Next Article in Journal
Human RNASET2: A Highly Pleiotropic and Evolutionary Conserved Tumor Suppressor Gene Involved in the Control of Ovarian Cancer Pathogenesis
Next Article in Special Issue
Advances in Anti-Cancer Activities of Flavonoids in Scutellariae radix: Perspectives on Mechanism
Previous Article in Journal
How to Use Respiratory Chain Inhibitors in Toxicology Studies—Whole-Cell Measurements
Previous Article in Special Issue
Application of Perinatal Derivatives on Oncological Preclinical Models: A Review of Animal Studies
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 23
Issue 16
10.3390/ijms23169077
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Experimental Evidence for the Anti-Metastatic Action of Ginsenoside Rg3: A Systematic Review

by
Hyeon-Muk Oh
1,
Chong-Kwan Cho
1,2 and
Chang-Gue Son
1,3,*
1
College of Korean Medicine, Daejeon University, Daejeon 35235, Korea
2
East-West Cancer Center, Daejeon Korean Medicine Hospital of Daejeon University, Daejeon 35235, Korea
3
Liver and Immunology Research Center, Daejeon Korean Medicine Hospital of Daejeon University, Daejeon 35235, Korea
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(16), 9077; https://doi.org/10.3390/ijms23169077
Submission received: 20 July 2022 / Revised: 9 August 2022 / Accepted: 11 August 2022 / Published: 13 August 2022
(This article belongs to the Special Issue Natural Products and Phytochemicals in Preventing and Treating Cancers)
Browse Figures
Review Reports Versions Notes

Abstract

:
Cancer metastasis is the leading cause of death in cancer patients. Due to the limitations of conventional cancer treatment, such as chemotherapy, there is a need for novel therapeutics to prevent metastasis. Ginsenoside Rg3, a major active component of Panax ginseng C.A. Meyer, inhibits tumor growth and has the potential to prevent tumor metastasis. Herein, we systematically reviewed the anti-metastatic effects of Rg3 from experimental studies. We searched for articles in three research databases, MEDLINE (PubMed), EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) through March 2022. In total, 14 studies (eight animal and six in vitro) provide data on the anti-metastatic effects of Rg3 and the relevant mechanisms. The major anti-metastatic mechanisms of Rg3 involve cancer stemness, epithelial mesenchymal transition (EMT) behavior, and angiogenesis. Taken together, Rg3 would be one of the herbal resources in anti-metastatic drug developments through further well-designed investigations and clinical studies. Our review provides valuable reference data for Rg3-derived studies targeting tumor metastasis.

1. Introduction

Cancer metastasis is the main cause of cancer-related deaths, as 66% of the 10.0 million cancer deaths worldwide in 2020 were due to metastasis [1,2]. Despite scientific and technological advances, there has been no significant decrease in the mortality rate among metastatic cancer patients over the past decade [3]. The 5-year survival rate of metastatic cancer was significantly lower than primary cancer; nearly 0.25-fold for breast cancer, 0.13-fold for colorectal cancer, and 0.08-fold for pancreatic cancer [4]. Accordingly, reducing the risk of cancer metastasis is a crucial factor in the survival of cancer patients and cancer treatment [5].
In cancer treatment, the early detection and complete removal of a tumor is optimal [6,7]. Its failure, however, is very common, and approximately 40% of cancer patients are known to progress into metastasis during their treatment process after diagnosis [8]. Cancer metastasis is a complex and multistep process that consists of dissemination, intravasation, circulation, extravasation, and colonization [9]. As the tumor progresses into an advanced stage, the genetic alterations leading to pro-metastatic characteristics are obtained, which trigger the epithelial mesenchymal transition (EMT) known to induce tumor metastasis [10,11]. In addition, tumor microenvironments (TMEs) such as the extracellular matrix structure, matrix metalloproteinases (MMPs), growth factors, and chemokines are also known to play important roles in cancer metastasis [12].
Accordingly, there have been strong efforts to develop appropriate anti-metastatic drugs [13]. To date, two major anti-metastatic drugs, an anti-angiogenesis drug and an MMPs inhibitor, have been approved by the Food and Drug Administration in the USA [14]. They target MMPs, which play an important role in the processes of intravasation and angiogenesis, required for colonization and tumor growth in secondary metastatic organs [15,16]. Although the clinical trials did not show enough efficacy on anti-metastasis [17], the development of anti-metastatic drugs targeting these two mechanisms is in progress [18].
On the other hand, there is growing evidence that several natural compounds such as the ginsenoside in Panax ginseng C.A. Meyer (P. ginseng) and curcumin in Curcuma longa L. have the potential to prevent cancer metastasis [19,20,21]. P. ginseng has traditionally been used to treat various diseases for over a thousand years in Asian countries [22]. Among the numerous active compounds of P. ginseng, ginsenoside Rg3 has been most prevalently studied for its anticancer effects in many types of cancers, including breast cancer, gastrointestinal cancer, and prostate cancer [23,24,25]. Moreover, Rg3 has been known to enhance host immunity, reduce the adverse effects of chemotherapies, and increase survival periods, according to clinical studies [26,27]. Some groups also reported the modulations of TMEs, including anti-angiogenesis from animal studies [28,29]. In addition, some studies showed the inactivation of cancer stem cell (CSC) and EMT by Rg3, which would anticipate the anti-metastatic potentials of Rg3 [30,31].
In order to provide the basis for antimetastatic drug development using ginsenosides, we herein systematically reviewed the anti-metastatic effects of Rg3, a representative active compound of P. ginseng.

2. Materials and Methods

2.1. Search Strategy and Selection Criteria

Three electronic databases were searched for the systematic literature survey, including MEDLINE (PubMed), EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL), limited to papers published on or before March 2022. MeSH and Emtree searching were applied too. The search was conducted by combining keywords related to ginsenoside Rg3 and metastasis and its combination.
The inclusion criteria for studies were the evaluation of the anti-metastatic effects of Rg3 in an experimental study either in vivo or in vitro. We excluded studies only focusing on the inhibition of cancer initiation/progression by Rg3. Articles without full text were also excluded.

2.2. Data Extraction and Analysis

We extracted the following details: name of first author, publication year, cancer type (cell line), animal, metastatic model, target organ, type of Rg3, concentration, administration route, duration of Rg3 treatment, main outcome of study, and mechanism of actions. The authors carefully reviewed all included studies, and they are summarized in tables and figures.

3. Results

3.1. Characteristics of the Included Studies

Of the 43 related articles, 14 studies were finally selected with four animal and in vitro combined studies, four animal studies, and six in vitro studies. (Figure 1). Four types of Rg3 (ten datasets, 20 (R)-Rg3 for six datasets, 20 (S)-Rg3 for two datasets, and one of nanoparticle-conjugated Rg3) and eight different tissue-derived cancer cells (including two mutagen-inductions) were applied for targeting three organs/tissues (lung, liver, kidney, and peritoneum), respectively. All studies were conducted in Asian countries, including China (eight studies), Korea (four studies), and Japan (two studies) (Table 1).

3.2. Anti-Metastatic Effects of Rg3 in Animal Studies

Of the eight animal studies, seven studies (all except one study) reported statistically significant anti-metastatic effects, identifying a decreased number of metastatic nodules or colonies in the metastatic regions; lung (two melanoma, one ovarian cancer, one colorectal cancer, one thyroid cancer, and one HCC), peritoneum (one colorectal cancer), liver (two colorectal cancer), and kidney (one colorectal cancer) (Table 2). The mean concentration of Rg3 was 27.0 ± 26.1 mg/kg/day orally (four studies) and 4.0 ± 1.0 mg/kg/day subcutaneously (four studies), and the administration period was 28 ± 28 days.

3.3. Anti-Metastatic Mechanisms of Rg3 in the Tumor Tissues of Animal Studies

Regarding the underlying mechanisms in animal studies, the anti-angiogenic effect of Rg3 in metastasized regions most frequently appeared (six out of eight studies). Other mechanisms involved the inhibition of cancer stem cells in one colorectal liver-metastatic model and suppression of MMPs (MMP2 and MMP9) in two lung metastatic models from SKOV-3 ovarian cancer and B16 melanoma. Rg3 also suppressed tumor growth via modulation of the ERK/AKT/mTOR signaling pathway in melanoma (Table 2).

3.4. Anti-Invasion and Migration Effects of Rg3 in Cancer Cell Lines

Nine of the reported studies showed the anti-invasion activity of Rg3 in 18 cell lines of nine types of tumors, originating from lung, skin, colorectum, nasopharynx, liver, and bone tumors.
Similarly, eight out of ten in vitro datasets revealed the anti-migration activity of Rg3 using 17 cell lines of eight types of tumors, originating from lung, skin, colorectum, thyroid, liver, and bone tumors (Table 2).

3.5. Anti-Metastatic Mechanisms of Rg3 in Cancer Cell Lines

The three major anti-metastatic mechanisms of Rg3 involve cancer stemness, EMT behavior, and MMP-related activities, as summarized in Table 2.
Briefly, Rg3 repressed the cancer stemness in both colorectal cancer (LoVo, SW620, HCT116) and liver cancer cells (HepG2, MHCC-97L) via reductions in CD24, CD44, and the epithelial cell adhesion molecule (EpCAM) and activation of ARHGAP9, a tumor suppressor gene. Rg3 also modulated EMT-related molecules, such as activations of E-cadherin and Snail and suppressions of N-cadherin, Vimentin, and zing-finger E-box-binding homeobox factor (ZEB) 1 in five different cell lines: lung, nasopharynx, colorectum, and bone tumor, respectively. For EMT-related pathways, the modulations of ERK/AKT/mTOR in B16F1 melanoma cells and Wnt/β-catenin signaling in osteosarcoma cell lines (MG63, 143B) were reported. The pharmaceutical actions of Rg3 on the inhibition of MMPs were: MMP2 in six cell lines (originated from lung, thyroid, nasopharynx, colorectum, and bone tumor), MMP9 in four cell lines (lung, thyroid, nasopharynx, and bone tumor), and MMP13 in the B16F10 melanoma cell line, respectively.

4. Discussion

We systematically analyzed the studies for the anti-metastatic effects of ginsenoside Rg3. Rg3 was firstly identified in 1966 as one of the major active compounds in P. ginseng [46]. Along with the numerous beneficial effects of P. ginseng for subjects with sub-healthy conditions or many diseases, its active compounds have been also of interest [47,48,49,50]. P. ginseng has many active compounds, including more than 40 types of ginsenosides such as Rb1, Rg1, Rg3, Re, Rd, and Rh1 [51]. Of these, Rg3 has been particularly noted for its antitumor activity in various cancers, such as breast cancer, colon cancer, lung cancer, and ovarian cancer [52,53,54].
Clinical data have shown the beneficial effects of Rg3 on cancer patients. Administration of Rg3 improved the survival rates and quality of life in patients with esophageal cancer, gastric cancer, and lung cancer [55,56,57]. Rg3 also showed an adjuvant effect with conventional cancer therapy, which increased the response rate of chemotherapy in lung cancer and sensitized the effects of radiotherapy in colorectal cancer [58,59]. Another study presented the survival gain (1.7 months) in 115 metastatic lung cancer patients by Rg3 combination therapy compared to chemotherapy alone [60]. Furthermore, Rg3 ameliorated side effects such as myelosuppression in patients undergoing chemotherapy [27,61].
From the aspect of the clinical impact of metastasis during whole processes of tumor treatment, the above data may support the anti-metastatic effects of P. ginseng and its major active compound, Rg3. From our systematic review, a total of 14 studies reported the anti-metastatic effects of Rg3, including eight animal results and six in vitro studies. In general, lung and liver are two of the main target organs for systemic metastasis in clinics, depending on the circulation pattern and the anatomy of vessels [62]. Our results also showed that Rg3 exerted anti-metastatic effects against mainly lung (six cell line experiments from five kinds of tumors) [32,34,36,37,38,39] and liver metastasis [35,38] (Table 2). Three of eight animal studies provided evidence on the anti-metastatic activities of Rg3, using colorectal cancer targeting liver, peritoneum, lung, and kidney [33,35,38]. Owing to its reproducibility and similarity with human pathology, the colorectal cancer-derived animal model is the most representative experimental design to study the mechanistic and molecular analyses of tumor metastasis [63].
Regarding the molecular actions of Rg3′s anti-metastatic effects, Rg3 involved the major processes of tumor metastasis, such as CSC, EMT, and angiogenesis (Figure 2). CSCs, known as key factors in the initiation of metastasis by self-renewal and differentiation into multiple phenotypes [64,65], were suppressed by Rg3 in a colorectal cancer-induced liver metastasis mouse [35]. In addition, EMT is the most well-known metastatic process accelerating tumor invasion and migration, which is regulated by various factors, including the ZEB family, Snail, and Slug [66]. Rg3 modulated EMT-related molecules, such as E-cadherin, N-cadherin, Snail, Vimentin, and the ZEB family, as reported by five in vitro studies [38,40,42,43,45]. In addition, Rg3 inhibited MMPs, including MMP2 [36,37,38,40,42,43,45], MMP7 [45], MMP9 [36,37,43,45], and MMP13 [41]. These proteinase activations are an important factor that induce EMT behaviors and also promote tumor growth and metastasis [67,68]. After the disseminated cancer cells reach the distant metastatic organ, angiogenesis is essential for the tumor survival and growth [69]. Most of our animal data (six of eight studies) showed the anti-angiogenic actions of Rg3 in various type of cancers [32,33,34,35,36,37].
Additionally, various pathophysiological changes such as inflammation and oxidative stress are associated with the promotion of tumor metastasis by inducing tumor cell proliferation, malignant phenotype, and genetic instability [70]. In these pathological alterations, Rg3 alleviated the reactive oxygen species (ROS) [71] and reduced the inflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IL-13 [72]. These therapeutic activities of Rg3 have been proved to treat many diseases, such as liver diseases, neuroinflammatory diseases, and metabolic diseases [73,74,75]. These multifaceted properties of Rg3 may be involved in the inhibitory mechanisms of tumor metastasis.
To date, there was one set of clinical data showing a significant improvement in the 5-year metastatic-free rate more than twice (68.2% vs. 33.3% in the non-combination control) with the combination of P. ginseng and chemotherapy in gastric cancer patients [76]. Although, there is no Rg3-derived anti-metastatic clinical evidence yet, this clinical result may indicate the potential benefit of P. ginseng, including Rg3 on survival and anti-metastasis, especially as a format of combination therapy with existing agents. The present experimental data would support the potential of Rg3 decreasing the tumor metastatic risk.
The present study has some limitations. First, there were no clinical data on anti-metastatic effects of Rg3 supporting our results. The number of recently published studies is very small, and our study restricted the language to English only. Second, the doses of Rg3 from in vitro studies used were relatively high (up to 200 µg/mL), which might have a limited reliability. We, however, notice that four out of 10 in vitro studies are the supporting data of animal studies and the molecular weight of Rg3 (784.3 kDa) [77] is six times larger than 5-fluorouracil (5-FU) (130.1 kDa) [78]. Third, only one study engaged the positive control [37], so it is difficult to compare the anti-metastatic effect of Rg3 with other existing agents.
In spite of the above limitations, our results are valuable reference data for Rg3-derived studies targeting tumor metastasis. Rg3 has the advantage of safety that the no observed adverse effect level (NOAEL) is 180 mg/kg, and the lethal dose 50 percent (LD50) is above 800 mg/kg in Sprague Dawley (SD) rats [79]. Two clinical studies also reported on the safety that oral administration of Rg3 up to 50 mg/day causes no toxicity on patients with non-small cell lung carcinoma [80] and hepatocellular carcinoma [81]. Regarding pharmacokinetics of Rg3, the half-life of Rg3 was 14 min [82] and 18.5 min [83], both in SD rats after intravenous administration. On the other hand, Rg3 has been known to have a very low oral bioavailability (2.63%) [83,84] compared to other ginsenosides, including Rh2 (24.8%) [85], and Rg1 (18.4%) in SD rats [86]. This might have resulted from Rg3 being rapidly metabolized in the gastrointestinal tract through hydrolysis in the stomach [87]. These characteristics of Rg3 should be considered in future Rg3-derived drug development.
Taken together, we carefully suggest that Rg3 may provide an opportunity to develop novel anti-metastatic agents through further well-designed investigations and clinical studies.

Author Contributions

H.-M.O.: wrote the main manuscript text; C.-K.C.: conceptualized the study and supervised the manuscript; C.-G.S.: supervised the manuscript and directed the final version of all contents. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Research Foundation of Korea (NRF), grant number 2019R1A2C2088201.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data used for this study are available from the corresponding author upon request.

Conflicts of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

  1. Dillekas, H.; Rogers, M.S.; Straume, O. Are 90% of deaths from cancer caused by metastases? Cancer Med. 2019, 8, 5574–5576. [Google Scholar] [CrossRef] [PubMed]
  2. Ferlay, J.; Colombet, M.; Soerjomataram, I.; Parkin, D.M.; Piñeros, M.; Znaor, A.; Bray, F. Cancer statistics for the year 2020: An overview. Int. J. Cancer 2021, 149, 778–789. [Google Scholar] [CrossRef]
  3. Steeg, P.S. Targeting metastasis. Nat. Rev. Cancer 2016, 16, 201–218. [Google Scholar] [CrossRef]
  4. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA A Cancer J. Clin. 2019, 69, 7–34. [Google Scholar] [CrossRef] [PubMed]
  5. Polzer, B.; Klein, C.A. Metastasis awakening: The challenges of targeting minimal residual cancer. Nat. Med. 2013, 19, 274–275. [Google Scholar] [CrossRef] [PubMed]
  6. Hamilton, W.; Walter, F.M.; Rubin, G.; Neal, R.D. Improving early diagnosis of symptomatic cancer. Nat. Rev. Clin. Oncol. 2016, 13, 740–749. [Google Scholar] [CrossRef] [PubMed]
  7. Sullivan, R.; Alatise, O.I.; Anderson, B.O.; Audisio, R.; Autier, P.; Aggarwal, A.; Balch, C.; Brennan, M.F.; Dare, A.; D’Cruz, A.; et al. Global cancer surgery: Delivering safe, affordable, and timely cancer surgery. Lancet Oncol. 2015, 16, 1193–1224. [Google Scholar] [CrossRef]
  8. Siegel, R.; Ward, E.; Brawley, O.; Jemal, A. Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA A Cancer J. Clin. 2011, 61, 212–236. [Google Scholar] [CrossRef] [PubMed]
  9. Ganesh, K.; Massagué, J. Targeting metastatic cancer. Nat. Med. 2021, 27, 34–44. [Google Scholar] [CrossRef]
  10. Armaghany, T.; Wilson, J.D.; Chu, Q.; Mills, G. Genetic alterations in colorectal cancer. Gastrointest. Cancer Res. GCR 2012, 5, 19. [Google Scholar]
  11. Thiery, J.P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2002, 2, 442–454. [Google Scholar] [CrossRef] [PubMed]
  12. Guan, X. Cancer metastases: Challenges and opportunities. Acta Pharm. Sin. B 2015, 5, 402–418. [Google Scholar] [CrossRef] [PubMed]
  13. Gandalovičová, A.; Rosel, D.; Fernandes, M.; Veselý, P.; Heneberg, P.; Čermák, V.; Petruželka, L.; Kumar, S.; Sanz-Moreno, V.; Brábek, J. Migrastatics—Anti-metastatic and anti-invasion drugs: Promises and challenges. Trends Cancer 2017, 3, 391–406. [Google Scholar] [CrossRef] [PubMed]
  14. Lu, D.Y.; Huang, M.; Zhou, J.; Ding, J. Recent advances in anti-metastatic drug developments. In Acta Pharmacologica Sinica; Blackwell Publishing: Oxford, UK, 2006; Volume 27, pp. 66–67. [Google Scholar]
  15. Deryugina, E.I.; Quigley, J.P. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 2016, 25, 9–34. [Google Scholar] [CrossRef] [PubMed]
  16. Bielenberg, D.R.; Zetter, B.R. The contribution of angiogenesis to the process of metastasis. Cancer J. (Sudbury Mass.) 2015, 21, 267. [Google Scholar] [CrossRef] [PubMed]
  17. Overall, C.M.; Kleifeld, O. Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat. Rev. Cancer 2006, 6, 227–239. [Google Scholar] [CrossRef] [PubMed]
  18. Anderson, R.L.; Balasas, T.; Callaghan, J.; Coombes, R.C.; Evans, J.; Hall, J.A.; Kinrade, S.; Jones, D.; Jones, P.S.; Jones, R.; et al. A framework for the development of effective anti-metastatic agents. Nat. Rev. Clin. Oncol. 2019, 16, 185–204. [Google Scholar] [CrossRef]
  19. Mantena, S.K.; Baliga, M.S.; Katiyar, S.K. Grape seed proanthocyanidins induce apoptosis and inhibit metastasis of highly metastatic breast carcinoma cells. Carcinogenesis 2006, 27, 1682–1691. [Google Scholar] [CrossRef]
  20. Kim, S.P.; Nam, S.H.; Friedman, M. Hericium erinaceus (Lion’s Mane) mushroom extracts inhibit metastasis of cancer cells to the lung in CT-26 colon cancer-tansplanted mice. J. Agric. Food Chem. 2013, 61, 4898–4904. [Google Scholar] [CrossRef]
  21. Bandyopadhyay, D. Farmer to pharmacist: Curcumin as an anti-invasive and antimetastatic agent for the treatment of cancer1. Front. Chem. 2014, 2, 113. [Google Scholar] [CrossRef]
  22. Mahady, G.B.; Gyllenhaal, C.; Fong, H.H.; Farnsworth, N.R. Ginsengs: A review of safety and efficacy. Nutr. Clin. Care 2000, 3, 90–101. [Google Scholar] [CrossRef]
  23. Kim, H.S.; Lee, E.H.; Ko, S.R.; Choi, K.J.; Park, J.H.; Im, D.S. Effects of ginsenosides Rg3 and Rh2 on the proliferation of prostate cancer cells. Arch. Pharmacal Res. 2004, 27, 429–435. [Google Scholar] [CrossRef]
  24. He, B.C.; Gao, J.L.; Luo, X.; Luo, J.; Shen, J.; Wang, L.; Zhou, Q.; Wang, Y.T.; Luu, H.H.; Haydon, R.C.; et al. Ginsenoside Rg3 inhibits colorectal tumor growth through the down-regulation of Wnt/ss-catenin signaling. Int. J. Oncol. 2011, 38, 437–445. [Google Scholar] [CrossRef] [PubMed]
  25. Sun, M.; Ye, Y.; Xiao, L.; Duan, X.; Zhang, Y.; Zhang, H. Anticancer effects of ginsenoside Rg3. Int. J. Mol. Med. 2017, 39, 507–518. [Google Scholar] [CrossRef]
  26. Lu, P.; Su, W.; Miao, Z.H.; Niu, H.R.; Liu, J.; Hua, Q.L. Effect and mechanism of ginsenoside Rg3 on postoperative life span of patients with non-small cell lung cancer. Chin. J. Integr. Med. 2008, 14, 33–36. [Google Scholar] [CrossRef] [PubMed]
  27. Pan, L.; Zhang, T.; Cao, H.; Sun, H.; Liu, G. Ginsenoside Rg3 for chemotherapy-induced myelosuppression: A meta-analysis and systematic review. Front. Pharmacol. 2020, 11, 649. [Google Scholar] [CrossRef] [PubMed]
  28. Cao, Y.; Ye, Q.; Zhuang, M.; Xie, S.; Zhong, R.; Cui, J.; Zhou, J.; Zhu, Y.; Zhang, T.; Cao, L. Ginsenoside Rg3 inhibits angiogenesis in a rat model of endometriosis through the VEGFR-2-mediated PI3K/Akt/mTOR signaling pathway. PLoS ONE 2017, 12, e0186520. [Google Scholar] [CrossRef]
  29. Hu, S.; Zhu, Y.; Xia, X.; Xu, X.; Chen, F.; Miao, X.; Chen, X. Ginsenoside Rg3 prolongs survival of the orthotopic hepatocellular carcinoma model by inducing apoptosis and inhibiting angiogenesis. Anal. Cell. Pathol. 2019, 2019, 3815786. [Google Scholar] [CrossRef]
  30. Wang, J.; Tian, L.; Khan, M.N.; Zhang, L.; Chen, Q.; Zhao, Y.; Yan, Q.; Fu, L.; Liu, J. Ginsenoside Rg3 sensitizes hypoxic lung cancer cells to cisplatin via blocking of NF-κB mediated epithelial–mesenchymal transition and stemness. Cancer Lett. 2018, 415, 73–85. [Google Scholar] [CrossRef]
  31. Hong, S.; Cai, W.; Huang, Z.; Wang, Y.; Mi, X.; Huang, Y.; Lin, Z.; Chen, X. Ginsenoside Rg3 enhances the anticancer effect of 5-FU in colon cancer cells via the PI3K/Akt pathway. Oncol. Rep. 2020, 44, 1333–1342. [Google Scholar] [CrossRef]
  32. Mochizuki, M.; Yoo, Y.; Matsuzawa, K.; Sato, K.; Saiki, I.; Tonooka, S.; Samukawa, K.; Azuma, I. Inhibitory effect of tumor metastasis in mice by saponins, ginsenoside-Rb2, 20 (R)-and 20 (S)-ginsenoside-Rg3, of red ginseng. Biol. Pharm. Bull. 1995, 18, 1197–1202. [Google Scholar] [CrossRef]
  33. Iishi, H.; Tatsuta, M.; Baba, M.; Uehara, H.; Nakaizumi, A.; Shinkai, K.; Akedo, H.; Funai, H.; Ishiguro, S.; Kitagawa, I. Inhibition by ginsenoside Rg3 of bombesin-enhanced peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane in Wistar rats. Clin. Exp. Metastasis 1997, 15, 603–611. [Google Scholar] [CrossRef] [PubMed]
  34. Xu, T.M.; Cui, M.H.; Xin, Y.; Gu, L.P.; Jiang, X.; Su, M.M.; Wang, D.D.; Wang, W.J. Inhibitory effect of ginsenoside Rg3 on ovarian cancer metastasis. Chin. Med. J. 2008, 121, 1394–1397. [Google Scholar] [CrossRef] [PubMed]
  35. Tang, Y.C.; Zhang, Y.; Zhou, J.; Zhi, Q.; Wu, M.Y.; Gong, F.R.; Shen, M.; Liu, L.; Tao, M.; Shen, B.; et al. Ginsenoside Rg3 targets cancer stem cells and tumor angiogenesis to inhibit colorectal cancer progression in vivo. Int. J. Oncol. 2018, 52, 127–138. [Google Scholar] [CrossRef] [PubMed]
  36. 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. [Google Scholar] [CrossRef]
  37. Meng, L.; Ji, R.; Dong, X.; Xu, X.; Xin, Y.; Jiang, X. Antitumor activity of ginsenoside Rg3 in melanoma through downregulation of the ERK and Akt pathways. Int. J. Oncol. 2019, 54, 2069–2079. [Google Scholar] [CrossRef]
  38. Phi, L.T.H.; Wijaya, Y.T.; Sari, I.N.; Kim, K.S.; Yang, Y.G.; Lee, M.W.; Kwon, H.Y. 20 (R)-Ginsenoside Rg3 influences cancer stem cell properties and the epithelial-mesenchymal transition in colorectal cancer via the SNAIL signaling axis. OncoTargets Ther. 2019, 12, 10885. [Google Scholar] [CrossRef] [PubMed]
  39. Ren, Z.; Chen, X.; Hong, L.; Zhao, X.; Cui, G.; Li, A.; Liu, Y.; Zhou, L.; Sun, R.; Shen, S.; et al. Nanoparticle conjugation of ginsenoside Rg3 inhibits hepatocellular carcinoma development and metastasis. Small 2020, 16, 1905233. [Google Scholar] [CrossRef] [PubMed]
  40. Kim, Y.J.; Choi, W.I.; Jeon, B.N.; Choi, K.C.; Kim, K.; Kim, T.J.; Ham, J.; Jang, H.J.; Kang, K.S.; Ko, H. Stereospecific effects of ginsenoside 20-Rg3 inhibits TGF-β1-induced epithelial–mesenchymal transition and suppresses lung cancer migration, invasion and anoikis resistance. Toxicology 2014, 322, 23–33. [Google Scholar] [CrossRef]
  41. Lee, S.G.; Kang, Y.J.; Nam, J.O. Anti-metastasis effects of ginsenoside Rg3 in B16F10 cells. J. Microbiol. Biotechnol. 2015, 25, 1997–2006. [Google Scholar] [CrossRef]
  42. Tian, L.; Shen, D.; Li, X.; Shan, X.; Wang, X.; Yan, Q.; Liu, J. Ginsenoside Rg3 inhibits epithelial-mesenchymal transition (EMT) and invasion of lung cancer by down-regulating FUT4. Oncotarget 2016, 7, 1619. [Google Scholar] [CrossRef] [PubMed]
  43. Wang, D.; Wu, C.; Liu, D.; Zhang, L.; Long, G.; Hu, G.; Sun, W. Ginsenoside Rg3 inhibits migration and invasion of nasopharyngeal carcinoma cells and suppresses epithelial mesenchymal transition. BioMed Res. Int. 2019, 2019, 8407683. [Google Scholar] [CrossRef]
  44. Sun, M.Y.; Song, Y.N.; Zhang, M.; Zhang, C.Y.; Zhang, L.J.; Zhang, H. Ginsenoside Rg3 inhibits the migration and invasion of liver cancer cells by increasing the protein expression of ARHGAP9. Oncol. Lett. 2019, 17, 965–973. [Google Scholar] [CrossRef] [PubMed]
  45. Mao, X.; Jin, Y.; Feng, T.; Wang, H.; Liu, D.; Zhou, Z.; Yan, Q.; Yang, H.; Yang, J.; Ye, Y.; et al. Ginsenoside Rg3 Inhibits the growth of osteosarcoma and attenuates metastasis through the Wnt/β-Catenin and EMT signaling pathway. Evid.-Based Complement. Altern. Med. 2020, 2020, 6065124. [Google Scholar] [CrossRef] [PubMed]
  46. Shibata, S.; Tanaka, O.; Ando, T.; Sado, M.; Tsushima, S.; Ohsawa, T. Chemical studies on oriental plant drugs. XIV. Protopanaxadiol, a genuine sapogenin of ginseng saponins. Chem. Pharm. Bull. 1966, 14, 595–600. [Google Scholar] [CrossRef]
  47. Lee, M.S.; Yang, E.J.; Kim, J.I.; Ernst, E. Ginseng for cognitive function in Alzheimer’s disease: A systematic review. J. Alzheimer’s Dis. 2009, 18, 339–344. [Google Scholar] [CrossRef]
  48. Lee, C.H.; Kim, J.H. A review on the medicinal potentials of ginseng and ginsenosides on cardiovascular diseases. J. Ginseng Res. 2014, 38, 161–166. [Google Scholar] [CrossRef] [PubMed]
  49. Li, Z.; Ji, G.E. Ginseng and obesity. J. Ginseng Res. 2018, 42, 1–8. [Google Scholar] [CrossRef] [PubMed]
  50. Ong, W.Y.; Farooqui, T.; Koh, H.L.; Farooqui, A.A.; Ling, E.A. Protective effects of ginseng on neurological disorders. Front. Aging Neurosci. 2015, 7, 129. [Google Scholar] [CrossRef] [PubMed]
  51. Lu, J.M.; Yao, Q.; Chen, C. Ginseng compounds: An update on their molecular mechanisms and medical applications. Curr. Vasc. Pharmacol. 2009, 7, 293–302. [Google Scholar] [CrossRef] [PubMed]
  52. Zhang, Q.; Kang, X.; Yang, B.; Wang, J.; Yang, F. Antiangiogenic effect of capecitabine combined with ginsenoside Rg3 on breast cancer in mice. Cancer Biother. Radiopharm. 2008, 23, 647–654. [Google Scholar] [CrossRef] [PubMed]
  53. Joo, E.J.; Chun, J.; Ha, Y.W.; Ko, H.J.; Xu, M.Y.; Kim, Y.S. Novel roles of ginsenoside Rg3 in apoptosis through downregulation of epidermal growth factor receptor. Chem.-Biol. Interact. 2015, 233, 25–34. [Google Scholar] [CrossRef]
  54. Liu, T.; Zhao, L.; Zhang, Y.; Chen, W.; Liu, D.; Hou, H.; Ding, L.; Li, X. Ginsenoside 20 (S)-Rg3 targets HIF-1α to block hypoxia-induced epithelial-mesenchymal transition in ovarian cancer cells. PLoS ONE 2014, 9, e103887. [Google Scholar] [CrossRef]
  55. Huang, J.; Sun, Y.; Fan, Q.; Zhang, Y. Efficacy of Shenyi Capsule combined with gemcitabine plus cisplatin in treatment of advanced esophageal cancer: A randomized controlled trial. Zhong Xi Yi Jie He Xue Bao J. Chin. Integr. Med. 2009, 7, 1047–1051. [Google Scholar] [CrossRef]
  56. Chen, Z.J.; Cheng, J.; Huang, Y.P.; Han, S.L.; Liu, N.X.; Zhu, G.B.; Yao, J.G. Effect of adjuvant chemotherapy of ginsenoside Rg3 combined with mitomycin C and tegafur in advanced gastric cancer. Zhonghua Wei Chang. Wai Ke Za Zhi Chin. J. Gastrointest. Surg. 2007, 10, 64–66. [Google Scholar]
  57. Zhang, Y.; Wang, X.Q.; Liu, H.; Liu, J.; Hou, W.; Lin, H.S. A multicenter, large-sample, randomized clinical trial on improving the median survival time of advanced non-small cell lung cancer by combination of Ginseng Rg3 and chemotherapy. Zhonghua Zhong Liu Za Zhi Chin. J. Oncol. 2018, 40, 295–299. [Google Scholar]
  58. Hu, S.S.; Zhou, L.K.; Ba, Y.; Li, H.L.; Zhu, C.H. A meta-analysis of Ginsenoside Rg3 for non-small cell lung cancer. Clin. Oncol. Cancer Res. 2011, 8, 175–180. [Google Scholar] [CrossRef]
  59. Liu, T.; Duo, L.; Duan, P. Ginsenoside Rg3 sensitizes colorectal cancer to radiotherapy through downregulation of proliferative and angiogenic biomarkers. Evid.-Based Complement. Altern. Med. 2018, 2018, 1580427. [Google Scholar] [CrossRef] [PubMed]
  60. Zeng, D.X.; Bi, Y.Z.; Sheng, G.F.; Dong, Y.Z.; Song, H.L. Effectiveness and safety of single-agent ginsenoside Rg3 maintenance therapy after response to first-line chemotherapy in patients with advanced non-small cell lung cancer. Oncol. Prog. 2013, 11, 554–558. [Google Scholar]
  61. Pan, L.; Zhang, T.; Sun, H.; Liu, G. Ginsenoside Rg3 (Shenyi capsule) combined with chemotherapy for digestive system cancer in China: A meta-analysis and systematic review. Evid.-Based Complement. Altern. Med. 2019, 2019, 2417418. [Google Scholar] [CrossRef]
  62. Obenauf, A.C.; Massagué, J. Surviving at a distance: Organ-specific metastasis. Trends Cancer 2015, 1, 76–91. [Google Scholar] [CrossRef] [PubMed]
  63. Romano, G.; Chagani, S.; Kwong, L.N. The path to metastatic mouse models of colorectal cancer. Oncogene 2018, 37, 2481–2489. [Google Scholar] [CrossRef] [PubMed]
  64. Reya, T.; Morrison, S.J.; Clarke, M.F.; Weissman, I.L. Stem cells, cancer, and cancer stem cells. Nature 2001, 414, 105–111. [Google Scholar] [CrossRef] [PubMed]
  65. Visvader, J.E.; Lindeman, G.J. Cancer stem cells: Current status and evolving complexities. Cell Stem Cell 2012, 10, 717–728. [Google Scholar] [CrossRef] [PubMed]
  66. Kalluri, R.; Weinberg, R.A. The basics of epithelial-mesenchymal transition. J. Clin. Investig. 2009, 119, 1420–1428. [Google Scholar] [CrossRef]
  67. Moss LA, S.; Jensen-Taubman, S.; Stetler-Stevenson, W.G. Matrix metalloproteinases: Changing roles in tumor progression and metastasis. Am. J. Pathol. 2012, 181, 1895–1899. [Google Scholar] [CrossRef]
  68. Foda, H.D.; Zucker, S. Matrix metalloproteinases in cancer invasion, metastasis and angiogenesis. Drug Discov. Today 2001, 6, 478–482. [Google Scholar] [CrossRef]
  69. Ferrara, N. VEGF: An update on biological and therapeutic aspects. Curr. Opin. Biotechnol. 2000, 11, 617–624. [Google Scholar] [CrossRef]
  70. Sun, H.Y.; Lee, J.H.; Han, Y.S.; Yoon, Y.M.; Yun, C.W.; Kim, J.H.; Song, Y.S.; Lee, S.H. Pivotal roles of ginsenoside Rg3 in tumor apoptosis through regulation of reactive oxygen species. Anticancer Res. 2016, 36, 4647–4654. [Google Scholar] [CrossRef]
  71. Wei, X.; Su, F.; Su, X.; Hu, T.; Hu, S. Stereospecific antioxidant effects of ginsenoside Rg3 on oxidative stress induced by cyclophosphamide in mice. Fitoterapia 2012, 83, 636–642. [Google Scholar] [CrossRef]
  72. Lee, I.S.; Uh, I.; Kim, K.S.; Kim, K.H.; Park, J.; Kim, Y.; Jung, J.H.; Jung, H.J.; Jang, H.J. Anti-inflammatory effects of ginsenoside Rg3 via NF-κB pathway in A549 cells and human asthmatic lung tissue. J. Immunol. Res. 2016, 2016, 7521601. [Google Scholar] [CrossRef]
  73. Shin, Y.M.; Jung, H.J.; Choi, W.Y.; Lim, C.J. Antioxidative, anti-inflammatory, and matrix metalloproteinase inhibitory activities of 20 (S)-ginsenoside Rg3 in cultured mammalian cell lines. Mol. Biol. Rep. 2013, 40, 269–279. [Google Scholar] [CrossRef] [PubMed]
  74. Kang, L.J.; Choi, Y.J.; Lee, S.G. Stimulation of TRAF6/TAK1 degradation and inhibition of JNK/AP-1 signalling by ginsenoside Rg3 attenuates hepatitis B virus replication. Int. J. Biochem. Cell Biol. 2013, 45, 2612–2621. [Google Scholar] [CrossRef]
  75. Kim, J.C.; Jeon, J.Y.; Yang, W.S.; Kim, C.H.; Eom, D.W. Combined amelioration of ginsenoside (Rg1, Rb1, and Rg3)-enriched korean red ginseng and probiotic lactobacillus on non-alcoholic fatty liver disease. Curr. Pharm. Biotechnol. 2019, 20, 222–231. [Google Scholar] [CrossRef] [PubMed]
  76. Suh, S.O.; Kroh, M.; Kim, N.R.; Joh, Y.G.; Cho, M.Y. Effects of red ginseng upon postoperative immunity and survival in patients with stage III gastric cancer. Am. J. Chin. Med. 2002, 30, 483–494. [Google Scholar] [CrossRef] [PubMed]
  77. Kitagawa, I.; Yoshikawa, M.; Yoshihara, M.; Hayashi, T.; Taniyama, T. Chemical studies of crude drugs (1). Constituents of Ginseng radix rubra. Yakugaku Zasshi 1983, 103, 612–622. [Google Scholar] [PubMed]
  78. Kim, J.M.; Seo, K.S.; Jeong, Y.K.; Lee, H.B.; Kim, Y.S.; Khang, G. Co-effect of aqueous solubility of drugs and glycolide monomer on in vitro release rates from poly (D, L-lactide-co-glycolide) discs and polymer degradation. J. Biomater. Sci. Polym. Ed. 2005, 16, 991–1007. [Google Scholar] [CrossRef]
  79. Li, C.; Wang, Z.; Li, G.; Wang, Z.; Yang, J.; Li, Y.; Gao, Y.; Jin, H.; Qiao, J.; Wang, H.; et al. Acute and repeated dose 26-week oral toxicity study of 20 (S)-ginsenoside Rg3 in Kunming mice and Sprague–Dawley rats. J. Ginseng Res. 2020, 44, 222–228. [Google Scholar] [CrossRef]
  80. Li, Y.; Wang, Y.; Niu, K.; Chen, X.; Xia, L.; Lu, D.; Kong, R.; Chen, Z.; Duan, Y.; Sun, J. Clinical benefit from EGFR-TKI plus ginsenoside Rg3 in patients with advanced non-small cell lung cancer harboring EGFR active mutation. Oncotarget 2016, 7, 70535. [Google Scholar] [CrossRef]
  81. Zhou, B.; Yan, Z.; Liu, R.; Shi, P.; Qian, S.; Qu, X.; Zhu, L.; Zhang, W.; Wang, J. Prospective study of transcatheter arterial chemoembolization (TACE) with ginsenoside Rg3 versus TACE alone for the treatment of patients with advanced hepatocellular carcinoma. Radiology 2016, 280, 630–639. [Google Scholar] [CrossRef]
  82. Cai, Z.; Qian, T.; Wong, R.N.; Jiang, Z.H. Liquid chromatography–electrospray ionization mass spectrometry for metabolism and pharmacokinetic studies of ginsenoside Rg3. Anal Chim Acta X 2003, 492, 283–293. [Google Scholar] [CrossRef]
  83. Qian, T.; Cai, Z.; Wong, R.N.; Mak, N.K.; Jiang, Z.H. In vivo rat metabolism and pharmacokinetic studies of ginsenoside Rg3. J. Chromatogr. B 2005, 816, 223–232. [Google Scholar] [CrossRef] [PubMed]
  84. Xie, H.T.; Wang, G.J.; Sun, J.G.; Tucker, I.; Zhao, X.C.; Xie, Y.Y.; Wang, W.; Jiang, X.L.; Wang, R.; Xu, M.J.; et al. High performance liquid chromatographic—Mass spectrometric determination of ginsenoside Rg3 and its metabolites in rat plasma using solid-phase extraction for pharmacokinetic studies. J. Chromatogr. B 2005, 818, 167–173. [Google Scholar] [CrossRef]
  85. Xie, H.T.; Wang, G.J.; Lv, H.; Sun, J.G.; Wang, R.; Jiang, X.L.; Li, H.; Wang, W.; Huang, C.R.; Xu, M.J. Development of a HPLC-MS assay for ginsenoside Rh2, a new anti-tumor substance from natural product and its pharacokinetic study in dogs. Eur. J. Drug. Metab. Pharmacokinet. 2005, 30, 63–67. [Google Scholar] [CrossRef] [PubMed]
  86. Xu, Q.F.; Fang, X.L.; Chen, D.F. Pharmacokinetics and bioavailability of ginsenoside Rb1 and Rg1 from Panax notoginseng in rats. J. Ethnopharmacol. 2003, 84, 187–192. [Google Scholar] [PubMed]
  87. Peng, M.; Li, X.; Zhang, T.; Ding, Y.; Yi, Y.; Le, J.; Yang, Y.; Chen, X. Stereoselective pharmacokinetic and metabolism studies of 20 (S)-and 20 (R)-ginsenoside Rg3 epimers in rat plasma by liquid chromatography-electrospray ionization mass spectrometry. J. Pharm. Biomed. Anal. 2016, 121, 215–224. [Google Scholar] [CrossRef] [PubMed]
Ijms 23 09077 g001 550
Figure 1. Flow diagram of literature search process.
Figure 1. Flow diagram of literature search process.
Ijms 23 09077 g001
Ijms 23 09077 g002 550
Figure 2. Anti-metastatic actions of ginsenoside Rg3.
Figure 2. Anti-metastatic actions of ginsenoside Rg3.
Ijms 23 09077 g002
Table
Table 1. Characteristics of 14 included studies.
Table 1. Characteristics of 14 included studies.
ItemsIn Vivo + In VitroIn VivoIn VitroTotal
Number of study44614
Number of data84618
Mean Rg3 dose (days)27.0 ± 26.1 mg/kg orally, 4.0 ± 1.0 mg/kg subcutaneously (28 ± 28 days)
Rg3 type *
Rg362210
20(R)-Rg32136
20(S)-Rg30112
NpRg30101
Cancer type (Cell line)
Colorectal cancer41 (AOM induction)05
Melanoma2114
Liver cancer (HCC)01 (DEN induction)12
Lung cancer (NSCLC)0022
Thyroid cancer2002
Nasopharyngeal cancer0011
Osteosarcoma0011
Ovarian cancer0101
Metastatic model
SC injection23 (1 AOM, 1 DEN) 5
Tail vein injection21 3
Target organ *
Lung33 6 *
Liver20 2
Kidney10 1
Peritoneum01 1
Animal
C57BL/6 mouse12 3
BALB/c mouse20 2
Athymic nude mouse01 1
NSG mouse10 1
Wistar rat01 1
Country (N. of studies)
China 8
Korea 4
Japan 2
* Duplicate data from the same study are indicated. NpRg3, Nanoparticle conjugated Rg3; AOM, azoxymethane; HCC, Hepatocellular carcinoma; DEN, Dimethyl nitrosamine; NSCLC, Non-small cell lung cancer; SC, subcutaneous; NSG, NOD scid gamma mouse.
Table
Table 2. Summary of 14 studies on anti-metastatic effects of ginsenoside Rg3.
Table 2. Summary of 14 studies on anti-metastatic effects of ginsenoside Rg3.
Author (Year)Cancer Type
(Cell Line)		Animal (Sex)Metastatic ModelTarget OrganRg3Concentration #/
Administration/Duration		Main OutcomeMechanism of Actions
In vivo
Mochizuki et al. (1995) [32]Melanoma
(B16-BL6)		C57BL/6, FFootpad SC inj.Lung20(R)-Rg3, 20(S)-Rg31.5 mg/kg, PO
14 days		N. of metastatic colonies *Angiogenesis ↓
Iishi et al.
(1997) [33]		Colorectal cancerWistar rat, MSC inj. of AOMPeritoneumRg35.0 mg/kg, SC
100 days		N. of peritoneal metastasisAngiogenesis ↓
Xu et al.
(2008) [34]		Ovarian cancer
(SKOV-3)		Athymic nude mouseTail vain inj.LungRg30.3 mg/kg, SC
20 days		N. of metastatic colonies *
N. of invaded cells *		Angiogenesis ↓
MMP9 ↓
Tang et al.
(2018) [35]		Colorectal cancer
(LoVo, SW620)		BALB/c, FFlank SC inj.LiverRg325.0 mg/kg, PO
12 days		N. of metastatic nodules *Cancer stem cell markers (CD24, CD44, EpCAM) ↓
Angiogenesis ↓
Wu et al.
(2018) [36]		Thyroid cancer
(C643)		BALB/c, FTail vain inj.LungRg310.0 mg/kg, PO
18 days		N. of metastatic nodules *Angiogenesis ↓
Meng et al.
(2019) [37]		Melanoma
(B16)		C57BL/6, MFootpad SC inj.LungRg30.3 mg/kg, SC
28 days		N. of metastatic nodules *Angiogenesis ↓
MMP2 ↓, MMP9 ↓
ERK ↓, AKT ↓, mTOR ↓
Phi et al.
(2019) [38]		Colorectal cancer
(HT29)		NSG mouseTail vain inj.Liver, lung, kidney20(R)-Rg35.0 mg/kg, SC
28 days		N. of metastatic nodules *-
Ren et al.
(2020) [39]		HCCC57BL/6, MSC inj. of DENLungNpRg370.0 mg/kg, PO
5 days		N. of metastatic nodules *-
In vitro
Kim et al.
(2014) [40]		Lung cancer
(A549)		 20(R)-Rg325.0 μg/mLWound-healing migration ability *
N. of migrated/invaded cells *		E-cadherin ↓, Snail ↓
MMP2 ↓
Lee et al.
(2015) [41]		Melanoma
(B16F10)		 Rg325.0 μg/mLWound-healing migration ability *
N. of migrated/invaded cells *		MMP13 ↓
Tian et al.
(2016) [42]		Lung cancer
(A549, H1299, H358)		 20(R)-Rg325.0 μg/mLWound-healing migration ability *
N. of migrated/invaded cells *		MMP2 ↓, MMP9 ↓
E-cadherin ↑, Snail ↓, N-cadherin ↓, Vimentin ↓
Tang et al.
(2018) [35]		Colorectal cancer
(LoVo, SW620, HCT116)		 Rg3200.0 μg/mLWound-healing migration ability *
N. of migrated/invaded cells *		Cancer stem cell markers (CD24, CD44, EpCAM) ↓
Wu et al.
(2018) [36]		Thyroid cancer
(TPC1, BCPAP, C43, Ocut-2c)		 Rg350.0 μg/mLWound-healing migration ability *MMP2 ↓, MMP9 ↓
VEGF-A ↓, VEGF-C ↓
Meng et al.
(2019) [37]		Melanoma
(B16F1)		 Rg35.0 µg/mLWound-healing migration ability *
N. of migrated/invaded cells *		VEGF ↓
ERK ↓, AKT ↓, mTOR ↓
Wang et al.
(2019) [43]		Nasopharyngeal cancer
(HNE1, CNE2)		 20(S)-Rg325.0 µg/mLN. of migrated/invaded cells *MMP2 ↓, MMP9 ↓
E-cadherin ↑, N-cadherin ↓, Vimentin ↓, ZEB1 ↓
Sun et al.
(2019) [44]		Liver cancer
(HepG2, MHCC-97L)		 20(R)-Rg32.5 μg/mLWound-healing migration ability *
N. of migrated/invaded cells *		ARHGAP9 ↑
Phi et al.
(2019) [38]		Colorectal cancer
(HT29, SW620)		 20(R)-Rg310.0 μg/mLN. of migrated/invaded cells *MMP2 ↓
E-cadherin ↓, Snail ↓
EGFR ↓, AKT ↓
Mao et al.
(2020) [45]		Osteosarcoma
(MG63, 143B)		 Rg350.0 μg/mLWound-healing migration ability *
N. of migrated/invaded cells *		MMP2 ↓, MMP7 ↓, MMP9 ↓
N-cadherin ↓, Vimentin ↓
Wnt/β-catenin signaling pathway (β-catenin, c-Myc, Cyclin D1) ↓
AOM, azoxymethane; MMP, Matrix metallopeptidase; FUT4, Fucosyltransferase 4; EpCAM, Epithelial Cell Adhesion Molecule; VEGF, Vascular endothelial growth factor; ERK, extracellular signal-regulated kinase; AKT, Protein kinase B; mTOR, mammalian target of rapamycin; EMT, Epithelial-mesenchymal transition; ZEB1, Zinc Finger E-Box Binding Homeobox 1; ARHGAP9, Rho GTPase Activating Protein 9; EGFR, Epidermal growth factor receptor; NSG, NOD scid gamma; HCC, Hepatocellular carcinoma; DEN, Dimethyl nitrosamine; NpRg3, Nanoparticle conjugated Rg3 # The concentration indicated the lowest concentration showing the positive pharmacological activity. * Statistically significant results are indicated.; ↓: indicate that the mechanism is inhibited by Rg3. ↑: indicate that the mechanism is increased by Rg3.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Oh, H.-M.; Cho, C.-K.; Son, C.-G. Experimental Evidence for the Anti-Metastatic Action of Ginsenoside Rg3: A Systematic Review. Int. J. Mol. Sci. 2022, 23, 9077. https://doi.org/10.3390/ijms23169077

AMA Style

Oh H-M, Cho C-K, Son C-G. Experimental Evidence for the Anti-Metastatic Action of Ginsenoside Rg3: A Systematic Review. International Journal of Molecular Sciences. 2022; 23(16):9077. https://doi.org/10.3390/ijms23169077

Chicago/Turabian Style

Oh, Hyeon-Muk, Chong-Kwan Cho, and Chang-Gue Son. 2022. "Experimental Evidence for the Anti-Metastatic Action of Ginsenoside Rg3: A Systematic Review" International Journal of Molecular Sciences 23, no. 16: 9077. https://doi.org/10.3390/ijms23169077

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop