70% ethanol at −20°C. The cells were then stained with propidium iodide solution (Sigma-Aldrich) containing RNase A (1 mg/mL) (Roche, Mannheim, Germany). Cell-cycle analysis was performed with the FACSCalibur Flow Cytometer (BD Biosciences, San Jose, CA, USA) and the data were analyzed with the Cell Quest and the Modfit LT Version 3.0 software (Verity Software House, Topsham, Maine, USA).
Western blot analysis
After drug treatment, cytosolic and nuclear lysates were extracted with the NE-PER Nuclear Protein Extraction Kit (Millipore, Bedford, MD, USA) according to the manufacturer’s protocol. The cytosolic fraction was extracted with cytoplasmic lysis buffer (1× cytoplasmic lysis buffer, 0.5 mM DTT, 1:1000 dilution of inhibitor cocktail) while the nuclear fraction was extracted with nuclear extraction buffer (1× nuclear extraction buffer, 1:1000 dilution of inhibitor cocktail). Protein concentrations were determined with the Bio-Rad Dc protein assay kit (Bio-Rad, Hercules, CA, USA). Equal amounts of protein samples were separated by SDS-PAGE and transferred onto a nitrocellulose membrane. The membrane was then probed with primary antibodies (anti-AIF) (Cell Signaling, Beverly, MA, USA) and subsequently incubated with secondary antibodies (HRP-conjugated goat anti-rabbit IgG) (Invitrogen). After washing with 0.1% TBS-T (USB), the membrane was visualized by an enhanced chemiluminescence detection system (Bio-Rad). For the cytosolic fraction, protein expression was compared with β-actin (Sigma-Aldrich). For the nuclear fraction, lamin A/C (Santa Cruz Biotechnology, Santa Cruz, CA, USA) was used for normalization.
Xenografts in nude mice
Male BALB/c nude mice were purchased from the Animal Services Centre of Chinese University of Hong Kong. For the animal study, HK-1 cells were harvested and washed twice with PBS. For each site of injection, 3 × 106 HK-1 cells were suspended in 100 μL serum-free RPMI-1640 culture medium and mixed with Matrigel in a 1:1 ratio (BD Biosciences). The cell-matrigel mixture was inoculated subcutaneously into the left and right flanks of 6–7 week-old nude mice. When the tumors were palpable (8 days after injection), the tumor-bearing animals were randomly divided into two groups (four mice per group). In group 1, mice were treated with 10 mg/kg/day CK orally (CK was mixed in a 0.5% carboxymethyl cellulose [CMC] suspension). In group 2, mice were treated with 0.5% CMC orally as the control. Tumor sizes were measured daily and calculated using the formula (L × W2)/2 mm3 (L = length; W = width). The experiment was performed according to the Animals (Control of Experiments) Ordinance (Hong Kong) and followed the Hong Kong Baptist University’s guidelines on animal experimentation. The tumor inhibition (%) was calculated as follows:
Tumor inhibition (%) = (Tumor volume of control group − Tumor volume of CK-treated group)/(Tumor volume of control group).
Detection of mitochondrial membrane potential
HK-1 cells were incubated with 5 μg/mL JC-1 dye (Invitrogen) for 30 min. After that, cells were trypsinized and resuspended in PBS for flow cytometry analysis. JC-1 monomers and J-aggregates were detected by a flow cytometer on the FL1 and FL2 channels, respectively. The mitochondrial membrane potential is presented by the 580/530 nm ratio.
HK-1 cells were seeded on a glass coverslip at a density of 2 × 105 cells/well in a 6-well plate and incubated overnight. Cells were starved with 1% FBS medium for 24 h and then treated with or without CK for another 8 and 24 h. The medium was then removed and the glass cover slips were washed with PBS. After that, cells were fixed with 4% paraformaldehyde (Sigma Aldrich) for 10 min followed by washing with PBS three times. Cells were permeabilized with 0.2% of Triton X-100 for 10 min followed by washing with PBS. Cells were probed with anti-AIF antibody in 3% BSA (Sigma Aldrich) overnight at 4°C and then secondary antibody (PE-conjugated goat-anti-rabbit IgG) (Invitrogen) for 2 h at room temperature. After washing with PBS, the coverslip was incubated with DAPI (0.5 g/mL) (Invitrogen) for 5 min. Coverslips were mounted with fluorescence mounting medium on slides and were subjected to examination and image capture by an Olympus FV1000 confocal scanning laser microscope (Essex, UK).
Transfection of small interference RNA (siRNA)
HK-1 cells were seeded onto 6-well plates overnight, cells were then transfected with AIFM1 specific siRNA (50 nM) (Ambion, Austin, TX, USA) using Lipofectamine RNAiMAX transfection reagent (Invitrogen) in antibiotic-free RPMI-1640 culture medium. Drug treatment was performed 48 h after transfection.
All data were presented as mean ± standard deviation (S.D). Comparisons were subjected to Student’s t-test or Kruskal-Wallis One Way Analysis of Variance (ANOVA) followed by Dunnets post hoc test for multiple comparisons. Statistical significance was accepted at P < 0.05.
Ginsenosides 20(S)-Rh2, CK, PD, and PPD exhibited cytotoxicities towards HK-1 cells
Ginsenosides induced apoptosis in HK-1 cells
Ginsenosides induced caspase activation in HK-1 cells
CK attenuated HK-1 xenograft tumors in vivo and induced caspase-independent apoptosis
CK induced apoptosis-inducing factor (AIF) translocation and mitochondrial membrane depolarization
Ginsenosides were reported to exhibit anti-proliferative, anti-metastatic, and anti-angiogenic activities in different in vitro and in vivo tumor models [10, 32–35]. However, different ginsenosides induced diverse biological effects on different models due to structural differences. The number of sugar moieties were found to mediate ginsenosides activity by altering hydrophilicity. Moreover, aglycone ginsenosides (i.e., CK, PPD, and PPT) showed higher cytotoxicity than glycosides. This property of ginsenosides also mediated their affinity towards different molecular targets. CK is the major metabolite of all PPD-type ginsenosides in both rat and human plasma [20, 21, 31]. Aside from its tumoricidal effects, CK was shown to have neuroprotective, hypoglycemic, and antidepressant-like effects in mice, and enhancement of type I procollagen levels in ultraviolet-A-irradiated fibroblasts [36–39]. In the present study, HK-1 cells had a similar response towards 20(S)-Rh2, CK, PD, and PPD, and ginsenoside CK showed the most potent sub-G1 phase induction.
Apoptosis is a common type of cell death induced by anti-cancer drugs. Ginsenosides can induce apoptosis in different cancer models including human astrocytoma cells, HT-29 colon cells, A431 cells, and HeLa cells [14, 17, 18, 40]. Apoptosis is mainly induced by a caspase cascade or translocation of AIF . There are two pathways of caspase activation, which are the cell surface death receptor pathway (extrinsic) and mitochondria-initiated pathway (intrinsic). Caspase-3 is the “execute” caspase for the apoptotic induction, while caspase-8 and caspase-9 are the critical caspases and signify the activation of the extrinsic and intrinsic pathways, respectively . In our study, we demonstrated apoptosis induction and caspase activation of ginsenosides in NPC cells. And pretreatment with caspase inhibitors did not reverse the cell death of CK-treated cells. This indicated that CK-induced cell death was caspase-independent. Besides inducing apoptosis, caspase activation was involved in other cellular responses, such as differentiation or cell migration . Therefore, the CK-activated caspase cascade did not participate in the apoptotic execution.
Ginsenoside CK-induced apoptosis of HK-1 cells was mediated by the mitochondrial pathway and could significantly inhibit tumor growth in vivo.
The present work is supported by the Area of Excellence Scheme (AoE/M-06/08) by the Research Grant Council of Hong Kong SAR Government; the Faculty Research Grant (FRG2/09-10/068) of the Hong Kong Baptist University, and Dr. Gilbert Hung Ginseng Laboratory Fund. We also thank Mr Yuk-Kit Chan for technical assistance.
- Lo KW, To KF, Huang DP: Focus on nasopharyngeal carcinoma. Cancer Cell. 2004, 5: 423-428. 10.1016/S1535-6108(04)00119-9.View ArticlePubMedGoogle Scholar
- Suarez C, Rodrigo JP, Rinaldo A, Langendijk JA, Shaha AR, Ferlito A: Current treatment options for recurrent nasopharyngeal cancer. Eur Arc of oto-rhino-laryngology. 2010, 267: 1811-1824. 10.1007/s00405-010-1385-x.View ArticleGoogle Scholar
- Yue PY, Huang Y, Wong RN: Ginsenoside Rg3 and Rh2: The anti-cancer and anti-angiogenic saponins from ginseng. Atta-ur-Rahman. Edited by: Choudhary MI. 2007, USA: Anti-angiogenesis drug discovery and development. Bentham Science Publishers Ltd, 34-57.Google Scholar
- Cheng Y, Shen LH, Zhang JT: Anti-amnestic and anti-aging effects of ginsenoside Rg1 and Rb1 and its mechanism of action. Acta Pharmacol Sin. 2005, 26: 143-149. 10.1111/j.1745-7254.2005.00034.x.View ArticlePubMedGoogle Scholar
- Nah S: Ginseng: Recent advances and trends. Korean J Ginseng Sci. 1997, 21: 1-12.Google Scholar
- Attele AS, Wu JA, Yuan CS: Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol. 1999, 58: 1685-1693. 10.1016/S0006-2952(99)00212-9.View ArticlePubMedGoogle Scholar
- Liu CC, Xiao PG: Recent advances on ginseng research in China. J Ethnopharmacol. 1992, 36: 27-38. 10.1016/0378-8741(92)90057-X.View ArticlePubMedGoogle Scholar
- Nag SA, Qin JJ, Wang W, Wang MH, Wang H, Zhang R: Ginsenosides as Anticancer Agents: In vitro and in vivo Activities, Structure-Activity Relationships, and Molecular Mechanisms of Action. Front Pharmacol. 2012, 3: 25-PubMed CentralView ArticlePubMedGoogle Scholar
- Lu JM, Yao Q, Chen C: Ginseng compounds: an update on their molecular mechanisms and medical applications. Curr Vasc Pharmacol. 2009, 7: 293-302. 10.2174/157016109788340767.PubMed CentralView ArticlePubMedGoogle Scholar
- Yue PY, Wong DY, Wu P, Leung P, Mak N, Yeung H, Liu L, Cai Z, Jiang Z, Fan DT, Wong RN: The angiosuppressive effects of ginsenoside-Rg3. Biochem Pharmacol. 2006, 72: 437-445. 10.1016/j.bcp.2006.04.034.View ArticlePubMedGoogle Scholar
- Kim HE, Oh JH, Lee SK, Oh YJ: Ginsenoside Rh-2 induces apoptotic cell death in rat C6 glioma via a reactive oxygen- and caspase-dependent but Bcl-X (L)-independent pathway. Life Sci. 1999, 65: L33-L40.Google Scholar
- Liu GY, Bu X, Yan H, Jia WW: 20S-protopanaxadiol-induced programmed cell death in glioma cells through caspase-dependent and -independent pathways. J Nat Prod. 2007, 70: 259-264. 10.1021/np060313t.View ArticlePubMedGoogle Scholar
- Popovich DG, Kitts DD: Ginsenosides 20(S)-protopanaxadiol and Rh2 reduce cell proliferation and increase sub-G1 cells in two cultured intestinal cell lines, Int-407 and Caco-2. Can J Physiol Pharmacol. 2004, 82: 183-190. 10.1139/y04-001.View ArticlePubMedGoogle Scholar
- Choi K, Choi C: Proapoptotic ginsenosides compound K and Rh enhance Fas-induced cell death of human astrocytoma cells through distinct apoptotic signaling pathways. Cancer Res Treat. 2009, 41: 36-44. 10.4143/crt.2009.41.1.36.PubMed CentralView ArticlePubMedGoogle Scholar
- Kim SM, Lee SY, Yuk DY, Moon DC, Choi SS, Kim Y, Han SB, Oh KW, Hong JT: Inhibition of NF-kappaB by ginsenoside Rg3 enhances the susceptibility of colon cancer cells to docetaxel. Arch Pharm Res. 2009, 32: 755-765. 10.1007/s12272-009-1515-4.View ArticlePubMedGoogle Scholar
- Kumar A, Kumar M, Park TY, Park MH, Takemoto T, Terado T, Kitano M, Kimura H: Molecular mechanisms of ginsenoside Rp1-mediated growth arrest and apoptosis. Int J Mol Med. 2009, 24: 381-386.PubMedGoogle Scholar
- Park EK, Lee EJ, Lee SH, Koo KH, Sung JY, Hwang EH, Park JH, Kim CW, Jeong KC, Park BK, Kim YN: Induction of apoptosis by the ginsenoside Rh2 by internalization of lipid rafts and caveolae and inactivation of Akt. Br J Pharmacol. 2010, 160: 1212-1223.PubMed CentralView ArticlePubMedGoogle Scholar
- Yuan HD, Quan HY, Zhang Y, Kim SH, Chung SH: 20 (S)-Ginsenoside Rg3-induced apoptosis in HT-29 colon cancer cells is associated with AMPK signaling pathway. Molecular Med Report. 2010, 3: 825-831.Google Scholar
- Bae EA, Han MJ, Kim EJ, Kim DH: Transformation of ginseng saponins to ginsenoside Rh2 by acids and human intestinal bacteria and biological activities of their transformants. Arch Pharm Res. 2004, 27: 61-67. 10.1007/BF02980048.View ArticlePubMedGoogle Scholar
- Akao T, Kanaoka M, Kobashi K: Appearance of compound K, a major metabolite of ginsenoside Rb1 by intestinal bacteria, in rat plasma after oral administration–measurement of compound K by enzyme immunoassay. Biol Pharm Bull. 1998, 21: 245-249. 10.1248/bpb.21.245.View ArticlePubMedGoogle Scholar
- Akao T, Kida H, Kanaoka M, Hattori M, Kobashi K: Intestinal bacterial hydrolysis is required for the appearance of compound K in rat plasma after oral administration of ginsenoside Rb1 from Panax ginseng. J Pharm Pharmacol. 1998, 50: 1155-1160. 10.1111/j.2042-7158.1998.tb03327.x.View ArticlePubMedGoogle Scholar
- Jeong JC, Shin WY, Kim TH, Kwon CH, Kim JH, Kim YK, Kim KH: Silibinin induces apoptosis via calpain-dependent AIF nuclear translocation in U87MG human glioma cell death. J Exp Clin Cancer Res. 2011, 19: 30-44.Google Scholar
- Ip SW, Lan SH, Lu HF, Huang AC, Yang JS, Lin JP, Huang HY, Lien JC, Ho CC, Chiu CF, Wood W, Chung JG: Capssaicin mediates apoptosis in human nasopharyngeal carcinoma NPC-TW 039 cells through mitochondrial depolarization and endoplasmic reticulum stress. Hum Exp Toxicol. 2012, 31: 539-549. 10.1177/0960327111417269.View ArticlePubMedGoogle Scholar
- Lin ML, Lu YC, Chung JG, Li YC, Wang SG, Ng SH, Wu CY, Su HL, Chen SS: Aloe-emodin induces apoptosis of human nasopharyngeal carcinoma cells via caspase-8-mediated activation of the mitochondrial death pathway. Cancer Lett. 2010, 291: 46-58. 10.1016/j.canlet.2009.09.016.View ArticlePubMedGoogle Scholar
- Lin ML, Chen SS, Lu YC, Liang RY, Ho YT, Yang CY, Chung JG: Rhein induces apoptosis through induction of endoplasmic reticulum stress and Ca2+-dependent mitochondrial death pathway in human nasopharyngeal carcinoma cells. Anticancer Res. 2007, 27: 3313-3322.PubMedGoogle Scholar
- Hu C, Song G, Zhang B, Liu Z, Chen R, Zhang H, Hu T: Intestinal metabolite compound K of panaxoside inhibits the growth of gastric carcinoma by augmenting apoptosis via Bid-mediated mitochondrial pathway. J Cell Mol Med. 2012, 16: 96-106. 10.1111/j.1582-4934.2011.01278.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Cho SH, Chung KS, Choi JH, Kim DH, Lee KT: Compound K, a metabolite of ginseng saponin, induces apoptosis via caspase-8-dependent pathway in HL-60 human leukemia cells. BMC Cancer. 2009, 9: 449-10.1186/1471-2407-9-449.PubMed CentralView ArticlePubMedGoogle Scholar
- Lee SJ, Ko WG, Kim JH, Sung JH, Moon CK, Lee BH: Induction of apoptosis by a novel intestinal metabolite of ginseng saponin via cytochrome c-mediated activation of caspase-3 protease. Biochem Pharmacol. 2000, 60: 677-685. 10.1016/S0006-2952(00)00362-2.View ArticlePubMedGoogle Scholar
- Kikuchi Y, Sasa H, Kita T, Hirata J, Tode T, Nagata I: Inhibition of human ovarian cancer cell proliferation in vitro by ginsenoside Rh2 and adjuvant effects to cisplatin in vivo. Anti-cancer Drugs. 1991, 2: 63-67. 10.1097/00001813-199102000-00009.View ArticlePubMedGoogle Scholar
- Zhang Q, Kang X, Zhao W: Antiangiogenic effect of low-dose cyclophosphamide combined with ginsenoside Rg3 on Lewis lung carcinoma. Biochem Biophys Res Commun. 2006, 342: 824-828. 10.1016/j.bbrc.2006.02.044.View ArticlePubMedGoogle Scholar
- Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G: Molecular characterization of mitochondrial apoptosis-inducing factor. Nature. 1999, 397: 441-446. 10.1038/17135.View ArticlePubMedGoogle Scholar
- Chen QJ, Zhang MZ, Wang LX: Gensenoside Rg3 inhibits hypoxia-induced VEGF expression in human cancer cells. Cell Physiol Biochem. 2010, 26: 849-858. 10.1159/000323994.View ArticlePubMedGoogle Scholar
- Kim YJ, Kwon HC, Ko H, Park JH, Kim HY, Yoo JH, Yang HO: Anti-tumor activity of the ginsenoside Rk1 in human hepatocellular carcinoma cells through inhibition of telomerase activity and induction of apoptosis. Biol Pharm Bull. 2008, 31: 826-830. 10.1248/bpb.31.826.View ArticlePubMedGoogle Scholar
- Yoon JH, Choi YJ, Lee SG: Ginsenoside Rh1 suppresses matrix metalloproteinase-1 expression through inhibition of activator protein-1 and mitogen-activated protein kinase signaling pathway in human hepatocellular carcinoma cells. Eur J Pharmacol. 2012, 679: 24-33. 10.1016/j.ejphar.2012.01.020.View ArticlePubMedGoogle Scholar
- Lee J, Lee E, Kim D, Lee J, Yoo J, Koh B: Studies on absorption, distribution and metabolism of ginseng in humans after oral administration. J Ethnopharmacol. 2009, 122: 143-148. 10.1016/j.jep.2008.12.012.View ArticlePubMedGoogle Scholar
- He D, Sun J, Zhu X, Nian S, Liu J: Compound K increases type I procollagen level and decreases matrix metalloproteinase-1 activity and level in ultraviolet-A-irradiated fibroblasts. J Formos Med Assoc. 2011, 110: 153-160. 10.1016/S0929-6646(11)60025-9.View ArticlePubMedGoogle Scholar
- Li W, Zhang M, Gu J, Meng ZJ, Zhao LC, Zheng YN, Chen L, Yang GL: Hypoglycemic effect of protopanaxadiol-type ginsenosides and compound K on Type 2 diabetes mice induced by high-fat diet combining with streptozotocin via suppression of hepatic gluconeogenesis. Fitoterapia. 2012, 83: 192-198. 10.1016/j.fitote.2011.10.011.View ArticlePubMedGoogle Scholar
- Park JS, Shin JA, Jung JS, Hyun JW, Van Le TK, Kim DH, Park EM, Kim HS: Anti-inflammatory mechanism of compound K in activated microglia and its neuroprotective effect on experimental stroke in mice. J Pharmacol Exp Ther. 2012, 2341: 59-67.View ArticleGoogle Scholar
- Yamada N, Araki H, Yoshimura H: Identification of antidepressant-like ingredients in ginseng root (Panax ginseng C.A. Meyer) using a menopausal depressive-like state in female mice: participation of 5-HT2A receptors. Psychopharmacology (Berl). 2011, 216: 589-599. 10.1007/s00213-011-2252-1.View ArticleGoogle Scholar
- Kim DY, Park MW, Yuan HD, Lee HJ, Kim SH, Chung SH: Compound K induces apoptosis via CAMK-IV/AMPK pathways in HT-29 colon cancer cells. J Agric Food Chem. 2009, 57: 10573-10578. 10.1021/jf902700h.View ArticlePubMedGoogle Scholar
- Hengartner MO: The biochemistry of apoptosis. Nature. 2000, 407: 770-776. 10.1038/35037710.View ArticlePubMedGoogle Scholar
- Budihardjo I, Oliver H, Lutter M, Luo X, Wang X: Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol. 1999, 15: 269-290. 10.1146/annurev.cellbio.15.1.269.View ArticlePubMedGoogle Scholar
- Li J, Yuan J: Caspases in apoptosis and beyond. Oncogene. 2008, 27: 6194-6206. 10.1038/onc.2008.297.View ArticlePubMedGoogle Scholar
- Chung YC, Tang FY, Liao JW, Chung CH, Jong TT, Chen SS, Tsai CH, Chiang EP: Isatis indigotica induces hepatocellular cancer cell death via caspase-independent apoptosis-inducing factor translocation apoptotic pathway in vitro and in vivo. Integr Cancer Ther. 2011, 10: 201-214. 10.1177/1534735410387420.View ArticlePubMedGoogle Scholar
- Shih CM, Wu JS, Ko WC, Wang LF, Wei YH, Liang HF, Chen YC, Chen CT: Mitochondria-mediated caspase-independent apoptosis induced by cadmium in normal human lung cells. J Cell Biochem. 2003, 89: 335-347. 10.1002/jcb.10488.View ArticlePubMedGoogle Scholar
- Modjtahedi N, Giordanetto F, Madeo F, Kroemer G: Apoptosis-inducing factor: vital and lethal. Trends Cell Biol. 2006, 16: 264-272. 10.1016/j.tcb.2006.03.008.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.