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Zhou Y, Wang Z, Ren S, Li W. Mechanism of action of protopanaxadiol ginsenosides on hepatocellular carcinoma and network pharmacological analysis. CHINESE HERBAL MEDICINES 2024; 16:548-557. [PMID: 39606268 PMCID: PMC11589304 DOI: 10.1016/j.chmed.2024.06.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/24/2024] [Accepted: 06/18/2024] [Indexed: 11/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies globally, posing a major challenge to global health care. Protopanaxadiol ginsenosides (PDs) have been believed to significantly improve liver diseases. PDs, such as Rg3, have been developed as a new class of anti-cancer drugs. Ginsenosides Rb1, Rd, Rg3, and Rh2 exhibit effective anti-inflammatory and anti-tumor activities. Studies have confirmed that PDs could be used to treat HCC. However, the mechanism of action of PDs on HCC remains unclear. In the study, we reviewed the anti-HCC effects and mechanisms of PDs including Rb1, Rd, Rg3, Rg5, Rh2, Rk1, and Compound K (CK). Then, we searched for relevant targets of PDs and HCC from databases and enriched them for analysis. Subsequently, molecular docking was simulated to reveal molecular mechanisms. We found that PDs may treat HCC through multiple signaling pathways and related targets. PDs could inhibit the proliferation, invasion, and metastasis of HCC while promoting apoptosis and inducing differentiation. In conclusion, this review and network pharmacological analysis might offer a direction for in-depth research on related mechanisms. These insights will aid in the direction of further pharmacological studies and the development of safe and effective clinical drugs.
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Affiliation(s)
- Yue Zhou
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Zi Wang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Shen Ren
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
| | - Wei Li
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130118, China
- College of Life Sciences, Jilin Agricultural University, Changchun 130118, China
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2
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Jiang YX, Zhao YN, Yu XL, Yin LM. Ginsenoside Rd Induces Differentiation of Myeloid Leukemia Cells via Regulating ERK/GSK-3β Signaling Pathway. Chin J Integr Med 2024; 30:588-599. [PMID: 38085388 DOI: 10.1007/s11655-023-3561-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/17/2023] [Indexed: 06/28/2024]
Abstract
OBJECTIVE To investigate the role of ginsenoside Rd (GRd) in acute myeloid leukemia (AML) cell differentiation. METHODS AML cells were treated with GRd (25, 50, 100 and 200 µg/mL), retinoic acid (RA, 0.1g/L) and PD98059 (20 mg/mL) for 72 h, cell survival was detected by methylthiazolyldiphenyl-tetrazolium bromide and colony formation assays, and cell cycle was detected by flow cytometry. Cell morphology and differentiation were observed by Wright-Giemsa staining, peroxidase chemical staining and cellular immunochemistry assay, respectively. The protein expression levels of GATA binding protein 1 (GATA-1), purine rich Box-1 (PU.1), phosphorylated-extracellular signal-related kinase (p-ERK), ERK, phosphorylated-glycogen synthase kinase-3β (p-GSK3β), GSK3β and signal transducer and activator of transcription 1 (STAT1) were detected by Western blot. Thirty-six mice were randomly divided into 3 groups using a random number table: model control group (non-treated), GRd group [treated with 200 mg/(kg·d) GRd] and homoharringtonine (HTT) group [treated with 1 mg/(kg·d) HTT]. A tumor-bearing nude mouse model was established, and tumor weight and volume were recorded. Changes of subcutaneous tumor tissue were observed after hematoxylin and eosin staining. WT1 and GATA-1 expressions were detected by immunohistochemical staining. RESULTS The cell survival was inhibited by GRd in a dose-dependent manner and GRd caused G0/G1 cell arrest (p<0.05). GRd treatment induced leukemia cell differentiation, showing increased expressions of peroxidase and specific proteins concerning erythrogenic or granulocytic differentiation (p<0.05). GRd treatment elicited upregulation of p-ERK, p-GSK-3β and STAT1 expressions in cells, and reversed the effects of PD98059 on inhibiting the expressions of peroxidase, GATA-1 and PU.1 (P<0.05). After GRd treatment, tumor weight and volume of mice were decreased, and tumor cells underwent massive apoptosis and necrosis (P<0.05). WT1 level was decreased, and GATA-1 level was significantly increased in subcutaneous tumor tissues (P<0.05 or P<0.01). CONCLUSION GRd might induce the differentiation of AML cells via regulating the ERK/GSK-3β signaling pathway.
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Affiliation(s)
- Yu-Xia Jiang
- Department of Hematology, Tongde Hospital of Zhejiang Province, Hangzhou, 310012, China
| | - Yan-Na Zhao
- Institute of Hematology Research, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310006, China
| | - Xiao-Ling Yu
- Institute of Hematology Research, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310006, China
| | - Li-Ming Yin
- Institute of Hematology Research, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310006, China.
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3
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Wan X, Jin X, Wu X, Dong D, Yang H, Tan R, Sun Y, Liu X, Sun K, Wu W, Chen C. Ginsenoside Rd reduces cell proliferation of non-small cell lung cancer cells by p53-mitochondrial apoptotic pathway. Heliyon 2024; 10:e32483. [PMID: 38933967 PMCID: PMC11201117 DOI: 10.1016/j.heliyon.2024.e32483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 06/04/2024] [Accepted: 06/04/2024] [Indexed: 06/28/2024] Open
Abstract
Ginsenoside Rd is a tetracyclic triterpenoid derivative, widely existing in Panax ginseng, Panax notoginseng and other traditional Chinese medicines. Many studies have proved that ginsenoside Rd have a variety of significant biological activities on certain types of cancer. However, the mechanism of ginsenoside Rd remains unclear in lung cancer. The findings of this study reveal that GS-Rd inhibits the proliferation of NSCLC cells, induces apoptosis, and suppresses migration and invasion. The results showed Ginsenoside Rd inhibited the cell proliferation (∼99.52 %) by S phase arrest in cell cycle and promoted the apoptosis (∼54.85 %) of NSCLC cells. It also inhibited the migration and invasion of cells (p < 0.001). The expression levels of related mitochondrial apoptosis proteins (Bax/Bcl-2/Cytochrome C) and matrix metalloproteinases (MMP-2/-9) were significantly changed. The results showed that ginsenoside Rd inhibited the proliferation of tumor cells by activating p53/bax-mediated mitochondrial apoptosis and the expression of key enzymes for cell apoptosis caspase-3/cleaved-caspase-3 were significantly increased. This research contributes to a better understanding of the anti-tumor effects and molecular mechanisms of GS-Rd, paving the way for its potential development and clinical application in NSCLC therapy.
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Affiliation(s)
- Xilin Wan
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Xin Jin
- Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE), Northeast Normal University, Changchun, 130024, China
| | - Xinmin Wu
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China
| | - Dan Dong
- Gynaecology and Obstetrics Center, First Hospital of Jilin University, Changchun, 130021, China
| | - Hongmei Yang
- The Public Experimental Center, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Renbo Tan
- Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Ying Sun
- Clinical Laboratory, The Second Affiliated Hospital of Dalian Medical University, 116023, Dalian, China
| | - Xinze Liu
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Kaijing Sun
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Wei Wu
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Changbao Chen
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130117, China
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Islam MT, Jang NH, Lee HJ. Natural Products as Regulators against Matrix Metalloproteinases for the Treatment of Cancer. Biomedicines 2024; 12:794. [PMID: 38672151 PMCID: PMC11048580 DOI: 10.3390/biomedicines12040794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 03/21/2024] [Accepted: 03/29/2024] [Indexed: 04/28/2024] Open
Abstract
Cancers are currently the major cause of mortality in the world. According to previous studies, matrix metalloproteinases (MMPs) have an impact on tumor cell proliferation, which could lead to the onset and progression of cancers. Therefore, regulating the expression and activity of MMPs, especially MMP-2 and MMP-9, could be a promising strategy to reduce the risk of cancers. Various studies have tried to investigate and understand the pathophysiology of cancers to suggest potent treatments. In this review, we summarize how natural products from marine organisms and plants, as regulators of MMP-2 and MMP-9 expression and enzymatic activity, can operate as potent anticancer agents.
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Affiliation(s)
- Md. Towhedul Islam
- Department of Chemistry, Faculty of Science, Mawlana Bhashani Science and Technology University, Santosh, Tangail 1902, Bangladesh
| | - Nak Han Jang
- Department of Chemistry Education, Kongju National University, Gongju 32588, Chungcheongnam-do, Republic of Korea
| | - Hyuck Jin Lee
- Department of Chemistry Education, Kongju National University, Gongju 32588, Chungcheongnam-do, Republic of Korea
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Shah MA, Abuzar SM, Ilyas K, Qadees I, Bilal M, Yousaf R, Kassim RMT, Rasul A, Saleem U, Alves MS, Khan H, Blundell R, Jeandet P. Ginsenosides in cancer: Targeting cell cycle arrest and apoptosis. Chem Biol Interact 2023; 382:110634. [PMID: 37451663 DOI: 10.1016/j.cbi.2023.110634] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 07/04/2023] [Accepted: 07/12/2023] [Indexed: 07/18/2023]
Abstract
Despite the existence of extensive clinical research and novel therapeutic treatments, cancer remains undefeated and the significant cause of death worldwide. Cancer is a disease in which growth of cells goes out of control, being also able to invade other parts of the body. Cellular division is strictly controlled by multiple checkpoints like G1/S and G2/M which, when dysregulated, lead to uncontrollable cell division. The current remedies which are being utilized to combat cancer are monoclonal antibodies, chemotherapy, cryoablation, and bone marrow transplant etc. and these have also been greatly disheartening because of their serious adverse effects like hypotension, neuropathy, necrosis, leukemia relapse and many more. Bioactive compounds derived from natural products have marked the history of the development of novel drug therapies against cancer among which ginsenosides have no peer as they target several signaling pathways, which when abnormally regulated, lead to cancer. Substantial research has reported that ginsenosides like Rb1, Rb2, Rb3, Rc, Rd, Rg3, Rh2 etc. can prevent and treat cancer by targeting different pathways and molecules by induction of autophagy, neutralizing ROS, induction of cancerous cell death by controlling the p53 pathway, modulation of miRNAs by decreasing Smad2 expression, regulating Bcl-2 expression by normalizing the NF-Kb pathway, inhibition of inflammatory pathways by decreasing the production of cytokines like IL-8, causing cell cycle arrest by restricting cyclin E1 and CDC2, and induction of apoptosis during malignancy by decreasing β-catenin levels etc. In this review, we have analyzed the anti-cancer therapeutic potential of various ginsenoside compounds in order to consider their possible use in new strategies in the fight against cancer.
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Affiliation(s)
| | - Syed Muhammad Abuzar
- Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan
| | - Kainat Ilyas
- Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan
| | - Irtaza Qadees
- Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan
| | - Momna Bilal
- Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan
| | - Rimsha Yousaf
- Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan
| | | | - Azhar Rasul
- Department of Zoology, Government College University, Faisalabad, Pakistan
| | - Uzma Saleem
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan
| | - Maria Silvana Alves
- Laboratory of Cellular and Molecular Bioactivity, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Federal University of Juiz de Fora, Minas Gerais, Brazil
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakistan
| | - Renald Blundell
- Department of Physiology and Biochemistry, Faculty of Medicine, University of Malta, Msida, MSD2080, Malta; Centre for Molecular Medicine and Biobanking, University of Malta, MSD2080 Imsida, Malta
| | - Philippe Jeandet
- University of Reims, Research Unit Induced Resistance and Plant Bioprotection USC INRAe 1488 Department of Biology and Biochemistry, Faculty of Sciences, 51100, Reims, France.
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Janta S, Pranweerapaiboon K, Vivithanaporn P, Plubrukarn A, Chairoungdua A, Prasertsuksri P, Apisawetakan S, Chaithirayanon K. Holothurin A Inhibits RUNX1-Enhanced EMT in Metastasis Prostate Cancer via the Akt/JNK and P38 MAPK Signaling Pathway. Mar Drugs 2023; 21:345. [PMID: 37367670 DOI: 10.3390/md21060345] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/01/2023] [Accepted: 06/02/2023] [Indexed: 06/28/2023] Open
Abstract
Due to the challenge of prostate cancer (PCa) management, there has been a surge in efforts to identify more safe and effective compounds that can modulate the epithelial-mesenchymal transition (EMT) for driving metastasis. Holothurin A (HA), a triterpenoid saponin isolated from Holothuria scabra, has now been characterized for its diverse biological activities. However, the mechanisms of HA in EMT-driven metastasis of human PCa cell lines has not yet been investigated. Moreover, runt-related transcription factor 1 (RUNX1) acts as an oncogene in prostate cancer, but little is known about its role in the EMT. Thus, the purpose of this study was to determine how RUNX1 influences EMT-mediated metastasis, as well as the potential effect of HA on EMT-mediated metastasis in endogenous and exogenous RUNX1 expressions of PCa cell lines. The results demonstrated that RUNX1 overexpression could promote the EMT phenotype with increased EMT markers, consequently driving metastatic migration and invasion in PC3 cell line through the activation of Akt/MAPK signaling pathways. Intriguingly, HA treatment could antagonize the EMT program in endogenous and exogenous RUNX1-expressing PCa cell lines. A decreasing metastasis of both HA-treated cell lines was evidenced through a downregulation of MMP2 and MMP9 via the Akt/P38/JNK-MAPK signaling pathway. Overall, our approach first demonstrated that RUNX1 enhanced EMT-driven prostate cancer metastasis and that HA was capable of inhibiting the EMT and metastatic processes and should probably be considered as a candidate for metastasis PCa treatment.
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Affiliation(s)
- Sirorat Janta
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Kanta Pranweerapaiboon
- Department of Anatomy, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
- Chulabhorn International College of Medicine, Thammasat University, Pathumthani 12120, Thailand
| | - Pornpun Vivithanaporn
- Chakri Naruebodindra Medical Institute, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10540, Thailand
| | - Anuchit Plubrukarn
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Songkhla 09112, Thailand
| | - Arthit Chairoungdua
- Department of Physiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | | | - Somjai Apisawetakan
- Department of Anatomy, Faculty of Medicine, Srinakharinwirot University, Wattana, Bangkok 10110, Thailand
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Chen XM, Liu YH, Ji SF, Xue XM, Wang LL, Zhang M, Chang YM, Wang XC. Protective effect of ginsenoside Rd on military aviation noise-induced cochlear hair cell damage in guinea pigs. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:23965-23981. [PMID: 36331733 DOI: 10.1007/s11356-022-23504-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 10/04/2022] [Indexed: 06/16/2023]
Abstract
Noise pollution has become one of the important social hazards that endanger the auditory system of residents, causing noise-induced hearing loss (NIHL). Oxidative stress has a significant role in the pathogenesis of NIHL, in which the silent information regulator 1(SIRT1)/proliferator-activated receptor-gamma coactivator 1α (PGC-1α) signaling pathway is closely engaged. Ginsenoside Rd (GSRd), a main monomer extract from ginseng plants, has been confirmed to suppress oxidative stress. Therefore, the hypothesis that GSRd may attenuate noise-induced cochlear hair cell loss seemed promising. Forty-eight male guinea pigs were randomly divided into four groups: control, noise exposure, GSRd treatment (30 mg/kg Rd for 10d + noise), and experimental control (30 mg/kg glycerol + noise). The experimental groups received military helicopter noise exposure at 115 dB (A) for 4 h daily for five consecutive days. Hair cell damage was evaluated by using inner ear basilar membrane preparation and scanning electron microscopy. Terminal dUTP nick end labeling (TUNEL) and immunofluorescence staining were conducted. Changes in the SIRT1/PGC-1α signaling pathway and other apoptosis-related markers in the cochleae, as well as oxidative stress parameters, were used as readouts. Loss of outer hair cells, more disordered cilia, prominent apoptosis, and elevated free radical levels were observed in the experimental groups. GSRd treatment markedly mitigated hearing threshold shifts, ameliorated outer hair cell loss and lodging or loss of cilia, and improved apoptosis through decreasing Bcl-2 associated X protein (Bax) expression and increasing Bcl-2 expression. In addition, GSRd alleviated the noise-induced cochlear redox injury by upregulating superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) levels, decreasing malondialdehyde (MDA) levels, and enhancing the activity of SIRT1 and PGC-1α messenger ribonucleic acid (mRNA) and protein expression. In conclusion, GSRd can improve structural and oxidative damage to the cochleae caused by noise. The underlying mechanisms may be associated with the SIRT1/PGC-1α signaling pathway.
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Affiliation(s)
- Xue-Min Chen
- Department of Aerospace Hygiene, School of Aerospace Medicine, Air Force Medical University, Xi'an, China
- Medical School of Chinese PLA, Beijing, China
- Senior Department of Otolaryngology-Head & Neck Surgery, Chinese PLA General Hospital; National Clinical Research Center for Otolaryngologic Diseases; State Key Lab of Hearing Science, Ministry of Education; Beijing Key Lab of Hearing Impairment Prevention and Treatment, Beijing, China
| | - Yu-Hui Liu
- Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Key Laboratory of Aerospace Medicine of Ministry of Education, Air Force Medical University, Xi'an, China
- Department of Aviation Medicine, The First Affiliated Hospital of Air Force Military Medical University, Xi'an, China
- Air Force Health Care Center for Special Services, Hangzhou, China
| | - Shuai-Fei Ji
- Medical School of Chinese PLA, Beijing, China
- Research Center for Tissue Repair and Regeneration Affiliated to the Medical Innovation Research Department and 4th Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xin-Miao Xue
- Medical School of Chinese PLA, Beijing, China
- Senior Department of Otolaryngology-Head & Neck Surgery, Chinese PLA General Hospital; National Clinical Research Center for Otolaryngologic Diseases; State Key Lab of Hearing Science, Ministry of Education; Beijing Key Lab of Hearing Impairment Prevention and Treatment, Beijing, China
| | - Lin-Lin Wang
- Senior Department of Otolaryngology-Head & Neck Surgery, Chinese PLA General Hospital; National Clinical Research Center for Otolaryngologic Diseases; State Key Lab of Hearing Science, Ministry of Education; Beijing Key Lab of Hearing Impairment Prevention and Treatment, Beijing, China
| | - Min Zhang
- Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Key Laboratory of Aerospace Medicine of Ministry of Education, Air Force Medical University, Xi'an, China
- Department of Aviation Medicine, The First Affiliated Hospital of Air Force Military Medical University, Xi'an, China
| | - Yao-Ming Chang
- Department of Aerospace Hygiene, School of Aerospace Medicine, Air Force Medical University, Xi'an, China
| | - Xiao-Cheng Wang
- Center of Clinical Aerospace Medicine, School of Aerospace Medicine, Key Laboratory of Aerospace Medicine of Ministry of Education, Air Force Medical University, Xi'an, China.
- Department of Aviation Medicine, The First Affiliated Hospital of Air Force Military Medical University, Xi'an, China.
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Ginsenoside Rb1 from Panax notoginseng Suppressed TNF-α-Induced Matrix Metalloproteinase-9 via the Suppression of Double-Strand RNA-Dependent Protein Kinase (PKR)/NF-κB Pathway. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27228050. [PMID: 36432152 PMCID: PMC9692425 DOI: 10.3390/molecules27228050] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/12/2022] [Accepted: 11/16/2022] [Indexed: 11/22/2022]
Abstract
Chronic inflammation is commonly accompanied by the stimulation of matrix metalloproteinases (MMPs) production and the degradation of the extracellular matrix. The overexpression of MMP-9 (Gelatinase B) highly participates in the progression of pathetic cardiac remodeling and liver cancer metastasis. Panax notoginseng (Burkill) F. H. Chen (Sanqi), a widely used traditional Chinese medicinal herb, shows myocardial protective and anti-tumor effects. In this study, we examined the inhibitory effect of different PNG extracts on tumor necrosis factor (TNF)-α-induced MMP-9 expression in cardiac myoblast H9c2 cells. Using a bioassay-guided fractionation scheme, the most active extract was fractionated by silica gel column chromatography and high-performance liquid chromatography until an active compound was obtained. The compound was identified as Ginsenoside Rb1 by nuclear magnetic resonance. Ginsenoside Rb1 inhibited TNF-α-induced MMP-9 production in both H9c2 and liver carcinoma HepG-2 cells. Interestingly, it did not affect the MMP-2 (Gelatinase A) level and the cell proliferation of the two cell lines. The inhibitory effects of Ginsenoside Rb1 may be due to its modulation of double-strand RNA-dependent protein kinase and nuclear factor kappa B signaling pathways. The results reveal the potential use of Ginsenoside Rb1 for the treatment of inflammatory and MMP-9-related cardiac remodeling and metastasis of hepatocellular carcinomas.
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MMP1 Overexpression Promotes Cancer Progression and Associates with Poor Outcome in Head and Neck Carcinoma. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:3058342. [PMID: 36105241 PMCID: PMC9467809 DOI: 10.1155/2022/3058342] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/27/2022] [Accepted: 08/20/2022] [Indexed: 11/29/2022]
Abstract
Matrix metalloproteinase-1 (MMP1) has been reported to play key roles in a variety of cancers by degrading the extracellular matrix. However, its carcinogenic roles have not been shown yet in head and neck squamous cell carcinoma (HNSCC). This study aimed to elucidate its expression pattern and functional roles as well as clinical significance in HNSCC. The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and immunohistochemistry (IHC) were utilized to determine the MMP1 expression pattern and the associations between its expression and patients' outcome in HNSCC. Mice tongue squamous cell carcinoma model induced by 4-nitroquinoline 1-oxide (4NQO) and siRNA-mediated cellular assay in vitro were utilized to evaluate the oncogenic role of MMP1. The biological functions and cancer-related pathways involved in MMP1-related genes were found through bioinformatics analysis. Both mRNA and protein abundance of MMP1 were highly increased in HNSCC as compared to its non-tumor counterparts. MMP1 overexpression positively correlated with advanced tumor size, cervical node metastasis, and advanced pathological grade and lower patients' survival. In the 4NQO-induced animal model, MMP1 expression increased along with the progression of the disease. In HNSCC cells, siRNA-mediated knockdown of MMP1 significantly inhibited cell proliferation, migration, and invasion and activated apoptosis and epithelia-mesenchymal transition (EMT). GSEA, GO, and KEGG analyses showed that MMP1 expression was significantly related to cancer-related pathways and cancer-related functions. Together, our results demonstrated MMP1 serves as a novel prognostic biomarker and putative oncogene in HNSCC.
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Li J, Huang Q, Yao Y, Ji P, Mingyao E, Chen J, Zhang Z, Qi H, Liu J, Chen Z, Zhao D, Zhou L, Li X. Biotransformation, Pharmacokinetics, and Pharmacological Activities of Ginsenoside Rd Against Multiple Diseases. Front Pharmacol 2022; 13:909363. [PMID: 35928281 PMCID: PMC9343777 DOI: 10.3389/fphar.2022.909363] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 06/01/2022] [Indexed: 12/19/2022] Open
Abstract
Panax ginseng C.A. Mey. has a history of more than 4000 years and is widely used in Asian countries. Modern pharmacological studies have proved that ginsenosides and their compounds have a variety of significant biological activities on specific diseases, including neurodegenerative diseases, certain types of cancer, gastrointestinal disease, and metabolic diseases, in which most of the interest has focused on ginsenoside Rd. The evidentiary basis showed that ginsenoside Rd ameliorates ischemic stroke, nerve injury, cancer, and other diseases involved in apoptosis, inflammation, oxidative stress, mitochondrial damage, and autophagy. In this review, we summarized available reports on the molecular biological mechanisms of ginsenoside Rd in neurological diseases, cancer, metabolic diseases, and other diseases. We also discussed the main biotransformation pathways of ginsenoside Rd obtained by fermentation.
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Affiliation(s)
- Jing Li
- Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Qingxia Huang
- Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
- Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Yao Yao
- Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Peng Ji
- Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - E. Mingyao
- Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Jinjin Chen
- Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Zepeng Zhang
- Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
- College of Acupuncture and Tuina, Changchun University of Chinese Medicine, Changchun, China
| | - Hongyu Qi
- Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Jiaqi Liu
- Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Zhaoqiang Chen
- Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Daqing Zhao
- Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Lei Zhou
- Department of Pathology, Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, China
- *Correspondence: Lei Zhou, ; Xiangyan Li,
| | - Xiangyan Li
- Jilin Ginseng Academy, Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
- *Correspondence: Lei Zhou, ; Xiangyan Li,
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11
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Insights into Recent Studies on Biotransformation and Pharmacological Activities of Ginsenoside Rd. Biomolecules 2022; 12:biom12040512. [PMID: 35454101 PMCID: PMC9031344 DOI: 10.3390/biom12040512] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/15/2022] [Accepted: 03/24/2022] [Indexed: 12/11/2022] Open
Abstract
It is well known that ginsenosides—major bioactive constituents of Panax ginseng—are attracting more attention due to their beneficial pharmacological activities. Ginsenoside Rd, belonging to protopanaxadiol (PPD)-type ginsenosides, exhibits diverse and powerful pharmacological activities. In recent decades, nearly 300 studies on the pharmacological activities of Rd—as a potential treatment for a variety of diseases—have been published. However, no specific, comprehensive reviews have been documented to date. The present review not only summarizes the in vitro and in vivo studies on the health benefits of Rd, including anti-cancer, anti-diabetic, anti-inflammatory, neuroprotective, cardioprotective, ischemic stroke, immunoregulation, and other pharmacological effects, it also delves into the inclusion of potential molecular mechanisms, providing an overview of future prospects for the use of Rd in the treatment of chronic metabolic diseases and neurodegenerative disorders. Although biotransformation, pharmacokinetics, and clinical studies of Rd have also been reviewed, clinical trial data of Rd are limited; the only data available are for its treatment of acute ischemic stroke. Therefore, clinical evidence of Rd should be considered in future studies.
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12
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Ji D, Fleig A, Horgen FD, Feng ZP, Sun HS. Modulators of TRPM7 and its potential as a drug target for brain tumours. Cell Calcium 2021; 101:102521. [PMID: 34953296 DOI: 10.1016/j.ceca.2021.102521] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 12/14/2021] [Accepted: 12/15/2021] [Indexed: 12/14/2022]
Abstract
TRPM7 is a non-selective divalent cation channel with an alpha-kinase domain. Corresponding with its broad expression, TRPM7 has a role in a wide range of cell functions, including proliferation, migration, and survival. Growing evidence shows that TRPM7 is also aberrantly expressed in various cancers, including brain cancers. Because ion channels have widespread tissue distribution and result in extensive physiological consequences when dysfunctional, these proteins can be compelling drug targets. In fact, ion channels comprise the third-largest drug target type, following enzymes and receptors. Literature has shown that suppression of TRPM7 results in inhibition of migration, invasion, and proliferation in several human brain tumours. Therefore, TRPM7 presents a potential target for therapeutic brain tumour interventions. This article reviews current literature on TRPM7 as a potential drug target in the context of brain tumours and provides an overview of various selective and non-selective modulators of the channel relevant to pharmacology, oncology, and ion channel function.
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Affiliation(s)
- Delphine Ji
- Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8
| | - Andrea Fleig
- Center for Biomedical Research at The Queen's Medical Center and John A. Burns School of Medicine and Cancer Center at the University of Hawaii, Honolulu, Hawaii 96813, USA
| | - F David Horgen
- Department of Natural Sciences, Hawaii Pacific University, Kaneohe, Hawaii 96744, USA
| | - Zhong-Ping Feng
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
| | - Hong-Shuo Sun
- Department of Surgery, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8; Department of Pharmacology, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8; Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada M5S 3M2.
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13
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Arafa ESA, Refaey MS, Abd El-Ghafar OAM, Hassanein EHM, Sayed AM. The promising therapeutic potentials of ginsenosides mediated through p38 MAPK signaling inhibition. Heliyon 2021; 7:e08354. [PMID: 34825082 PMCID: PMC8605069 DOI: 10.1016/j.heliyon.2021.e08354] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/06/2021] [Accepted: 11/05/2021] [Indexed: 12/21/2022] Open
Abstract
The p38 mitogen-activated protein kinases (p38 MAPK) is a 38kD polypeptide recognized as the target for many potential anti-inflammatory agents. Accumulating evidence indicates that p38 MAPK could perform many roles in human disease pathophysiology. Therefore, great therapeutic benefits can be attained from p38 MAPK inhibitors. Ginseng is an exceptionally valued medicinal plant of the family Araliaceae (Panax genus). Recently, several studies targeted the therapeutic effects of purified individual ginsenoside, the most significant active ingredient of ginseng, and studied its particular molecular mechanism(s) of action rather than whole-plant extracts. Interestingly, several ginsenosides: ginsenosides compound K, F1, Rb1, Rb3, Rc, Rd, Re, Rf, Rg1, Rg2, Rg3, Rg5, Rh1, Rh2, Ro, notoginsenoside R1, and protopanaxadiol have shown to possess great therapeutic potentials mediated by their ability to downregulate p38 MAPK signaling in different cell lines and experimental animal models. Our review compiles the research findings of various ginsenosides as potent anti-inflammatory agents, highlighting the crucial role of p38 MAPK suppression in their pharmacological actions. In addition, in silico studies were conducted to explore the probable binding of these ginsenosides to p38 MAPK. The results obtained proposed p38 MAPK involvement in the beneficial pharmacological activities of ginsenosides in different ailments.
p38 MAPK plays many roles in human disease pathophysiology. Therefore, great therapeutic benefits can be attained from p38 MAPK inhibitors. Several ginsenosides showed to possess great therapeutic potentials mediated by its ability to downregulate p38 MAPK signaling. in silico studies were conducted to explore the binding of these ginsenosides to p38 MAPK and evidenced the promising their inhibitory effect.
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Affiliation(s)
- El-Shaimaa A Arafa
- Department of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab Emirates.,Center of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Mohamed S Refaey
- Department of Pharmacognosy, Faculty of Pharmacy, University of Sadat City, Sadat City, Menoufiya, 32958, Egypt
| | - Omnia A M Abd El-Ghafar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt
| | - Emad H M Hassanein
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
| | - Ahmed M Sayed
- Biochemistry Laboratory, Chemistry Department, Faculty of Science, Assiut University, Assiut, Egypt
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14
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Elekofehinti OO, Iwaloye O, Olawale F, Ariyo EO. Saponins in Cancer Treatment: Current Progress and Future Prospects. PATHOPHYSIOLOGY 2021; 28:250-272. [PMID: 35366261 PMCID: PMC8830467 DOI: 10.3390/pathophysiology28020017] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/03/2021] [Accepted: 06/03/2021] [Indexed: 12/14/2022] Open
Abstract
Saponins are steroidal or triterpenoid glycoside that is distinguished by the soap-forming nature. Different saponins have been characterized and purified and are gaining attention in cancer chemotherapy. Saponins possess high structural diversity, which is linked to the anticancer activities. Several studies have reported the role of saponins in cancer and the mechanism of actions, including cell-cycle arrest, antioxidant activity, cellular invasion inhibition, induction of apoptosis and autophagy. Despite the extensive research and significant anticancer effects of saponins, there are currently no known FDA-approved saponin-based anticancer drugs. This can be attributed to a number of limitations, including toxicities and drug-likeness properties. Recent studies have explored options such as combination therapy and drug delivery systems to ensure increased efficacy and decreased toxicity in saponin. This review discusses the current knowledge on different saponins, their anticancer activity and mechanisms of action, as well as promising research within the last two decades and recommendations for future studies.
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Affiliation(s)
- Olusola Olalekan Elekofehinti
- Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, PMB 704, Nigeria; (O.I.); (E.O.A.)
| | - Opeyemi Iwaloye
- Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, PMB 704, Nigeria; (O.I.); (E.O.A.)
| | - Femi Olawale
- Nanogene and Drug Delivery Group, Department of Biochemistry, University of Kwa-Zulu Natal, Durban 4000, South Africa;
- Department of Biochemistry, College of Medicine, University of Lagos, Lagos 101017, Nigeria
| | - Esther Opeyemi Ariyo
- Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology Akure, PMB 704, Nigeria; (O.I.); (E.O.A.)
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15
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Anti-Metastatic and Anti-Inflammatory Effects of Matrix Metalloproteinase Inhibition by Ginsenosides. Biomedicines 2021; 9:biomedicines9020198. [PMID: 33671187 PMCID: PMC7921986 DOI: 10.3390/biomedicines9020198] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/12/2021] [Accepted: 02/14/2021] [Indexed: 12/12/2022] Open
Abstract
Matrix metalloproteinases (MMPs) are proteolytic enzymes which cleave extracellular matrix (ECM) and other substrates. They are deeply involved in both cancer metastasis and human chronic inflammatory diseases such as osteoarthritis and Crohn’s disease. Regulation of MMPs is closely associated with signaling molecules, especially mitogen-activated protein kinases (MAPKs), including three representative kinases, extracellular signal regulated kinases (ERK), p38 and c-Jun N-terminal kinases (JNK). Ginseng (Panax sp.) is a plant which has been traditionally used for medicinal applications. Ginsenosides are major metabolites which have potentials to treat various human diseases. In this review, the pharmacological effects of ginsenosides have been rigorously investigated; these include anti-metastatic and anti-inflammatory activities of ginsenosides associated with suppression of MMPs via regulation of various signaling pathways. This will highlight the importance of MMPs as therapeutic targets for anti-metastatic and anti-inflammatory drug development based on ginsenosides.
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16
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Lim CJ, Lee Y, Lim HW, Yoon JY, Lee S, Ryu I, Park M, Chi Y. Skin-healing properties of ginsenoside Rd against Ultraviolet-B-induced photooxidative stress through up-regulation of antioxidant components in HaCaT keratinocytes. Pharmacogn Mag 2021. [DOI: 10.4103/pm.pm_319_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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17
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Zhong C, Jiang C, Ni S, Wang Q, Cheng L, Wang H, Zhang Q, Liu W, Zhang J, Liu J, Wang M, Jin M, Shen P, Yao X, Wang G, Zhou F. Identification of bioactive anti-angiogenic components targeting tumor endothelial cells in Shenmai injection using multidimensional pharmacokinetics. Acta Pharm Sin B 2020; 10:1694-1708. [PMID: 33088689 PMCID: PMC7564034 DOI: 10.1016/j.apsb.2019.12.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/11/2019] [Accepted: 12/05/2019] [Indexed: 12/24/2022] Open
Abstract
Shenmai injection (SMI) is a well-defined herbal preparation that is widely and clinically used as an adjuvant therapy for cancer. Previously, we found that SMI synergistically enhanced the activity of chemotherapy on colorectal cancer by promoting the distribution of drugs in xenograft tumors. However, the underlying mechanisms and bioactive constituents remained unknown. In the present work, the regulatory effects of SMI on tumor vasculature were determined, and the potential anti-angiogenic components targeting tumor endothelial cells (TECs) were identified. Multidimensional pharmacokinetic profiles of ginsenosides in plasma, subcutaneous tumors, and TECs were investigated. The results showed that the concentrations of protopanaxadiol-type (PPD) ginsenosides (Rb1, Rb2/Rb3, Rc, and Rd) in both plasma and tumors, were higher than those of protopanaxatriol-type (Rg1 and Re) and oleanane-type (Ro) ginsenosides. Among PPD-type ginsenosides, Rd exhibited the greatest concentrations in tumors and TECs after repeated injection. In vivo bioactivity results showed that Rd suppressed neovascularization in tumors, normalized the structure of tumor vessels, and improved the anti-tumor effect of 5-fluorouracil (5FU) in xenograft mice. Furthermore, Rd inhibited the migration and tube formation capacity of endothelial cells in vitro. In conclusion, Rd may be an important active form to exert the anti-angiogenic effect on tumor after SMI treatment.
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18
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Lyu X, Xu X, Song A, Guo J, Zhang Y, Zhang Y. Ginsenoside Rh1 inhibits colorectal cancer cell migration and invasion in vitro and tumor growth in vivo. Oncol Lett 2019; 18:4160-4166. [PMID: 31579419 PMCID: PMC6757309 DOI: 10.3892/ol.2019.10742] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Accepted: 06/05/2019] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-associated mortality worldwide. Ginsenoside Rh1 (Rh1) is a traditional medicine monomer with antitumor activity; however, the effects of Rh1 in CRC remain to be determined. In the present study, SW620 cells were treated with different concentrations of Rh1. Cell Counting Kit-8, wound healing and Transwell assays were performed to measure cell viability and proliferation, migration and invasion, respectively. Subsequently, the mRNA expression levels of matrix metallopeptidase (MMP)1, MMP3 and tissue inhibitor of metalloproteinases 3 (TIMP3) were detected by reverse transcription-quantitative PCR analysis. In addition, the protein expression levels of MMP1, MMP3, TIMP3, and total or phosphorylated (p-)ERK1/2, P38, JNK were detected by western blotting. Furthermore, tumor growth was examined in a nude mouse xenograft model. The results of the present study indicated that Rh1 was not toxic to CRC cells at various concentrations (0, 50 or 100 µM) and treatment durations (24 or 48 h). However, cell proliferation was suppressed by Rh1 in a dose-dependent manner. Rh1 (100 µM) significantly inhibited cell migration and invasion in vitro. Additionally, Rh1 suppressed the mRNA and protein expression of MMP1 and MMP3, and promoted TIMP3 expression. Rh1 decreased the ratios of p-P38/P38, p-ERK1/2/ERK1-2 and p-JNK/JNK in vitro and in vivo, which suggested that Rh1 inactivated the mitogen-activated protein kinase (MAPK) signaling pathway. Notably, Rh1 markedly decreased tumor volume and weight in vivo. In conclusion, the present study demonstrated that Rh1 inhibited the proliferation, migration and invasion of CRC cells in vitro and tumor growth in vivo. This inhibition was at least partially due to the inhibition of MMP1 and MMP3 expression, the increase in TIMP3 expression level and the MAPK signaling pathway inactivation. Therefore, Rh1 may effectively inhibit the development of CRC as an anticancer drug, and may have a supporting effect during CRC treatment.
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Affiliation(s)
- Xi Lyu
- The Sixth Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Xiaodong Xu
- The Second Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Ailin Song
- The Sixth Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Jinyi Guo
- The Sixth Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Yawu Zhang
- The Second Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
| | - Youcheng Zhang
- The Second Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, P.R. China
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Zhang Q, Wang X, Lv L, Su G, Zhao Y. Antineoplastic Activity, Structural Modification, Synthesis and Structure-activity Relationship of Dammarane-type Ginsenosides: An Overview. CURR ORG CHEM 2019. [DOI: 10.2174/1385272823666190401141138] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Dammarane-type ginsenosides are a class of tetracyclic triterpenoids with the same dammarane skeleton. These compounds have a wide range of pharmaceutical applications for neoplasms, diabetes mellitus and other metabolic syndromes, hyperlipidemia, cardiovascular and cerebrovascular diseases, aging, neurodegenerative disease, bone disease, liver disease, kidney disease, gastrointestinal disease and other conditions. In order to develop new antineoplastic drugs, it is necessary to improve the bioactivity, solubility and bioavailability, and illuminate the mechanism of action of these compounds. A large number of ginsenosides and their derivatives have been separated from certain herbs or synthesized, and tested in various experiments, such as anti-proliferation, induction of apoptosis, cell cycle arrest and cancer-involved signaling pathways. In this review, we have summarized the progress in structural modification, shed light on the structure-activity relationship (SAR), and offered insights into biosynthesis-structural association. This review is expected to provide a preliminary guide for the modification and synthesis of ginsenosides.
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Affiliation(s)
- Qiang Zhang
- Shenyang Pharmaceutical University, Shenyang 110016, PR, China
| | - Xude Wang
- Shenyang Pharmaceutical University, Shenyang 110016, PR, China
| | - Liyan Lv
- Shenyang Pharmaceutical University, Shenyang 110016, PR, China
| | - Guangyue Su
- Shenyang Pharmaceutical University, Shenyang 110016, PR, China
| | - Yuqing Zhao
- Shenyang Pharmaceutical University, Shenyang 110016, PR, China
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20
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Park CR, Pyo MK, Lee H, Hong SY, Kim SH, Park CB, Oh SM. Acute and genetic toxicity of GS-E3D, a new pectin lyase-modified red ginseng extract. Regul Toxicol Pharmacol 2019; 104:157-162. [PMID: 30904430 DOI: 10.1016/j.yrtph.2019.03.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 03/15/2019] [Accepted: 03/16/2019] [Indexed: 11/28/2022]
Abstract
Korean red ginseng and its extract have been used as traditional medicines and functional foods in countries worldwide. Pectin lyase-modified red ginseng extract (GS-E3D) was newly developed as a dietary supplement for obesity, diabetes-related renal dysfunction, etc. In this study, the safety of GS-E3D on acute toxicity and genotoxicity was evaluated. For acute study, Sprague-Dawley rats were administrated by oral gavage at a dose of 5000 mg/kg GS-E3D. To evaluate genotoxicity of GS-E3D, we conducted three-battery tests, which are Ames test using Escherichia coli (WP2uvrA pKM101) and Salmonella typhimurium strains (TA98, TA100, TA1535 and TA1537), chromosomal aberration test -using Chinese hamster lung cells, and micronucleus test using ICR mice. In acute toxicity studies, there were no dead animals or abnormal necropsy findings in the control group and GS-E3D (5000 mg/kg) treated group. GS-E3D did not induce mutagenicity in the bacterial test, chromosomal aberrations in Chinese hamster lung cells and micronuclei in bone marrow cells of mice. Conclusively, the approximate lethal dose of GS-E3D was greater than 5000 mg/kg bw and GS-E3D has no genotoxic potential in the three-battery tests on genotoxicity.
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Affiliation(s)
| | - Mi Kyung Pyo
- International Ginseng and Herb Research Institute, Geumsan, 312-804, South Korea
| | - Hwan Lee
- International Ginseng and Herb Research Institute, Geumsan, 312-804, South Korea
| | | | - Su Hwan Kim
- Biotoxtech. Co. Ltd, Cheongju, 13000, South Korea
| | | | - Seung Min Oh
- Department of Nanofusion Technology, Hoseo University, Asan, 31499, South Korea.
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21
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Phi LTH, Sari IN, Wijaya YT, Kim KS, Park K, Cho AE, Kwon HY. Ginsenoside Rd Inhibits the Metastasis of Colorectal Cancer via Epidermal Growth Factor Receptor Signaling Axis. IUBMB Life 2018; 71:601-610. [PMID: 30576064 DOI: 10.1002/iub.1984] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 10/26/2018] [Accepted: 11/15/2018] [Indexed: 02/06/2023]
Abstract
Ginsenoside Rd is a saponin from ginseng and has been reported to have various biological activities. However, the effect of ginsenoside Rd on the metastasis of colorectal cancer (CRC) remains unknown. Here, we found that ginsenoside Rd decreased the colony-forming ability, migration, invasion, and wound-healing abilities of CRC cells, although it did not affect cell proliferation. In addition, using an inverse-docking assay, we found that ginsenoside Rd bound to epidermal growth factor receptor (EGFR) with a high binding affinity, inducing the downregulation of stemness- and epithelial-mesenchymal transition-related genes; these were partially rescued by either exogenous EGF treatment or ectopic expression of SOX2. Furthermore, ginsenoside Rd significantly decreased the number and size of tumor metastasis nodules in the livers, lungs, and kidneys of mouse model of metastasis. © 2018 IUBMB Life, 71(5):601-610, 2019.
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Affiliation(s)
- Lan Thi Hanh Phi
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Ita Novita Sari
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Yoseph Toni Wijaya
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Kwang Seock Kim
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, 31151, Republic of Korea
| | - Kichul Park
- Department of Bioinformatics, Korea University, 2511 Sejong-ro, Sejong, 30019, Republic of Korea
| | - Art E Cho
- Department of Bioinformatics, Korea University, 2511 Sejong-ro, Sejong, 30019, Republic of Korea
| | - Hyog Young Kwon
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, 31151, Republic of Korea
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22
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Gu B, Wang J, Song Y, Wang Q, Wu Q. The inhibitory effects of ginsenoside Rd on the human glioma U251 cells and its underlying mechanisms. J Cell Biochem 2018; 120:4444-4450. [PMID: 30260020 DOI: 10.1002/jcb.27732] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 08/30/2018] [Indexed: 01/26/2023]
Abstract
OBJECTIVE The current study was designed to investigate the inhibitory effects of ginsenoside Rd (Gs-Rd) on human glioma U251 cells in vitro and its possible underlying mechanisms. METHODS The groups included blank control group, low concentration Gs-Rd treatment group (20 μM), mid concentration Gs-Rd treatment group (40 μM), and high concentration Gs-Rd treatment group (80 μM). The proliferative activity of human glioma U251 cells was detected by the MTT assay. Flow cytometry was performed to measure cell apoptosis of human glioma U251 cells. In addition, the ELISA assay was used to measure the telomerase activities in different groups on 24 hours, 48 hours, and 72 hours. Furthermore, real-time quantitative polymerase chain reaction (RT-PCR) and Western blot analysis were performed to measure the expression of Bcl-2, human telomerase catalytic subunit (hTERT), and caspase-3 in different groups on 48 hours at both messenger RNA (mRNA) and protein levels. RESULTS The proliferation of U251 cells was inhibited by Gs-Rd with different concentrations in the dose- and time-dependent manners. In addition, Gs-Rd promoted U251 cell apoptosis rate in a dose-dependent manner. Gs-Rd with different concentrations (20 μM, 40 μM, and 80 μM) significantly enhanced the expression of teleomerase on 24 hours and 48 hours. In addition, Gs-Rd with different concentrations significantly increased caspase-3 and decreased Bcl-2 and hTERT expressions at both mRNA and protein levels. CONCLUSION The Gs-Rd can remarkably inhibit the proliferation and promote cell apoptosis of human glioma U251 cells. The possible underlying mechanisms could be related to inhibiting telomerase activity, downregulating expression of Bcl-2 and hTERT, and upregulating expression of caspase-3 of human glioma U251 cells.
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Affiliation(s)
- Biao Gu
- Department of Thoracic Surgery, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Jipeng Wang
- Department of Respiratory Medicine, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Yaqi Song
- Department of Radiation Oncology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Qi Wang
- Department of Thoracic Surgery, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
| | - Qingquan Wu
- Department of Thoracic Surgery, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China
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Wu W, Zhou Q, Zhao W, Gong Y, Su A, Liu F, Liu Y, Li Z, Zhu J. Ginsenoside Rg3 Inhibition of Thyroid Cancer Metastasis Is Associated with Alternation of Actin Skeleton. J Med Food 2018; 21:849-857. [PMID: 30136914 DOI: 10.1089/jmf.2017.4144] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Ginsenoside Rg3, a bioactive constituent from Panax ginseng, is a worldwide well-known traditional Chinese medicine used as a tonic. It also has good antitumor activity by inhibiting tumors metastasis. Tumor metastasis is a high risk in thyroid cancer. However, the effect and molecular mechanism underlying the antimetastatic activity of Rg3 in thyroid cancer have not been reported. In our study, we found that Rg3 inhibited the growth of thyroid cancer in vitro and in vivo and significantly inhibited metastasis of thyroid cancer. Rg3 apparently inhibited the migration and invasion in four papillary thyroid cancer (PTC) cells (TPC-1, BCPAP, C643, and Ocut-2c cells) and pulmonary metastasis in lung metastasis model of C643 cells in nude mice. We further found that a possible mechanism of Rg3 inhibiting thyroid cancer cells metastasis was associated with inhibiting cells actin skeleton function. Rg3 inhibited lamellipodia formation and induced microspike formation by inhibiting Rho GTPase in thyroid cancer cells. Rg3 decreased the levels of Rac-1 and Cdc42 proteins. In addition, Rg3 decreased the expression levels of matrix metalloproteinase-2 (MMP-2) and MMP-9 proteins in four thyroid cancer cells. The results that Rg3 remarkably inhibited the expression of vascular endothelial growth factor-C (VEGF-C) protein in PTC cells and VEGF-A protein in anaplastic thyroid cancer (ATC) cells and decreased the staining of CD31 in PTC and ATC tumors hinted that Rg3 might inhibit the lymph node metastasis in PTC and angiogenesis in ATC. These studies suggested that Rg3 might be a useful agent for the treatment of metastatic thyroid cancers.
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Affiliation(s)
- Wenshuang Wu
- Department of Thyroid Surgery, West China Hospital, Sichuan University , Chengdu, China
| | - Qian Zhou
- Department of Thyroid Surgery, West China Hospital, Sichuan University , Chengdu, China
| | - Wanjun Zhao
- Department of Thyroid Surgery, West China Hospital, Sichuan University , Chengdu, China
| | - Yanping Gong
- Department of Thyroid Surgery, West China Hospital, Sichuan University , Chengdu, China
| | - Anping Su
- Department of Thyroid Surgery, West China Hospital, Sichuan University , Chengdu, China
| | - Feng Liu
- Department of Thyroid Surgery, West China Hospital, Sichuan University , Chengdu, China
| | - Yang Liu
- Department of Thyroid Surgery, West China Hospital, Sichuan University , Chengdu, China
| | - Zhihui Li
- Department of Thyroid Surgery, West China Hospital, Sichuan University , Chengdu, China
| | - Jingqiang Zhu
- Department of Thyroid Surgery, West China Hospital, Sichuan University , Chengdu, China
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Sun Y, Lan M, Chen X, Dai Y, Zhao X, Wang L, Zhao T, Li Y, Zhu J, Zhang X, Jiang H, Wu X, Chen C, Zhang T, Yan Z. Anti-invasion and anti-metastasis effects of Valjatrate E via reduction of matrix metalloproteinases expression and suppression of MAPK/ERK signaling pathway. Biomed Pharmacother 2018; 104:817-824. [PMID: 29703569 DOI: 10.1016/j.biopha.2018.04.136] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 04/16/2018] [Accepted: 04/17/2018] [Indexed: 12/11/2022] Open
Abstract
Valjatrate E is an iridoid compound extracted from Valeriana jatamansi Jones herb and is the active ingredient in antitumor activity. Here, we reported its action on tumor invasion and metastasis in the human hepatocellular carcinoma HepG2, aiming at a better understanding of the potential mechanism of action of Valjatrate E. HepG2 cells were treated with Valjatrate E at different concentrations. Wound healing assay and transwell chamber assay were used to determine the effects of Valjatrate E on the migration and invasiveness of HepG2 cells, respectively. Moreover, homogeneity and heterotypic adhesion experiments evaluated the adhesion property of HepG2 cells. The molecular mechanisms by which Valjatrate E inhibited the invasion and migration of HepG2 cells were investigated by gelatin zymography experiment and western blot. Treatment with Valjatrate E inhibited the migration and invasion of HepG2 cells. It achieved this by reducing the expression of matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9), by inhibition of heterogeneous adhesion ability, by blocking mitogen-activated protein kinase (MAPK) signaling via inhibiting the phosphorylation of extracellular signal-regulated kinases (p-ERK). Taken together, these findings provide new evidence that mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) signaling pathway plays an important role in promoting invasion and metastasis in HepG2 cells through p-ERK, and MAPK/ERK signaling pathway may be a therapeutic target for tumor.
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Affiliation(s)
- Yong Sun
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China.
| | - Ming Lan
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China.
| | - Xiu Chen
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China.
| | - Yaolan Dai
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China.
| | - XiaoQin Zhao
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China.
| | - LiWen Wang
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China.
| | - TingTing Zhao
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China.
| | - YongBiao Li
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China.
| | - Jiali Zhu
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China.
| | - Xuemei Zhang
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China.
| | - HeZhong Jiang
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China.
| | - XiaoQing Wu
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China.
| | - Chang Chen
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, PR China.
| | - Tiane Zhang
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China.
| | - Zhiyong Yan
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China.
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Zhao H, Han Z, Li G, Zhang S, Luo Y. Therapeutic Potential and Cellular Mechanisms of Panax Notoginseng on Prevention of Aging and Cell Senescence-Associated Diseases. Aging Dis 2017; 8:721-739. [PMID: 29344413 PMCID: PMC5758348 DOI: 10.14336/ad.2017.0724] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 07/24/2017] [Indexed: 12/21/2022] Open
Abstract
Owing to a dramatic increase in average life expectancy, most countries in the world are rapidly entering an aging society. Therefore, extending health span with pharmacological agents targeting aging-related pathological changes, are now in the spotlight of gerosciences. Panax notoginseng (Burk.) F. H. Chen, a species of the genus Panax, has been called the "Miracle Root for the Preservation of Life," and has long been used as a Chinese herb with magical medicinal value. Panax notoginseng has been extensively employed in China to treat microcirculatory disturbances, inflammation, trauma, internal and external bleeding due to injury, and as a tonic. In recent years, with the deepening of the research pharmacologically, many new functions have been discovered. This review will introduce its pharmacological function on lifespan extension, anti-vascular aging, anti-brain aging, and anti-cancer properties, aiming to lay the ground for fully elucidating the potential mechanisms of Panax notoginseng's anti-aging effect to promote its clinical application.
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Affiliation(s)
- Haiping Zhao
- Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Ziping Han
- Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Guangwen Li
- Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Sijia Zhang
- Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Yumin Luo
- Cerebrovascular Diseases Research Institute, Xuanwu Hospital of Capital Medical University, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China
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Kee JY, Han YH, Mun JG, Park SH, Jeon HD, Hong SH. Effect of Korean Red Ginseng extract on colorectal lung metastasis through inhibiting the epithelial-mesenchymal transition via transforming growth factor-β1/Smad-signaling-mediated Snail/E-cadherin expression. J Ginseng Res 2017; 43:68-76. [PMID: 30662295 PMCID: PMC6323168 DOI: 10.1016/j.jgr.2017.08.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 07/28/2017] [Accepted: 08/09/2017] [Indexed: 12/31/2022] Open
Abstract
Background In colorectal cancer (CRC), 40-60% of patients develop metastasis. The epithelial-mesenchymal transition (EMT) is a pivotal and intricate process that increases the metastatic potential of CRC. The aim of this study was to investigate the effect of Korean Red Ginseng extract (RGE) on colorectal metastasis through inhibition of EMT and the metastatic abilities of CRC cells. Methods To investigate the effect of RGE on the metastatic phenotypes of CRC cells, CT26 and HT29 cells were evaluated by using an adhesion assay, a wound-healing assay, an invasion assay, zymography, and real-time reverse transcription-polymerase chain reaction. Western-blot analysis was conducted to elucidate the molecular mechanisms of RGE, which showed an inhibitory effect on the transforming growth factor-β1 (TGF-β1)-induced EMT in HT29 cells. Additionally, the antimetastatic effect of RGE was evaluated in a mouse model of lung metastasis injected with CT26 cells. Results RGE decreased the adhesion and migration ability of the CT26 cells and TGF-β1-treated HT29 cells. The invasion ability was also reduced by RGE treatment through the inhibition of matrix metalloproteinase-9 expression and activity. Moreover, RGE suppressed the TGF-β1-induced EMT via TGF-β1/Smad-signaling-mediated Snail/E-cadherin expression in HT29 cells and lung tissue in CT26 tumor-bearing mice. Conclusion Our results demonstrated that RGE inhibited colorectal lung metastasis through a reduction in metastatic phenotypes, such as migration, invasion, and the EMT of CRC cells.
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Affiliation(s)
- Ji-Ye Kee
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Republic of Korea
| | - Yo-Han Han
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Republic of Korea
| | - Jeong-Geon Mun
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Republic of Korea
| | - Seong-Hwan Park
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Republic of Korea
| | - Hee Dong Jeon
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Republic of Korea
| | - Seung-Heon Hong
- Department of Oriental Pharmacy, College of Pharmacy, Wonkwang-Oriental Medicines Research Institute, Wonkwang University, Iksan, Republic of Korea
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Ahuja A, Kim JH, Kim JH, Yi YS, Cho JY. Functional role of ginseng-derived compounds in cancer. J Ginseng Res 2017; 42:248-254. [PMID: 29983605 PMCID: PMC6026353 DOI: 10.1016/j.jgr.2017.04.009] [Citation(s) in RCA: 122] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Accepted: 04/18/2017] [Indexed: 12/19/2022] Open
Abstract
Ginseng is a natural product best known for its curative properties in diverse physiological processes such as cancer, neurodegenerative disorders, hypertension, and maintenance of hemostasis in the immune system. In previous decades, there have been some promising studies into the pharmacology and chemistry of ginseng components and the relationship between their structure and function. The emerging use of modified ginseng and development of new compounds from ginseng for clinical studies have been topics of study for many researchers. The present review deals with the anticancer, anti-inflammatory, antioxidant, and chemopreventive effects, and recent advances in microRNA technology related to red ginseng. The review also summarizes the current knowledge on the effect of ginsenosides in the treatment of cancer.
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Affiliation(s)
- Akash Ahuja
- Department of Genetic Engineering, Sungkyunkwan University, Suwon, Republic of Korea
| | - Ji Hye Kim
- Department of Genetic Engineering, Sungkyunkwan University, Suwon, Republic of Korea
| | - Jong-Hoon Kim
- Department of Physiology, College of Veterinary Medicine, Chonbuk National University, Iksan, Republic of Korea
| | - Young-Su Yi
- Department of Pharmaceutical Engineering, Cheongju University, Cheongju, Republic of Korea
| | - Jae Youl Cho
- Department of Genetic Engineering, Sungkyunkwan University, Suwon, Republic of Korea
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Wang M, Gao F, Zheng H, Zhang T, Guo M. Microencapsulation of ginsenosides using polymerised whey protein (PWP) as wall material and its application in probiotic fermented milk. Int J Food Sci Technol 2017. [DOI: 10.1111/ijfs.13365] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Mu Wang
- Department of Food Science and Engineering; Jilin University; Changchun Jilin 130062 China
| | - Feng Gao
- Department of Food Science and Engineering; Jilin University; Changchun Jilin 130062 China
| | - Huajie Zheng
- Department of Food Science and Engineering; Jilin University; Changchun Jilin 130062 China
| | - Tiehua Zhang
- Department of Food Science and Engineering; Jilin University; Changchun Jilin 130062 China
| | - Mingruo Guo
- Department of Food Science and Engineering; Jilin University; Changchun Jilin 130062 China
- Department of Nutrition and Food Sciences; The University of Vermont; Burlington Vermont 05405 USA
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Castro-Aceituno V, Ahn S, Simu SY, Singh P, Mathiyalagan R, Lee HA, Yang DC. Anticancer activity of silver nanoparticles from Panax ginseng fresh leaves in human cancer cells. Biomed Pharmacother 2016; 84:158-165. [DOI: 10.1016/j.biopha.2016.09.016] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 08/29/2016] [Accepted: 09/06/2016] [Indexed: 12/11/2022] Open
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Wang P, Du X, Xiong M, Cui J, Yang Q, Wang W, Chen Y, Zhang T. Ginsenoside Rd attenuates breast cancer metastasis implicating derepressing microRNA-18a-regulated Smad2 expression. Sci Rep 2016; 6:33709. [PMID: 27641158 PMCID: PMC5027393 DOI: 10.1038/srep33709] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 09/01/2016] [Indexed: 12/25/2022] Open
Abstract
Metastasis remains a major cause of mortality and poor prognosis in breast cancer patients. Anti-metastatic therapies are in great need to achieve optimal clinical outcome in breast cancer patients. Panax Notoginseng Saponins (PNS) has previously been shown to inhibit breast cancer metastasis in mouse. Here the potential anti-metastatic effect of one of the chemical compounds of PNS, ginsenoside Rd (Rd), was further evaluated in mouse mammary carcinoma 4T1 cells. The results revealed that Rd treatment dose-dependently suppressed cell migration and invasion in cultured 4T1 cells. In 4T1 cell-inoculated mice, Rd treatment led to decreased number of tumor lesions in lungs in both spontaneous and experimental metastasis models. Rd treatment resulted in increased expression of Smad2 in cultured 4T1 cells and in tumors grown from inoculated 4T1 cells. Rd treatment decreased the expression of microRNA (miR)-18a in cultured 4T1 cells and in tumors derived from inoculated 4T1 cells. Smad2 was further verified to be a direct target of miR-18a in 4T1 cells. The significant impact of Rd on counteracting miR-18a-medidated downregulation of Smad2 expression was also demonstrated. Together, the current work shows for the first time that Rd treatment attenuates breast cancer metastasis in part through derepressing miR-18a-mediated Smad2 expression regulation.
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Affiliation(s)
- Peiwei Wang
- Yueyang Hospital &Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Xiaoye Du
- Yueyang Hospital &Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Minqi Xiong
- Yueyang Hospital &Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Jingang Cui
- Yueyang Hospital &Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Qinbo Yang
- Yueyang Hospital &Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Wenjian Wang
- Yueyang Hospital &Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Yu Chen
- Yueyang Hospital &Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
| | - Teng Zhang
- Yueyang Hospital &Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
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Jeong YT, Baek SH, Jeong SC, Yoon YD, Kim OH, Oh BC, Jung JW, Kim JH. Osteoprotective Effects of Polysaccharide-Enriched Hizikia fusiforme Processing Byproduct In Vitro and In Vivo Models. J Med Food 2016; 19:805-14. [PMID: 27458685 DOI: 10.1089/jmf.2015.3646] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The traditional manufacturing method used to produce goods from Hizikia fusiforme, utilizes extraction steps with hot water. The byproduct (of hot water extraction) is rich in polysaccharide and is considered a waste. To evaluate the osteogenic effects of the byproduct of H. fusiforme (HFB), osteogenic cells and animal models were used to test it effects on osteogenesis. The HFB-treated mouse myoblast C2C12 cells exhibited significant dose dependently elevated alkaline phosphatase (ALP) activity and slightly increased bone morphogenetic protein-2 (BMP-2). HFB also suppressed the formation of tartrate-resistant acid phosphatase (TRAP) activity and TRAP staining in the bone marrow-derived macrophages (BMM) cells that had been stimulated with the receptor activator of the nuclear factor kB ligand/macrophage colony-stimulating factor kB ligand. In addition, HFB also increased the phosphorylation of extracellular signal-regulated protein kinase (p-ERK) level. Finally, osteogenic effects of HFB were clearly confirmed in the three in vivo models: zebrafish, ovariectomized mice, and mouse calvarial bones. HFB accelerated the rate of skeletal development in zebrafish and prevented much of the mouse femoral bone density loss of ovariectomized mice. Moreover, HFB enhanced woven bone formation over the periosteum of mouse calvarial bones. Our result showed that HFB functions as a bone resorption inhibitor as well as an activator of bone formation in vivo and in osteogenic in vitro cell systems.
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Affiliation(s)
- Yong Tae Jeong
- 1 HK Bio, Business Incubator, Daegu Haany University , Gyeongsan, Korea
| | - Seung Hwa Baek
- 2 Department of Food Science & Biotechnology, Graduate School, Kyungpook National University , Daegu, Korea
| | - Sang Chul Jeong
- 3 Freshwater Bioresources Utilization Division, Nakdonggang National Institute of Biological Resources , SangJu, Korea
| | - Yeo Dae Yoon
- 4 Korea Research Institute of Bioscience and Biotechnology , Yuseong, Daejeon, Korea
| | - Ok Hee Kim
- 5 Lee Gil Ya Cancer and Diabetes Institute, Gachon University Graduate School of Medicine , Yeonsu-ku, Incheon, Korea
| | - Byung Chul Oh
- 5 Lee Gil Ya Cancer and Diabetes Institute, Gachon University Graduate School of Medicine , Yeonsu-ku, Incheon, Korea
| | - Ji Wook Jung
- 6 Department of Natural Cosmetic Ingredient, Daegu Haany University , Gyeongsan, Korea
| | - Jin Hee Kim
- 7 College of Herbal Bio-Industry, Daegu Haany University , Gyeongsan, Korea
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Anticancer Activities of Protopanaxadiol- and Protopanaxatriol-Type Ginsenosides and Their Metabolites. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 2016:5738694. [PMID: 27446225 PMCID: PMC4944051 DOI: 10.1155/2016/5738694] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 04/27/2016] [Indexed: 01/30/2023]
Abstract
Recently, most anticancer drugs are derived from natural resources such as marine, microbial, and botanical sources, but the low success rates of chemotherapies and the development of multidrug resistance emphasize the importance of discovering new compounds that are both safe and effective against cancer. Ginseng types, including Asian ginseng, American ginseng, and notoginseng, have been used traditionally to treat various diseases, due to their immunomodulatory, neuroprotective, antioxidative, and antitumor activities. Accumulating reports have shown that ginsenosides, the major active component of ginseng, were helpful for tumor treatment. 20(S)-Protopanaxadiol (PDS) and 20(S)-protopanaxatriol saponins (PTS) are two characteristic types of triterpenoid saponins in ginsenosides. PTS holds capacity to interfere with crucial metabolism, while PDS could affect cell cycle distribution and prodeath signaling. This review aims at providing an overview of PTS and PDS, as well as their metabolites, regarding their different anticancer effects with the proposal that these compounds might be potent additions to the current chemotherapeutic strategy against cancer.
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Cong L, Chen W. Neuroprotective Effect of Ginsenoside Rd in Spinal Cord Injury Rats. Basic Clin Pharmacol Toxicol 2016; 119:193-201. [PMID: 26833867 DOI: 10.1111/bcpt.12562] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 01/26/2016] [Indexed: 12/16/2022]
Abstract
In this study, the neuroprotective effects of ginsenoside Rd (GS Rd) were evaluated in a rat model of spinal cord injury (SCI). Rats in SCI groups received a T8 laminectomy and a spinal contusion injury. GS Rd 12.5, 25 and 50 mg/kg were administered intraperitoneally 1 hr before the surgery and once daily for 14 days. Dexamethasone 1 mg/kg was administered as a positive control. Locomotor function was evaluated using the BBB score system. H&E staining and Nissl staining were performed to observe the histological changes in the spinal cord. The levels of MDA and GSH and the activity of SOD were assessed to reflect the oxidative stress state. The production of TNF-α, IL-1β and IL-1 was assessed using ELISA kits to examine the inflammatory responses in the spinal cord. TUNEL staining was used to detect the cell apoptosis in the spinal cord. Western blot analysis was used to examine the expression of apoptosis-associated proteins and MAPK proteins. The results demonstrated that GS Rd 25 and 50 mg/kg significantly improved the locomotor function of rats after SCI, reduced tissue injury and increased neuron survival in the spinal cord. Mechanically, GS Rd decreased MDA level, increased GSH level and SOD activity, reduced the production of pro-inflammatory cytokines and prevented cell apoptosis. The effects were equivalent to those of dexamethasone. In addition, GS Rd effectively inhibited the activation of MAPK signalling pathway induced by SCI, which might be involved in the protective effects of GS Rd against SCI. In conclusion, GS Rd attenuates SCI-induced secondary injury through reversing the redox-state imbalance, inhibiting the inflammatory response and apoptosis in the spinal cord tissue.
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Affiliation(s)
- Lin Cong
- Department of Orthopaedic Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Wenting Chen
- Disease Control and Prevention Center of Shenyang Railway Bureau, Shenyang, China
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Rino Y, Yukawa N, Yamamoto N. Does herbal medicine reduce the risk of hepatocellular carcinoma? World J Gastroenterol 2015; 21:10598-10603. [PMID: 26457019 PMCID: PMC4588081 DOI: 10.3748/wjg.v21.i37.10598] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2015] [Revised: 06/15/2015] [Accepted: 08/25/2015] [Indexed: 02/06/2023] Open
Abstract
Many herbal medicines are effective anti-inflammatory agents and may therefore suppress the development of hepatocellular carcinoma (HCC). Recently, treatment with a single-tablet regimen containing ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with hepatitis C virus genotype 1 infection who did not respond to prior interferon-based treatment. Patients with chronic hepatitis C are expected to receive this treatment worldwide. However, many patients have hepatitis-like fatty liver and nonalcoholic steatohepatitis. A strategy to prevent the development of HCC in this subgroup of patients is urgently required. Whether herbal medicines can suppress the development of HCC remains to be established. However, herbal medicines are effective anti-inflammatory agents and may inhibit the development of HCC. Clinical trials exploring the effectiveness of herbal medicines in the prevention and treatment of HCC are therefore warranted. The current lack of knowledge and of educational programs is a barrier to increasing the use of potentially effective herbal medicines and performing prospective clinical trials.
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Wong AST, Che CM, Leung KW. Recent advances in ginseng as cancer therapeutics: a functional and mechanistic overview. Nat Prod Rep 2015; 32:256-72. [PMID: 25347695 DOI: 10.1039/c4np00080c] [Citation(s) in RCA: 197] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Cancer is one of the leading causes of death worldwide. Ginseng, a key ingredient in traditional Chinese medicine, shows great promise as a new treatment option. As listed by the U.S. National Institutes of Health as a complementary and alternative medicine, its anti-cancer functions are being increasingly recognized. This review covers the mechanisms of action of ginsenosides and their metabolites, which can modulate signaling pathways associated with inflammation, oxidative stress, angiogenesis, metastasis, and stem/progenitor-like properties of cancer cells. The emerging use of structurally modified ginsenosides and recent clinical studies on the use of ginseng either alone or in combination with other herbs or Western medicines which are exploited as novel therapeutic strategies will also be explored.
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Affiliation(s)
- Alice S T Wong
- State Key Laboratory of Oncogenes and Related Genes, and School of Biological Sciences, The University of Hong Kong, Hong Kong.
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Li C, Wu X, Zhang H, Yang G, Hao M, Sheng S, Sun Y, Long J, Hu C, Sun X, Li L, Zheng J. A Huaier polysaccharide reduced metastasis of human hepatocellular carcinoma SMMC-7721 cells via modulating AUF-1 signaling pathway. Tumour Biol 2015; 36:6285-93. [PMID: 25787750 DOI: 10.1007/s13277-015-3314-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Accepted: 03/05/2015] [Indexed: 01/22/2023] Open
Abstract
TP-1 is a polysaccharide from one famous fungus Huaier. Treatment with TP-1 significantly inhibited the cell growth, adhesion, migration, and motility of SMMC-7721 cells in a dose-dependent manner. Real-time quantitative RT-PCR revealed a dose-dependent decrease in RNA-binding factor 1 (AUF-1) and astrocyte elevated gene-1 (AEG-1) messenger RNA (mRNA) levels in TP-1-treated SMMC-7721 cells, which is consistent with their protein expression detected by Western blotting. On the contrary, microRNA-122 (miR-122) expression increased in SMMC-7721 cells following TP-1 treatment. Moreover, TP-1 treatment at three doses apparently increased epithelial marker E-cadherin protein expression but decreased the mesenchymal marker N-cadherin protein level. In addition, the hematoxylin-eosin (H & E) staining showed that the TP-1 significantly inhibited the lung metastasis of liver cancer in mice orthotopic implanted with SMMC-7721 tumor tissue. Taken together, these findings proved the inhibitory effect of TP-1 on the growth and metastasis of SMMC-7721 cells, and TP-1 might be offered for future application as a powerful chemopreventive agent against hepatocellular carcinoma (HCC) metastasis.
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Affiliation(s)
- Cong Li
- Intervention Therapy Center of Liver Diseases, Beijing You An Hospital, Capital Medical University, 100069, Beijing, China
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Lu C, Yin Y. Pulsed electric field treatment combined with commercial enzymes converts major ginsenoside Rb1 to minor ginsenoside Rd. INNOV FOOD SCI EMERG 2014. [DOI: 10.1016/j.ifset.2013.12.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Mao Q, Zhang PH, Wang Q, Li SL. Ginsenoside F(2) induces apoptosis in humor gastric carcinoma cells through reactive oxygen species-mitochondria pathway and modulation of ASK-1/JNK signaling cascade in vitro and in vivo. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2014; 21:515-522. [PMID: 24252332 DOI: 10.1016/j.phymed.2013.10.013] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 09/03/2013] [Accepted: 10/11/2013] [Indexed: 06/02/2023]
Abstract
Ginsenoside F(2) (F(2)) is a potential bioactive metabolite of major ginsenosides. The potential anti-cancer effect of F(2) in gastric cancer cells has not been appraised. This study investigated the effects of F(2) on the production of reactive oxygen species (ROS). We also investigated the in vitro and in vivo effects of F(2) on the downstream signaling pathways leading to apoptosis in human gastric cancer cells. The in vitro data revealed that F(2) induces ROS accumulation followed by a decrease in mitochondrial transmembrane potential (MTP), and the release of cytochrome c (cyto c), which induced the caspase-dependent apoptosis. Further assay indicated that modulation of ASK-1/JNK pathway contributes to apoptosis. In vivo, F(2) exhibits the obvious anti-cancer effect compared with cisplatin with no obvious toxicity. Jointly, these results suggest that F(2) induces apoptosis by causing an accumulation of ROS and activating the ASK-1/JNK signaling pathway. This provides further support for the use of F(2) as a novel anticancer therapeutic candidate.
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Affiliation(s)
- Qian Mao
- Department of Pharmaceutical Analysis & Metabolomics, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, PR China
| | - Ping-Hu Zhang
- Jiangsu Center for New Drug Screening & National New Drug Screening Laboratory, China Pharmaceutical University, Nanjing, PR China
| | - Qiang Wang
- State Laboratory of Modern Chinese Medicines, China Pharmaceutical University, Nanjing, PR China.
| | - Song-Lin Li
- Department of Pharmaceutical Analysis & Metabolomics, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, PR China.
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Du JR, Long FY, Chen C. Research Progress on Natural Triterpenoid Saponins in the Chemoprevention and Chemotherapy of Cancer. Enzymes 2014; 36:95-130. [PMID: 27102701 DOI: 10.1016/b978-0-12-802215-3.00006-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Triterpenoid saponins are glycosides with remarkable structural and bioactive diversity. They are becoming increasingly significant in the treatment of cancer due to their efficacy and safety. This chapter provides an update on the sources, pharmacological effects, structure-activity relationships, and clinical studies of anticancer triterpenoid saponins with a particular focus on the molecular mechanisms underlying their therapeutic properties. The correlative references and study reports described were collected through PubMed. The anticancer triterpenoid saponins enable the inhibition of cancer formation and progression by modulating multiple signaling targets related to cellular proliferation, apoptosis, autophagy, metastasis, angiogenesis, inflammation, oxidative stress, multidrug resistance, cancer stem cells, and microRNAs. This review provides new insights into the molecular basis of triterpenoid saponins in the chemoprevention and chemotherapy of cancer.
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Affiliation(s)
- Jun-Rong Du
- Department of Pharmacology, West China School of Pharmacy, Sichuan University, Chengdu, P.R. China.
| | - Fang-Yi Long
- Department of Pharmacology, West China School of Pharmacy, Sichuan University, Chengdu, P.R. China
| | - Chu Chen
- Institute of Pharmaceutical Research, Sichuan Academy of Chinese Medicine Sciences, Chengdu, P.R. China.
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Choi JS, Chun KS, Kundu J, Kundu JK. Biochemical basis of cancer chemoprevention and/or chemotherapy with ginsenosides (Review). Int J Mol Med 2013; 32:1227-38. [PMID: 24126942 DOI: 10.3892/ijmm.2013.1519] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Accepted: 09/26/2013] [Indexed: 11/06/2022] Open
Abstract
Cancer still imposes a global threat to public health. After decades of research on cancer biology and enormous efforts in developing anticancer therapies, we now understand that the majority of cancers can be prevented. Bioactive phytochemicals present in edible plants have been shown to reduce the risk of various types of cancer. Ginseng (Panax ginseng C.A. Meyer), which contains a wide variety of saponins, known as ginsenosides, is an age-old remedy for human ailments, including cancer. Numerous laboratory-based studies have revealed the anticancer properties of ginsenosides, which compel tumor cells to commit suicide, arrest the proliferation of cancer cells in culture and inhibit experimentally-induced tumor formation in laboratory animals. Ginsenosides have been reported to inhibit tumor angiogenesis, as well as the invasion and metastasis of various types of cancer cells. Moreover, ginsenosides as combination therapy enhance the sensitivity of chemoresistant tumors to clinically used chemotherapeutic agents. This review sheds light on the molecular mechanisms underlying the cancer chemopreventive and/or chemotherapeutic activity of ginsenosides and their intestinal metabolites with particular focus on the modulation of cell signaling pathways associated with oxidative stress, inflammation, cell proliferation, apoptosis, angiogenesis and the metastasis of cancer cells.
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Affiliation(s)
- Joon-Seok Choi
- College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea
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Poudyal D, Cui X, Le PM, Hofseth AB, Windust A, Nagarkatti M, Nagarkatti PS, Schetter AJ, Harris CC, Hofseth LJ. A key role of microRNA-29b for the suppression of colon cancer cell migration by American ginseng. PLoS One 2013; 8:e75034. [PMID: 24130681 PMCID: PMC3794036 DOI: 10.1371/journal.pone.0075034] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Accepted: 08/07/2013] [Indexed: 11/29/2022] Open
Abstract
Metastasis of colon cancer cells increases the risk of colon cancer mortality. We have recently shown that American ginseng prevents colon cancer, and a Hexane extract of American Ginseng (HAG) has particularly potent anti-inflammatory and anti-cancer properties. Dysregulated microRNA (miR) expression has been observed in several disease conditions including colon cancer. Using global miR expression profiling, we observed increased miR-29b in colon cancer cells following exposure to HAG. Since miR-29b plays a role in regulating the migration of cancer cells, we hypothesized that HAG induces miR-29b expression to target matrix metalloproteinase-2 (MMP-2) thereby suppressing the migration of colon cancer cells. Results are consistent with this hypothesis. Our study supports the understanding that targeting MMP-2 by miR-29b is a mechanism by which HAG suppresses the migration of colon cancer cells.
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Affiliation(s)
- Deepak Poudyal
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, United States of America
| | - Xiangli Cui
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, United States of America
- Shanxi Medical University, Shanxi, China
| | - Phuong Mai Le
- Institute for National Measurement Standards, National Research Council, Ottawa, Canada
| | - Anne B. Hofseth
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, United States of America
| | - Anthony Windust
- Institute for National Measurement Standards, National Research Council, Ottawa, Canada
| | - Mitzi Nagarkatti
- School of Medicine, University of South Carolina, Columbia, South Carolina, United States of America
| | - Prakash S. Nagarkatti
- School of Medicine, University of South Carolina, Columbia, South Carolina, United States of America
| | - Aaron J. Schetter
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Curtis C. Harris
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Lorne J. Hofseth
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, South Carolina, United States of America
- * E-mail:
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Current understanding on antihepatocarcinoma effects of xiao chai hu tang and its constituents. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:529458. [PMID: 23853661 PMCID: PMC3703324 DOI: 10.1155/2013/529458] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Revised: 04/25/2013] [Accepted: 05/27/2013] [Indexed: 02/07/2023]
Abstract
Xiao Chai Hu Tang (XCHT), a compound formula originally recorded in an ancient Chinese medical book Shanghanlun, has been used to treat chronic liver diseases for a long period of time in China. Although extensive studies have been demonstrated the efficacy of this formula to treat chronic hepatitis, hepatic fibrosis, and hepatocarcinoma, how it works against these diseases still awaits full understanding. Here, we firstly present an overview arranging from the entire formula to mechanism studies of single herb in XCHT and their active components, from a new perspective of "separation study," and we tried our best to both detailedly and systematically organize the antihepatocarcinoma effects of it, hoping that the review will facilitate the strive on elucidating how XCHT elicits its antihepatocarcinoma role.
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Healy S, Khan P, Davie JR. Immediate early response genes and cell transformation. Pharmacol Ther 2013; 137:64-77. [DOI: 10.1016/j.pharmthera.2012.09.001] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2012] [Accepted: 09/06/2012] [Indexed: 01/20/2023]
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Ginseng and Its Active Components Ginsenosides Inhibit Adipogenesis in 3T3-L1 Cells by Regulating MMP-2 and MMP-9. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 2012:265023. [PMID: 23258984 PMCID: PMC3518923 DOI: 10.1155/2012/265023] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2012] [Revised: 09/27/2012] [Accepted: 10/04/2012] [Indexed: 11/29/2022]
Abstract
The growth and development of adipose tissue are believed to require adipogenesis, angiogenesis, and extracellular matrix remodeling. As our previous study revealed that ginseng reduces adipose tissue mass in part by decreasing matrix metalloproteinase (MMP) activity in obese mice, we hypothesized that adipogenesis can be inhibited by ginseng and its active components ginsenosides (GSs). Treatment of 3T3-L1 adipocytes with Korean red ginseng extract (GE) inhibited lipid accumulation and the expression of adipocyte-specific genes (PPARγ, C/EBPα, aP2, and leptin). GE decreased both the mRNA levels and activity of MMP-2 and MMP-9 in 3T3-L1 cells. These effects were further inhibited by total GSs (TGSs) and individual GSs. TGSs and individual GSs also significantly decreased MMP-2 and MMP-9 reporter gene activities in the presence of phorbol 12-myristate 13-acetate (PMA), the MMP inducer. Among the GSs, Rb1 most effectively inhibited MMP activity. In addition, PMA treatment attenuated the inhibitory actions of GE and GSs on adipogenesis. Moreover, GE and GSs reduced the expression of NF-κB and AP-1, the transcription factors of MMP-2 and MMP-9. These results demonstrate that ginseng, in particular GSs, effectively inhibits adipogenesis and that this process may be mediated in part through the suppression of MMP-2 and MMP-9. Thus, ginseng and GSs likely have therapeutic potential for controlling adipogenesis.
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Chen SL, Jiang JG. Application of gene differential expression technology in the mechanism studies of nature product-derived drugs. Expert Opin Biol Ther 2012; 12:823-39. [DOI: 10.1517/14712598.2012.683858] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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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. [PMID: 22403544 PMCID: PMC3289390 DOI: 10.3389/fphar.2012.00025] [Citation(s) in RCA: 243] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Accepted: 02/11/2012] [Indexed: 02/06/2023] Open
Abstract
Conventional chemotherapeutic agents are often toxic not only to tumor cells but also to normal cells, limiting their therapeutic use in the clinic. Novel natural product anticancer compounds present an attractive alternative to synthetic compounds, based on their favorable safety and efficacy profiles. Several pre-clinical and clinical studies have demonstrated the anticancer potential of Panax ginseng, a widely used traditional Chinese medicine. The anti-tumor efficacy of ginseng is attributed mainly to the presence of saponins, known as ginsenosides. In this review, we focus on how ginsenosides exert their anticancer effects by modulation of diverse signaling pathways, including regulation of cell proliferation mediators (CDKs and cyclins), growth factors (c-myc, EGFR, and vascular endothelial growth factor), tumor suppressors (p53 and p21), oncogenes (MDM2), cell death mediators (Bcl-2, Bcl-xL, XIAP, caspases, and death receptors), inflammatory response molecules (NF-κB and COX-2), and protein kinases (JNK, Akt, and AMP-activated protein kinase). We also discuss the structure–activity relationship of various ginsenosides and their potentials in the treatment of various human cancers. In summary, recent advances in the discovery and evaluation of ginsenosides as cancer therapeutic agents support further pre-clinical and clinical development of these agents for the treatment of primary and metastatic tumors.
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Affiliation(s)
- Subhasree Ashok Nag
- Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center Amarillo, TX, USA
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