The Anticancer Activity and Mechanisms of Ginsenosides: An Updated Review

Hongwei Chen; Haixia Yang; Daidi Fan; Jianjun Deng

doi:10.2991/efood.k.200512.001

<Previous Article In Issue

Download article (PDF)

Next Article In Issue>

Volume 1, Issue 3, June 2020, Pages 226 - 241

The Anticancer Activity and Mechanisms of Ginsenosides: An Updated Review

Authors

Hongwei Chen¹^{, 2}^{, 3}, Haixia Yang⁴, Daidi Fan¹^{, 2}^{, 3}, Jianjun Deng¹^{, 2}^{, 3}^{, *}

¹Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, Xi’an 710069, China

²Shaanxi R&D Center of Biomaterials and Fermentation Engineering, School of Chemical Engineering, Northwest University, Xi’an 710069, China

³Biotech & Biomed Research Institute, Northwest University, Xi’an 710069, China

⁴Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA

^*Corresponding author. Email: dengjianjun@nwu.edu.cn

Corresponding Author

Jianjun Deng

Received 7 April 2020, Accepted 11 May 2020, Available Online 22 May 2020.

DOI: 10.2991/efood.k.200512.001 How to use a DOI?
Keywords: Ginseng; ginsenosides; biological activity; cancer therapy; mechanism
Abstract: The annual global mortality rate of cancer has increased dramatically. Although various therapies are used for cancer, the results have not been satisfactory. Chemotherapy is currently the most common treatment option. However, serious side effects and drug resistance impede the therapeutic efficacy of chemotherapeutic drugs. Increasing evidence has shown that ginsenosides as a type of phytochemicals play an important role in the prevention and treatment of cancers, such as colon cancer, cervical cancer, ovarian cancer, breast cancer, lung cancer, pancreatic cancer, bladder cancer, esophageal cancer, and bone cancer. Ginsenosides block a variety of enzymes required for tumor growth, which regulate an array of cell progression, such as nitric oxide synthase activity, protein kinase activity, epidermal growth factor receptor intrinsic kinase activity, and nuclear factor-kappaB activity. Ginsenosides also inhibit lipid peroxidation and the production of reactive oxygen species. Thus, ginsenosides can be used as an adjuvant to conventional cancer therapies to improve efficacy and/or reduce side effects through synergistic activity. In this review, we summarized the latest research advances of the anticancer effects of ginsenosides and their potential mechanisms.
Graphical Abstract
Copyright: © 2020 International Association of Dietetic Nutrition and Safety. Publishing services by Atlantis Press International B.V.
Open Access: This is an open access article distributed under the CC BY-NC 4.0 license (http://creativecommons.org/licenses/by-nc/4.0/).

1. INTRODUCTION

Over the past few decades, researcher has revealed that the occurrence and progression of most human cancers involve certain molecular biology, biochemical, and cell biology principles. However, the occurrence of human cancer is a complicated process. The genetic variation of certain cells and genes drives normal cells to become highly malignant cancer cells [1]. Pathological analysis of a variety of organ tissues seems to reveal an intermediate step, which participates in the gradual evolution of the normal state to an invasive cancerous state through a series of precancerous conditions [2]. Observations of cancer models in humans and animals suggest that tumor progression involves a range of genetic changes, each of which confers one or more growth advantage. Due to the defect of the regulatory loop that maintains normal cell proliferation and homeostasis, resulting in the normal cells gradually transform into cancer cells in the tumor microenvironment.

The development of human tumors usually involves several hallmark biological capabilities: self-sufficiency in growth signals, insensitivity to growth inhibition (anti-growth) signals, a program to circumvent cell death (apoptosis), infinite replication potential, sustained angiogenesis, tissue invasion and metastasis, energy metabolism reprogramming, and the ability to evade immune destruction [3,4]. Together, these changes determine malignant growth. Tumors are not only island-like masses that proliferate cancer cells, but also are complex tissues composed of many different cell types that participate in each other’s heterotypic interactions. As normal cells gradually evolve into tumor states, they acquire the continuity of these iconic abilities. Cancer is the first or second leading cause of death before age 70 in 91 of 172 countries (WHO) [5]. According to the latest statistics from the Global Cancer Observatory in 2018 (http://gco.iarc.fr/today), the proportion of cancers with higher incidence and mortality estimated as shown in Figure 1A, indicating that the incidence of lung cancer, breast cancer, colorectal cancer, pancreas cancer, liver cancer, stomach cancer, and esophagus cancer is 11.6%, 11.6%, 10.2%, 7.1%, 4.7%, 5.7%, and 3.2%, and the corresponding mortality are 6.6%, 18.4%, 9.2%, 4.5%, 8.2%, 8.2%, and 5.3%; among the continents, Asia is hardest hit affected region for cancer with an estimated 8.7 million cases and 0.055 million deaths, followed by Europe, North America, Latin America & Caribbean, and Africa, and Oceania is the least affected (Figure 1B).

Cancer treatment is generally divided into drug therapy and non-drug therapy, of which chemotherapy is an important means of drug therapy. Tumor chemotherapy generally uses chemical drugs called cytotoxic drugs, with high side effect rates that cause very serious damage to normal cells [6,7]. Chemotherapy, surgery, and radiotherapy are the three major treatments for cancer and some cancer patients can achieve clinical cures or long-term survival through chemotherapy. Cisplatin exhibits an anti-lung tumor effect by impairing the structure and function of DNA, and pemetrexed regulates intracellular folate-dependent metabolism and inhibits cancer cell replication and proliferation [8]. Erlotinib inhibits tumor growth by targeting Epidermal Growth Factor (EGFR) to inhibit EGFR and its downstream signaling pathways [9]. However, clinical data indicate that these drugs have limited application at tolerated doses due to their toxic side effects and drug resistance [10]. Although chemotherapy has made great progress in the past few decades, targeted drugs have been developed in recent years. However, side effects and drug resistance have caused the most patients to die from cancer invasion and metastasis, with a 5-year survival rate of <15% [7]. Natural products have become a major resource for the development of anticancer agents due to their biochemical activity. Several plant-derived compounds, such as vinblastine, etoposide, paclitaxel, vinorelbine, and irinotecan, have been approved for clinical anticancer drugs. More than 35,000 plants in different countries are used for medicinal purposes around the world [11]. Almost 80% of the world’s population has primary healthcare that relies on traditional medicine, most of which involve the consumption of plant extracts [11]. Natural products can be used as the main source for screening of the targeted anticancer drugs due to the low toxicity and side effects.

Ginseng (Panax ginseng C.A. Mey) is a valuable oriental Chinese herbal medicine. Because of its effective medicinal activity, it has received increasing attention for the treatment of cardiovascular disease, diabetes, and central nervous system diseases [12–14]. Ginsenoside is an active pharmaceutical ingredient extracted from the traditional Chinese herb ginseng and is widely used for its anticancer [15], apoptosis [16], angiogenesis [17], oxidative stress [18], inflammation [19], and cancer metastasis [20] activities related to cell proliferation. Currently, 40 types of ginsenosides have been identified and most ginsenosides have a dammarane triterpenoid structure [21]. Differences in sugar types, the number of glycosyl groups, and the attachment position provide a diversity of ginsenoside structures. According to the presence of hydroxyl groups at C-6, ginsenosides can be divided into two groups, Protopanaxadiols (PPD) (including Rb1, Rd, Rh2, Rg3, Rg5, and Rk1) and Protopanaxatriols (PPT) (including Rg1, Rh1, RK3, and Rh4) [21]. Studies have shown that the steaming process results in the conversion of large amounts of ginsenosides in ginseng to new degradants, including Rh3, Rk3, Rh4, Rk1, Rk2, and Rg5 (Table 1), which are rare ginsenosides with significant chemo-preventive effects [22].

Ginsenoside	R1	R2	R3
20(S)-Rg3	glc(2-1)glc	OH	CH₃
20(R)-Rg3	glc(2-1)glc	CH₃	OH
Rb1	glc(2-1)glc	Oglc(6-1)glc	CH₃
Rb2	glc(2-1)glc	Oglc(6-1)arap	CH₃
Rh2	glc	CH₃	OH
Rc	glc(2-1)glc	Oglc(6-1)araf	CH₃
Rd	glc(2-1)glc	Oglc	CH₃
Compound K	H	Oglc	CH₃
PPD	H	OH	CH₃
Rg1	glc	Oglc	CH₃
Rg2	glc(2-1)rha	OH	CH₃
20(S)-Rh1	glc	OH	CH₃
20(R)-Rh1	glc	CH₃	OH
Re	glc(2-1)rha	Oglc	CH₃
Rf	glc(2-1)glc	OH	CH₃
F1	H	Oglc	CH₃
PPT	H	OH	CH₃
Rk3	H	Oglc	—
Rk1	glc(2-1)glc	H	—
Rk2	glc	H	—
Rh4	H	Oglc	—
Rg5	glc(2-1)glc	H	—
Rh3	glc	H	—

Glc, β-d-glucose; rha, α-l-rhamnose; arap, α-l-arabinose (pyranose); araf, α-l-arabinose (furanose).

Table 1

Structures of protopanaxadiols (PPD), protopanaxatriols (PPT), and rare ginsenosides

To systematically clarify the anticancer activity and mechanisms of ginsenosides, scientists have done many in-depth studies using in vivo and in vitro models over the past few decades. A comprehensive review [23] indicated that ginsenosides are a special molecule in many other naturally occurring cancer therapy compounds. The pleiotropic nature of sapogenin allows it to target the genome (DNA), messengers (RNA), and enzymes (protein) within the cell. Unlike other chemotherapeutic drugs, ginsenosides are pleiotropic and involve in Nuclear Factor-kappaB (NF-κB), Transcription Factor (TF), Activated Protein-1 (AP-1), tumor protein 53 (p53), and cell–cell adhesion molecules, Mitogen-activated Protein Kinase (MAPK), and nuclear β-catenin signaling. In this report, the available literature for the past 10 years was reviewed and discussed to facilitate further research of ginsenosides in cancer.

2. ANTICANCER ACTIVITY AND MECHANISMS

2.1. Breast Cancer

Globally, metastatic breast cancer is the most common cause of female death in recent years and one of the most common malignant tumors [24]. Chemotherapy, hormonal therapy, radiation therapy, and limited or radical surgery are treatments used for breast cancer. The surgical treatment of breast cancer includes Breast-conserving Surgery (BCS) or mastectomy [25]. Local tumors are treated with radiation therapy after BCS, with total long-term patient survival similar to that achieved by mastectomy. Rh2 inhibits the growth of MCF-7 breast cancer cells by inducing the expression of cyclin p21 and decreasing the level of cyclin D3, leading to the up-regulation of Cyclin-dependent Kinase (Cdk) inhibitor p21WAF1/CIP1, which reduces the binding of phosphorylated retinoblastoma protein and transcription factor E2F-1 [26]. In addition, p15 INK4B and p27 KIP1-dependent kinase activities are overexpressed in breast cancer cells and Rh2 regulatory kinase activity induces the cell cycle arrest of breast cancer cell lines in the G1 phase, lowering the viability of MCF-7 and MDA-MB-231 breast cancer cells [27]. Rg3 inhibits NF-κB signaling by regulation of Bax/Bcl-2 expression in triple negative breast cancer (TNBC) and promotes cytotoxicity and the apoptosis of TNBC cells and xenografts in response to treatment with paclitaxel [28]. Apoptosis is thought to be the primary mechanism by which chemotherapeutic agents kill cells. It is a highly conserved form of programmed cell death that regulates tissue homeostasis and/or eliminates damaged and infected cells. There are two major apoptotic pathways, the extrinsic pathway mediated by death receptors and the mitochondria-mediated intrinsic pathway [29]. In the MDA-MB-231 cell line, Rg3 suppresses the phosphorylation of Extracellular Signal-regulated Kinase (ERK) and protein kinase B (Akt), thereby preventing the activation of NF-κB to cause apoptosis [30]. Our group found that Rk1 induces cell cycle arrest and apoptosis in MDA-MB-231 triple negative breast cancer cells by regulation of ROS/PI3K/Akt signaling pathway [31]. The distant colonization of tumor cell metastasis is responsible for 90% of human cancer deaths [32]. C-X-C motif chemokine receptor 4 (CXCR4) is an important molecule for cancer migration and homing to the docking region. Rg3 treatment significantly inhibits the CXCR4 expression in MDA-MB-231 cells and reduces the number of migrating cells, causing chemotaxis and reducing the width of scars in wound healing [33]. Cancer stem cells retain self-renewal properties, which are responsible for cancer recurrence and resistance to anticancer therapies. Rg3 attenuated the expression of Sox-2 and Bmi-1 by inhibiting the nuclear localization of hypoxia-inducible factor-1α in MCF-7 mammary globules and blocked Akt-mediated self-renewal signaling to inhibit the specificity of breast cancer stem cells [34]. Mouse double minute 2 homolog (MDM2) oncogene is a negative regulator of p53 with a self-regulating loop between p53 and MDM2, which is amplified and overexpressed in various human cancers [35,36]. 25-OCH₃-PPD suppresses cell migration and the expression of MDM2 and Epithelial–mesenchymal Transition (EMT) markers by inducing apoptosis and G1 blockade in vitro, leading to the inhibition of breast tumor growth xenografts in vivo [37]. Treatment of breast cancer MCF-7 cells with Rg5 stimulates cell apoptosis and cell cycle arrest at G0/G1 phase by up-regulation of p53, p21WAF1/CIP1, and p15INK4B expression, and down-regulation of cyclin D1, cyclin E2, and cyclin dependent kinases (CDK4) expression [38]. Our recent study showed that Rg5 induced apoptosis and autophagy by inhibition of PI3K/Akt signaling pathway against breast cancer in vivo, the tumor growth inhibition rate of high dose Rg5 (20 mg/kg) was 71.4 ± 9.4%, similar to the positive control docetaxel (72.0 ± 9.1%) [39]. The three major anti-breast cancer pathways of ginsenosides were summarized as shown in Figure 2.

2.2. Colorectal Cancer

Colorectal Cancer (CRC) is a digestive system disease with high morbidity and mortality [40] and is the third most diagnosed cancer and the fourth most deadly cancer in the world [41]. It is reported that Rh2 stimulates apoptosis by activating the tumor suppressor factor p53 and inducing the proapoptotic regulator Bax in colorectal cancer cells. [42] The activation of transcriptional activator 3 (STAT3) is a major factor in the development of colon cancer, Interleukin-6 (IL-6) is a well-known and thoroughly studied cytokine in tumor-associated STAT3 signaling [43]. Rh2 effectively inhibits IL-6 induced signal transduction, STAT3 phosphorylation, and the expression of Matrix Metalloproteinases (MMPs), including MMP-1, -2, and -9, further prevents the invasion of cancer cells and enhances the sensitization of CRC cells to doxorubicin treatment [44]. Rg3 exhibits anti-angiogenic activity by reducing the incidence of peritoneal metastasis of intestinal adenocarcinoma induced by oxidized azomethane [45,46]. Rg3 is considered to be an effective adjuvant for the clinical treatment of colorectal cancer because it can inhibit the HCT116 cells growth by blocking the nuclear transport of β-catenin and decreasing the transcriptional activity of β-catenin/Tcf [46]. Additionally, combination of Rg3 and 5-fluorouracil down-regulates MMP levels to reduce the invasion of colon cancer SW480 cells, which may be because Rg3 enhances the cytotoxicity of 5-fluorouracil and oxaliplatin in xenografts [47]. The ginsenoside compound K (CK) is a gut microbial metabolite of Rb1 and a major component of American ginseng. CK exhibits significant anti-proliferative effects in HCT-116 and SW-480 cells at concentrations of 30–50 μM [48]. CK activates the expression of caspase-8 and -9 in HCT-116 and SW-480 cells and docking data indicates that CK forms hydrogen bonds with Lys253, Thr904, and Gly362 in caspase-8, as well as Thr62, Ser63, and Arg207 in caspase-9 arrested the progress of division and induces apoptosis [48]. Our group study found that Rh4 exhibits high anti-colorectal cancer activity with low toxicity and few side effects, and stimulates apoptosis and autophagic cell death via activation of the ROS/JNK/p53 pathway to inhibit the colorectal tumor growth [49]. EMT plays an important role in the migration, invasion, and metastasis of many types of cancer including CRC [50]. Rb2 binds to the hydrophobic pocket of Transforming Growth Factor (TGF-β1), which partially overlaps with the binding site on TGF-β1, thereby disrupting TGF-β1 dimerization and inhibiting the expression of Smad4 and Smad2/3 phosphorylation. Therefore, the TGF-β1/Smad/EMT signaling pathway may become a potential target for the treatment of colorectal cancer [51]. O-β-d-glucopyranosyl-20(S)-protopanaxadiol, a metabolite of ginsenoside, reduces cell viability, stimulates cytoplasmic Ca²⁺ and annexin-V positive early apoptosis, and induces G1-phase aggregation and concentration of colon cancer cells in CT-26 mice in vitro, leading to inhibition of tumor growth in vivo [52]. The detailed information for the anti-colorectal cancer mechanism of ginsenosides is shown in Figure 3.

2.3. Ovarian Cancer

Ovarian cancer, cervical cancer, and breast cancer are known as the three major killers of female cancer [53]. According to 2018 statistics, ovarian cancer accounts for 4.4% of all female deaths from cancer [54], and the mortality is increasing year-by-year. Rg3 can significantly inhibit the metastasis of ovarian cancer [55,56], one potential reason is that Rg3 partially inhibits the tumor-induced angiogenesis, and decreases the invasive ability and MMP-9 expression of SKOV-3 cells [57]. 20(R)-Rg3 and 20(S)-Rg3 are stereoisomer formed by different orientations of OH groups on C-20, previous study indicated that 20(S)-Rg3 can inhibit the glycolysis of ovarian cancer cells by regulating Hexokinase 2 (HK2) and Pyruvate Kinase M2 (PKM2) by reducing the hypoxia-inducible factor-1α expression and activating the proteasome pathway [58]. 20(S)-Rg3 also inhibits EMT in ovarian cancer cells, thereby inhibiting cancer progression in vitro and in vivo via targeting the DNMT3A/miR-145/FSCN1 pathway [55,59], and inhibits the Warburg effect in ovarian cancer cells via regulation of H19/miR-324-5p/PKM2 pathway [56]. Rb1 is a potential therapeutic candidate for the treatment of ovarian cancer because it can reverse hypoxia-induced EMT by eliminating the inhibition of EP300 and E-cadherin miR-25 [60]. Cancer Stem Cells (CSCs) represents a subpopulation with self-renewal and differentiation capabilities that make these cells therapeutically tolerant. Rb1 and its metabolite CK specifically target the formation and expansion of CSCs, which can induce synergistic cytotoxicity by enhancing chemo-sensitivity to the clinical anticancer drugs cisplatin and paclitaxel, then inhibit cancer cell growth through Wnt/β-catenin signaling and EMT regulation [61,62]. Treatment of ovarian cancer SKOV3 cells with Rh2 significantly induces apoptosis by promoting the expression of lysed Poly-ADP Ribose Polymerase (PARP) and cleaved caspase-3, leading to inhibition of SKOV3 cells growth and its migrating invasive ability [63].

2.4. Gastric Cancer

Gastric cancer is the most commonly diagnosed digestive tract cancer with a high recurrence rate, high metastasis rate, and resistance to chemotherapeutic drugs [64]. Rg3 can induce apoptosis by activation of caspase-3, -8, and -9 in the human gastric cancer cell AGS by increasing the number of cells in the sub-G1 phase, caspase-3 activity, and the degree of PARP cleavage of the caspase-3 substrate [65]. The triol type triterpene glycoside Re can be converted into less polar ginsenosides, namely Rg2, Rg6, and F4, by heat treatment, which can activate the expression of caspase-3, -8, -9 and the cleaved PARP in AGS cells in a dose-dependent manner, further inhibits the phosphorylation of CDK2 at Thr160 by up-regulating p21 levels against the gastric cancer cells growth [66]. Helicobacter pylori CagA promotes the proliferation of gastric cancer cells through the overexpression of Fucosyltransferase (FUT4) in cells, tissues, and blood samples of gastric cancer patients [66]. Rg3 significantly induces FUT4-mediated apoptosis by activation of caspase-3, -8, and -9 and PARP expression in Helicobacter pylori CagA-treated gastric cancer cells through inhibition of FUT4 expression by up-regulation of Specific Protein 1 (SP1) and down-regulation of Heat Shock Factor protein 1 (HSF1) [67]. Rg3 can inhibit cell proliferation increase, migration, and invasion in TGF-β1 induced gastric cancer SNU-601 cell line by increased the expression of the epithelial marker E-cadherin, and repressed the expression of the mesenchymal marker Vimentin [68]. Rh2 can significantly induce apoptosis by up-regulation of Bax and down-regulation of Bcl-2 in a dose-dependent manner in human gastric cancer SGC7901 cells [69]. F2 treatment suppresses the SGC7901 growth by activation of p53 signaling pathway and the Bcl-xl/Beclin-1 pathway through up-regulation of some related protein expression such as Atg5, Atg7, Atg10, and PUMA, Bcl-xl, Beclin-1, UVRAG, and AMBRA-1, indicating that F2 can be used as a potential natural product for anti-gastric cancer [70].

2.5. Liver Cancer

Primary liver cancer is one of the most aggressive tumor types [71]. Early primary liver cancer is mainly treated by surgery (resection or transplantation), but the systemic metastasis of cancer and the prognosis of patients after relapse are poor [72]. Hepatocellular Carcinoma (HCC) is one of the most common forms of liver cancer and has a very poor prognosis. Sorafenib is the only drug approved by the U.S. Food and Drug Administration for the treatment of advanced HCC. However, this drug does not delay the progression of the symptoms of the disease and the monthly treatment cost is about 5400 US$ [73], also associated with serious side effects including the significant risk of bleeding [74]. More and more researches have indicated that natural product with low toxic side effects has become the focus for liver cancer treatment or prevention. Rho GTPase activating protein 9 (ARHGAP9) is closely related to tumor metastasis [75], inhibition of ARHGAP9 protein expression by Rg3 can significantly suppress the migration and invasion of human hepatoma cells HepG2 and MHCC-97L in vitro, and prevent the growth of HepG2 and MHCC-97L tumors in BABL/c nude mice in vivo [76]. Rg3 also can effectively inhibit cell proliferation and promote cell apoptosis through activation of endogenous mitochondria-mediated caspase-dependent apoptosis pathway in SMMC-7721 and HepG2 cells [77]. Previous studies have shown that Rh2 induced HepG2 cells apoptosis by activating the ROS-mediated lysosomal-mitochondrial apoptosis pathway [78]. The inhibitory effect of Rh2 on the migration ability of HepG2 cells is achieved by recruiting histone deacetylase, which leads to the inhibition of AP-1 transcription factors [79]. The treatment of HCC cells with Short Hairpin small interfering RNA (shRNA) that expresses Atg7 completely abolished the effect of Rh2 on β-catenin and cell viability, whereas β-catenin overexpression eliminated the effects of Rh2 on autophagy and cell viability [80]. In the canonical Wnt pathway, the binding of a Wnt protein ligand to a Frizzled family receptor activates β-catenin, whose nuclear translocation and retention lead to the regulation of gene transcription [81]. Rh2 increases autophagy and inhibits β-catenin signaling by inhibiting HCC cells growth [82]. In the Alcoholic Liver Disease (ALD) mice model, our recent study found that Rk3 significantly reduced AST and ALT levels in serum, reduced oxidative stress, restored the liver tissue antioxidant balance, and significantly reduced mice expression of inflammatory cytokines such as NF-κB, TNF-α, IL-6, and IL-1β [83]. The potential mechanisms of ginsenosides resistance to liver cancer are summarized in Figure 4.

2.6. Lung Cancer

Lung cancer is the leading cause of cancer-related death worldwide and Lung Adenocarcinoma (LUAD). Despite the recent development of targeted therapies for some of the genetic subtypes of human LUAD, the overall survival rate of this cancer remains very low [84]. As mucosal tissue with the largest surface area in the body, the lungs inhale various airborne microbes and environmental contaminants. The development of lung cancer is closely related to chronic inflammation, which is characterized by the infiltration of inflammatory cells and the accumulation of pro-inflammatory factors, including cytokines, chemokines, and prostaglandins, that stimulate cell proliferation, angiogenesis, tissue remodeling, and metastasis [85]. The survival rate of PPT-treated SK-MES-1 cells is reduced to 66.8% and the therapeutic effect is close to that of cisplatin-treated lung cancer [86]. 20(R)-Rg3 epimer inhibits the EMT of lung adenocarcinoma by increasing the expression of E-cadherin and inhibiting the expression of vimentin and up-regulation of snail [87]. Rg3 also can inhibit the EMT and invasion of lung cancer by down-regulating FUT4-mediated EGFR inactivation and blocking the MAPK/NF-κB signaling pathway [88]. Rg3 can stimulate NF-κB expression by regulation of transcription factors including Cyclooxygenase-2 (COX2), MMP-9, VEGF, c-Myc, and cyclin D1 to make lung cancer tumors sensitive to radiation and stimulate apoptosis [89]. Rg3 can effectively inhibit the volume and weight of tumors in xenograft models and inducing apoptosis by inhibiting the PI3K/Akt signaling pathway [90]. Administration of Rg3 to lung cancer mice can improve the immune-regulation activities by increasing spleen cell proliferation [91]. Our previous research demonstrated that Rg3 treatment reduced the expression of cyclin D1 and CDK4 in Non-small Cell Lung Cancer Cells (NSCLC), up-regulated the expression of P21, inhibited cell proliferation and colony formation, and induced cell cycle arrest in G1 phase [89]. Rh2 prevents mitochondrial-dependent pathways by inducing ROS-mediated Endoplasmic Reticulum (ER) stress, thereby stimulating cisplatin resistance in NSCLC A549/DDP cells [92], it can also significantly induce apoptosis in A549 cells [93]. Mitomycin C (MMC) is an anticancer agent that causes intrachain DNA cross-linking and blocks DNA processes in transcription and replication levels [94]. It is reported that Total Ginsenoside extract (TGS) is a novel adjuvant anticancer compound, and combined treatment with TGS and MMC can effectively enhance the cytotoxicity of MMC against NSCLC in vitro and in vivo [95]. The potential mechanisms of anti-lung cancer are summarized in Figure 5.

2.7. Prostate Cancer

Prostate cancer is the second most commonly diagnosed cancer and the sixth leading cause of cancer death among men worldwide, with an estimated 1,276,000 new cancer cases and 359,000 deaths in 2018 [5]. Based on prostate-specific antigen screening and surgery for the diagnosis of latent cancer of benign prostatic hyperplasia [96], the diagnosis rate has decreased significantly in recent years, these declines are limited to early disease, while the incidence of late disease increases. At present, the clinical treatment of prostate cancer is radical local treatment plus/minus systemic treatment. Among patients receiving systemic treatment, the first choice is androgen deprivation therapy [97], but its side effects are large, so natural products need to be explored for treatment of prostate cancer. Rg3 (50 μM) combined with the conventional drug docetaxel (5 nM), or with cisplatin (10 μM) and doxorubicin (2 μM) inhibits prostate cancer cell growth and induces apoptosis by suppression of NF-κB activity and up-regulation of Apoptosis Inhibitory Protein (IAP-1), X chromosome IAP, and NF-κB targeted genes expression including Bax, caspase-3, and -9, and inhibited Bcl-2 [98]. Rg3 can effectively suppress migration of prostate cancer cells (PC-3M) by down-regulating AQP1 expression through activation of p38 MAPK pathway and some transcription factors acting on the AQP1 promoter [99]. The EC₅₀s of Rg3 and Rh2 against the prostate cancer PC-3M cells were 8.4 and 5.5 μM, respectively, and those of LNCaP cells were 14.1 and 4.4 μM, respectively [100]. Both Rg3 and Rh2 induced apoptosis and regulated three MAP kinase activity modules in LNCaP and PC3M cells to inhibit the proliferation of prostate cancer cells [100]. PC-3M cells treated with processed ginseng (MG) showed the highest activity with a half-maximal inhibitory concentration of 48 μg/mL, which inhibited the growth of human prostate cancer cell xenografts in athymic nude mice [101].

2.8. Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic head and neck cancer. Distant metastasis is the main reason for the difficulty in the treatment of NPC. The common treatment for NPC is radiation therapy. Chemotherapy is another option for treating nasopharyngeal cancer patients, but resistance to conventional drugs is a challenge [102]. Rg3 can inhibit the expression of MMP-2 and -9 as well as EMT-related transcription factors, especially the zinc finger E-Box binding homeobox 1, which blocked cell migration and invasion in HNE1 and CNE2 cell lines [103], indicating that Rg3 may be a potentially effective agent for the treatment of NPC. Rg3 promotes lymphocyte proliferation in NPC patient with radiotherapy in a dose-dependent manner by up-regulating the ratio of CD4+/CD8+, the expression of IgG, IgM and IL-2, and down-regulating the expression of CD8+ and IL-6 [104]. Treatment with 20(S)-Rh2, CK, or PPD exhibits a significant role in inducing apoptosis of NPC cells (HK-1 cells) in a concentration-dependent manner [105]. CK most broadly inhibits HK-1 xenograft tumor growth and depletion of mitochondrial membrane potential depolarization induces AIF transfer from the cytoplasm of HK-1 cells to the nucleus [105]. Rh2 significantly inhibits the proliferation of nasopharyngeal carcinoma CSCs in vitro and promotes apoptosis [106]. Moreover, Rg1 can significantly inhibit the growth of anaplastic thyroid carcinoma and prolong the survival time of tumor-bearing mice [107].

2.9. Gallbladder Cancer

Gallbladder Carcinoma (GBC) is a malignant tumor of the biliary tract, accounting for 80–95% of the global biliary tract cancer and ranking sixth in gastrointestinal cancers with high mortality, late diagnosis and chemotherapy resistance [108]. Most patients were diagnosed with advanced GBC and cannot be treated by resection [109]. 20(R)-Rg3 acts as a dominant inhibitor of gallbladder cancer growth by activating the p53 pathway and subsequent cell senescence in vitro and in vivo [110].

2.10. Bladder Cancer

About 80% of bladder cancers are superficial tumors that can be easily treated with minimally invasive surgery. However, the recurrence of superficial transitional cell carcinoma of the bladder after transurethral resection is a major problem in the treatment of bladder cancer [111]. Since the late 1980s, cisplatin-based combination chemotherapy has become the standard treatment for advanced bladder cancer [112]. The serious side effects caused by anti-tumor drugs are the main obstacles to the success of their application and treatment, so the study of natural compounds with little or no toxicity has received much attention. Combination of Rg3 and cisplatin decreased cyclin Bcl-2 expression, but increased the expression of cytochrome C and apoptosis-related protein caspase-3 in T24R2 cells, indicating that the endogenous apoptotic pathway was activated [113].

2.11. Cervical Cancer

Cervical cancer is a major cause of cancer in women around the world with more than 510,000 new cases and 288,000 deaths each year [114]. Human Papillomavirus (HPV) infection is the most direct source of cervical cancer. HPV infection is usually asymptomatic and transient but can promote pre-cervical precancerous lesions. The treatment of cervical cancer, including radiation and chemotherapy, used together with various herbs [115], can significantly improve the treatment effects and increase the sensitivity of cancer cells. Rd inhibits the growth of human cervical cancer (HeLa) cells in a concentration and time-dependent manner, with an IC₅₀ value of 150.5 ± 0.8 μg/mL incubation for 48 h. Its mechanism of action is to induce apoptosis by activating the caspase-3 pathway, reducing Bcl-2 expression and mitochondrial transmembrane potential and up-regulating Bax expression [116]. Sun Ginseng (SG), a major component of red ginseng, contains approximately the same amount of three major ginsenosides (RK1, Rg3, and Rg5) [117]. Combination of SG and epirubicin/paclitaxel synergistically induce the apoptosis of cervical cancer cells by increasing the caspase-9/-3 expression, the mitochondrial accumulation of Bax and Bak, and the cytochrome C release [117]. Rg5 exhibits significant genotoxic effects in HeLa and MS751 human cervical cancer cell lines [118]. 20(s)-Rg3 loaded magnetic human serum albumin nanospheres [20(S)-Rg3/HSAMNP] prepared by the desolvation-crosslinking method increased the water solubility and bioavailability of 20(S)-Rg3, combined with magnetic hyperthermia, it can effectively induce apoptosis of HeLa cervical cancer cells [119]. HeLa cells treated with microwave-irradiated product of ginseng (MG) can inhibit the growth of human cervical cancer xenografts in athymic nude mice in vivo, which is associated with cell death and the induction of autophagy [120].

2.12. Pancreatic Cancer

Pancreatic Cancer (PC) has a very high mortality rate with a 1-year survival rate of <10% [121]. The success rate of the surgical resection of PC is not high and the effect of chemotherapy is not work well. The current standard chemotherapy for pancreatic cancer is the pyrimidine analog Gemcitabine alone, or in combination with 5-Fluorouracil (5-FU) or a platinum reagent (e.g., cisplatin or oxaliplatin) [122]. However, the toxic side effects are accompanied by a certain degree of drug resistance, so combinations with natural products improve the drug sensitivity as an anticancer agent or adjuvant therapy. PC treatment with 25-OH-PPD and 25-OCH₃-PPD can inhibit the MDM2 oncogenes and its related pathways to exert anticancer activity, which prevent the growth of xenograft tumors without any host toxicity [123]. Vasculogenic Mimicry (VM) is a novel tumor microcirculatory system that differs from classically described endothelium-dependent angiogenesis. VM is expressed in 71.79% (84/117) of the pancreatic cancer cases [124], so inhibition of VM channels by ginsenosides is extremely important to the prevention and treatment of PC. Rg3 effectively inhibits pancreatic cancer by down-regulating the expression of VE-cadherin, epithelial cell kinase (EphA2), MMP-2 and -9 [125]. As an adjuvant for the treatment of pancreatic cancer, Rg3 is used simultaneously with erlotinib to enhance the anti-proliferation and apoptosis effects in BxPC-3 and AsPC-1 pancreatic cancer cells and xenograft models by up-regulation of caspase-3, 9, and PARP cleavage expression and down-regulation of p-EGFR, p-PI3K, and p-Akt expression [126].

2.13. Melanoma

Melanoma is a type of skin cancer that develops from melanocytes located in the basal layer of the epidermis [127]. In the early stage, melanoma can be cured by surgical resection and the 5-year survival rate is >95% [128]. However, advanced metastatic melanoma is a malignant tumor. Due to drug resistance, there is no effective treatment. The involvement of MAPK [129], the PI3K/Akt pathway [130], and some mutant oncogenes, including BRAF [131], c-KIT [132], provides new potential targets for the diagnosis and treatment of melanoma. Rg3 has been shown to reduce melanoma cell proliferation by reducing histone deacetylase 3 and increasing p53 acetylation [133]. Rg3 also can reduce the expression of ERK and Akt in vivo and in vitro, thereby down-regulating VEGF in B16 cells, weakening the proliferation and migration of vascular endothelial cells, and inhibiting blood vessels generate [134].

To facilitate the readers to understand the antitumor activity of different types of ginsenosides on different types of cancer in recent years, we have classified the main information in Table 2.

Cancer type	Cells/Animal model/Human clinical trials	Ginsenosides	Doses	Durations	Biological effects	References
Breast cancer	MDA-MB-231 cell xenograft nude mice	Rk1	10–20 mg/kg/day	21 days	Inhibited cell proliferation and repressed tumor growth by ROS/PI3K/Akt pathway	[31]
	MDA-MB-231 cells	GER	1–2.5 mg/mL	48 h	Inhibit the self-renewal ability of stem cell-like breast cancer cells	[34]
	MDA-MB-468 cell xenograft nude mice	25-OCH₃-PPD	20 mg/kg/day	4 weeks	Down-regulation EMT/MDM2 to induction of apoptosis and G1 phase arrest	[37]
	BALB/c nude mouse	Rg5	10–20 mg/kg/day	30 days	Induction of apoptosis and autophagy	[39]
	MCF-7 cells	Rh2	20–50 μM	24 h	Induces expression of cyclin p21 and decreases cyclin D3 levels, enhances immunogenicity and inhibits cancer cell growth	[26]
	MDA-MB-231 cells	Rg3	0–30 μM	24 h	Promote apoptosis by ROS/PI3K/Akt pathway	[30]
Colorectal cancer	Wistar rats	Rg3	2.5–5 mg/kg/3 days	6 weeks	Inhibit peritoneal metastasis of intestinal adenocarcinoma	[46]
	Caco-2 cells xenograft nude mice	Rh2	20–40 mg/kg/day	30 days	Induction of apoptosis and autophagy by ROS/JNK/p53 pathway	[49]
	HCT-116 and SW-480 cells	CK	30–50 μM	48 h	Anti-proliferative effects	[48]
Ovarian cancer	SKOV-3 cell tumor-bearing mice	Rg3	053 mg/kg/day	20 days	Inhibits ovarian tumor-induced angiogenesis and lung metastasis	[55]
	SKOV-3 cells	20(S)-Rg3	80 μg/mL	24 h	Inhibit cancer cell invasion and metastasis	[57]
	3AO cells	20(S)-Rg3	160 μg/mL	24 h	Inhibit cancer cell invasion and metastasis	[57]
	SKOV-3 cells	Rb1	0–320 μg/mL	24 h	Inhibit cancer metastasis by EMT	[60]
Prostate cancer	PC-3 cells	Rg3	10 μM	24 h	Down-regulation of AQP1 expression through the p38 MAPK pathway effectively inhibits migration of PC-3M cells	[99]
	PC-3 cells	Rh2	150–200 μM	24 h	Inhibit proliferation	[100]
	LNCaP cells	Rh2	150–200 μM	24 h	Inhibit proliferation	[100]
	DU145 cells	MG	50–100 μg/mL	24 h	Induction of apoptosis and autophagy	[101]
	LNCaP cells
	PC-3 cells
	Athymic xenograft nude mice		200 mg/kg/day	5 weeks
Gastric cancer	AGS cells	20(S)-Rg3	0–100 μg/mL	24 h	Induction of caspase-3, -8 and -9 activation leading to apoptotic cell death	[65]
Gastric cancer	SGC7901 cells	F2	20 μM	12 h	Activation of ribosomal protein-p53 signaling pathway and Bcl-xl/Beclin-1 pathway inhibit cancer cells	[70]
Lung cancer	A549	Rg3	0–100 μg/mL	24–48 h	Down-regulates FUT4-mediated EGFR inactivation and blocks MAPK and NF-κB signaling pathways to inhibit EMT and lung cancer invasion	[88]
	H1299
	H358
	A549 cell xenograft nude mice		10 mg/kg/3 days	3 weeks
	H460 cell xenograft nude mice	Rg3-RGP	100 mg/kg/day	28 days	Antitumor activities via indirect immunomodulatory actions	[91]
	A549 cells	Rh2	25 mg/L	48 h	Inhibit cell proliferation	[93]
	A549 cells	TGS + MMC	1 mg/mL	24 h	Reverses MMC-induced S-phase cell cycle arrest and inhibits Rad51-mediated DNA damage repair, enhancing cytotoxicity to cancer cells	[95]
Liver cancer	HepG2 cells	Rg3	0–5 μg/mL	24 h	Suppressed the migration and invasion of liver cancer cells by up-regulating the protein expression of ARHGAP9	[76]
	MHCC-97L cells		0–5 μg/mL	24 h
	BABL/c nude mice		0–10 mg/kg/day	21 days
	HepG2 cells	Rh2	80 μM	24–72 h	Reduce the expression levels of MMP3 gene and protein inhibit migratory ability	[79]
	BABL/c nude mice	Rk3	25–50 mg/kg/day	6 weeks	Antioxidant, anti-apoptotic, and anti-inflammatory activities	[83]
Nasopharyngeal carcinoma	HNE1 and CNE2 cells	Rg3	100 μg/mL	24 h	Inhibits migration and invasion by regulating the expression of MMP-2 and MMP-9 and inhibiting EMT	[103]
	HK-1 cells	CK	15 μM	24 h	Apoptosis mediated through the mitochondrial pathway	[105]
	CNE-2S cells	Rh2	30–60 μM	6 days	Apoptosis	[106]
Gallbladder cancer	NOZ cell xenograft nude mice	20(S)-Rg3	20–40 mg/kg/day	3 weeks	Activation of the p53 pathway and subsequent induction of cell senescence and mitochondrial-dependent apoptosis to attenuate GBC growth	[110]
Gallbladder cancer	NOZ GBC-SD cells	20(S)-Rg3	0–400 μM	48 h		[110]
Bladder cancer	T24R2 cells	Rg3	50 μM	48 h	Activation of the intrinsic apoptotic pathway and the enhancement of cell cycle alterations	[113]
Cervical cancer	HeLa cells	SG	80 μg/mL	48 h	Significantly enhanced the anticancer activity of epirubicin and paclitaxel in a synergistic manner	[117]
	HeLa cells	Rg5	5 μM	48 h	Induces apoptosis and DNA damage	[118]
	MS751 cells	Rg5	10 μM	48 h	Induces apoptosis and DNA damage	[118]
Pancreatic	PANC-1 cells	Rg3	10–80 μM	24 h	Induction of apoptosis and down-regulation of the EGF/PI3K/AKT pathway to enhance the efficacy of erlotinib in inhibiting the proliferation of pancreatic cancer cells	[126]
Melanoma	B16 cells	Rg3	0–5 μg/mL	48 h	Mediated through suppression of ERK and Akt signaling to inhibit tumor growth	[134]

Table 2

The inhibitory effect of different types of ginsenosides on different types of cancer

3. CONCLUSION

Ginsenosides play a role in the complex process of tumor development, including proliferation, apoptosis, migration, angiogenesis, and tumor immunogenicity [135]. Unlike targeted drugs, ginsenosides have multiple targets and exhibit anticancer activity through a variety of mechanisms, including targeting multiple tumor-associated signaling pathways and regulating intracellular ROS [136]. For example, the inhibition of proliferation (cyclin D1, COX-2, angiogenic factors (interleukin-8 and VEGF), invasion (MMP-9 and NF-κB) activation and metastasis and its down-regulation of gene products regulated by NF-κB, which have a significant role in anti-apoptosis [Cytostatics of IAP-1 (cIAP-1), Bcl-2, apolipoprotein precipitation protein inhibitors and Bcl-xl]. By referring to a large number of literatures, ginsenosides, through activation of the p53 tumor suppressor gene, cooperate with other cytokines to inhibit tumor growth, metastasis and promote apoptosis are the most common mechanisms for ginseng to treat different cancers (Figure 6). Due to the high toxicity of anticancer drugs and serious damage to organs, and with the gradual clarification of cancer pathogenesis, the exploration of ginsenosides as effective anticancer drugs or anticancer adjuvants holds good prospect.

CONFLICTS OF INTEREST

The authors declare they have no conflicts of interest.

AUTHORS’ CONTRIBUTION

HC and JD contributed to study design and writing original draft preparation. HY and DF contributed to revising and editing. All authors read and approved the final manuscript.

ACKNOWLEDGMENTS

This work was financially supported by the National Natural Science Foundation of China (21776228, 21978236, 21978229 and 21676212), and the Key Research and Development Program of Shaanxi (2019ZDLSF03-01-02 and 2019NY140).

Footnotes

Peer review under responsibility of the International Association of Dietetic Nutrition and Safety

REFERENCES

[1]A Balmain, JC Barrett, H Moses, and MJ Renan, How many mutations are required for tumorigenesis? Implications from human cancer data, Mol Carcinogen, Vol. 7, 1993, pp. 139-46.

[2]L Foulds, The experimental study of tumor progression: a review, Cancer Res, Vol. 14, 1954, pp. 327-39.

[3]D Hanahan and RA Weinberg, Hallmarks of cancer: the next generation, Cell, Vol. 144, 2011, pp. 646-74.

[4]D Hanahan and RA Weinberg, The hallmarks of cancer, Cell, Vol. 100, 2000, pp. 57-70.

[5]F Bray, J Ferlay, I Soerjomataram, RL Siegel, LA Torre, and A Jemal, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J Clin, Vol. 68, 2018, pp. 394-424.

[6]JS Choi, KS Chun, J Kundu, and JK Kundu, Biochemical basis of cancer chemoprevention and/or chemotherapy with ginsenosides (Review), Int J Mol Med, Vol. 32, 2013, pp. 1227-38.

[7]B Zaric, V Stojsic, A Tepavac, T Sarcev, P Zarogoulidis, K Darwiche, et al., Adjuvant chemotherapy and radiotherapy in the treatment of non-small cell lung cancer (NSCLC), J Thorac Dis, Vol. 5, 2013, pp. S371-S7.

[8]CC Tièche, RW Peng, P Dorn, L Froment, RA Schmid, and TM Marti, Prolonged pemetrexed pretreatment augments persistence of cisplatin-induced DNA damage and eliminates resistant lung cancer stem-like cells associated with EMT, BMC cancer, Vol. 16, 2016, pp. 125.

[9]R Rosell, RV Lord, M Taron, and N Reguart, DNA repair and cisplatin resistance in non-small-cell lung cancer, Lung Cancer, Vol. 38, 2002, pp. 217-27.

[10]JU Lim, IS Woo, YH Jung, JH Byeon, CK Park, TJ Kim, et al., Transformation into large-cell neuroendocrine carcinoma associated with acquired resistance to erlotinib in nonsmall cell lung cancer, Korean J Intern Med, Vol. 29, 2014, pp. 830-3.

[11]AA Elujoba, OM Odeleye, and MC Cyril-Olutayo, Traditional medicine development for medical and dental primary health care delivery system in Africa, Afr J Tradit Complem Alt Med, Vol. 2, 2005, pp. 46-61.

[12]MS Lee, EJ Yang, JI Kim, and E Ernst, Ginseng for cognitive function in Alzheimer’s disease: a systematic review, J Alzheimer’s Dis, Vol. 18, 2009, pp. 339-44.

[13]Y Zhu, C Zhu, H Yang, J Deng, and D Fan, Protective effect of ginsenoside Rg5 against kidney injury via inhibition of NLRP3 inflammasome activation and the MAPK signaling pathway in high-fat diet/streptozotocin-induced diabetic mice, Pharmacol Res, Vol. 155, 2020. 104746.

[14]E Shishtar, E Jovanovski, A Jenkins, and V Vuksan, Effects of Korean white ginseng (Panax Ginseng C.A. Meyer) on vascular and glycemic health in Type 2 diabetes: results of a randomized, double blind, placebo-controlled, multiple-crossover, acute dose escalation trial, Clin Nutr Res, Vol. 3, 2014, pp. 89-97.

[15]KS Chung, SH Cho, JS Shin, DH Kim, JH Choi, SY Choi, et al., Ginsenoside Rh2 induces cell cycle arrest and differentiation in human leukemia cells by upregulating TGF-β expression, Carcinogenesis, Vol. 34, 2013, pp. 331-40.

[16]J Li, Q Wei, GW Zuo, J Xia, ZM You, CL Li, et al., Ginsenoside Rg1 induces apoptosis through inhibition of the EpoR-mediated JAK2/STAT5 signalling pathway in the TF-1/Epo human leukemia cell line, Asian Pac J Cancer Prev, Vol. 15, 2014, pp. 2453-9.

[17]D Zeng, J Wang, P Kong, C Chang, J Li, and J Li, Ginsenoside Rg3 inhibits HIF-1α and VEGF expression in patient with acute leukemia via inhibiting the activation of PI3K/Akt and ERK1/2 pathways, Int J Clin Exp Pathol, Vol. 7, 2014, pp. 2172-8.

[18]Q Mao, PH Zhang, Q Wang, and SL Li, 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, Vol. 21, 2014, pp. 515-22.

[19]YM Shin, HJ Jung, WY Choi, and CJ Lim, Antioxidative, anti-inflammatory, and matrix metalloproteinase inhibitory activities of 20(S)-ginsenoside Rg3 in cultured mammalian cell lines, Mol Biol Rep, Vol. 40, 2013, pp. 269-79.

[20]H Yu, L Teng, Q Meng, Y Li, X Sun, J Lu, et al., Development of liposomal Ginsenoside Rg3: formulation optimization and evaluation of its anticancer effects, Int J Pharm, Vol. 450, 2013, pp. 250-8.

[21]LW Qi, HY Wang, H Zhang, CZ Wang, P Li, and CS Yuan, Diagnostic ion filtering to characterize ginseng saponins by rapid liquid chromatography with time-of-flight mass spectrometry, J Chromatogr A, Vol. 1230, 2012, pp. 93-9.

[22]K Quan, Q Liu, JY Wan, YJ Zhao, RZ Guo, RN Alolga, et al., Rapid preparation of rare ginsenosides by acid transformation and their structure-activity relationships against cancer cells, Sci Rep, Vol. 5, 2015, pp. 8598.

[23]LO Linus, C Hanson, RN Alolga, W Zhou, and L Qi, Targeting the key factors of inflammation in cancer: plant intervention, Int J Clin Exp Med, Vol. 10, 2017, pp. 15834-65.

[24]GN Hortobagyi and MJ Piccart-Gebhart, Current management of advanced breast cancer, Semin Oncol, Vol. 26, 1996, pp. 1-5.

[25]S Litière, G Werutsky, IS Fentiman, E Rutgers, MR Christiaens, E Van Limbergen, et al., Breast conserving therapy versus mastectomy for stage I–II breast cancer: 20 year follow-up of the EORTC 10801 phase 3 randomised trial, Lancet Oncol, Vol. 13, 2012, pp. 412-9.

[26]M Oh, Y Choi, S Choi, H Chung, K Kim, SI Kim, et al., Anti-proliferating effects of ginsenoside Rh2 on MCF-7 human breast cancer cells, Int J Oncol, Vol. 14, 1999, pp. 869-75.

[27]S Choi, TW Kim, and SV Singh, Ginsenoside Rh2-mediated G1 phase cell cycle arrest in human breast cancer cells is caused by p15 Ink4B and p27 Kip1-dependent inhibition of cyclin-dependent kinases, Pharm Res, Vol. 26, 2009, pp. 2280-8.

[28]Z Yuan, H Jiang, X Zhu, X Liu, and J Li, Ginsenoside Rg3 promotes cytotoxicity of Paclitaxel through inhibiting NF-κB signaling and regulating Bax/Bcl-2 expression on triple-negative breast cancer, Biomed Pharmacother, Vol. 89, 2017, pp. 227-32.

[29]JS Fridman and SW Lowe, Control of apoptosis by p53, Oncogene, Vol. 22, 2003, pp. 9030-40.

[30]BM Kim, DH Kim, JH Park, YJ Surh, and HK Na, Ginsenoside Rg3 inhibits constitutive activation of NF-κB signaling in human breast cancer (MDA-MB-231) cells: ERK and Akt as potential upstream targets, J Cancer Prev, Vol. 19, 2014, pp. 23-30.

[31]Y Hong and D Fan, Ginsenoside Rk1 induces cell cycle arrest and apoptosis in MDA-MB-231 triple negative breast cancer cells, Toxicology, Vol. 418, 2019, pp. 22-31.

[32]MB Sporn, The war on cancer, Lancet, Vol. 347, 1996, pp. 1377-81.

[33]XP Chen, LL Qian, H Jiang, and JH Chen, Ginsenoside Rg3 inhibits CXCR4 expression and related migrations in a breast cancer cell line, Int J Clin Oncol, Vol. 16, 2011, pp. 519-23.

[34]J Oh, HJ Yoon, JH Jang, DH Kim, and YJ Surh, The standardized Korean Red Ginseng extract and its ingredient ginsenoside Rg3 inhibit manifestation of breast cancer stem cell–like properties through modulation of self-renewal signaling, J Ginseng Res, Vol. 43, 2019, pp. 421-30.

[35]K Onel and C Cordon-Cardo, MDM2 and prognosis, Mol Cancer Res, Vol. 2, 2004, pp. 1-8.

[36]AJ Levine and M Oren, The first 30 years of p53: growing ever more complex, Nat Rev Cancer, Vol. 9, 2009, pp. 749-58.

[37]W Wang, X Zhang, JJ Qin, S Voruganti, SA Nag, MH Wang, et al., Natural product ginsenoside 25-OCH3-PPD inhibits breast cancer growth and metastasis through down-regulating MDM2, PLoS One, Vol. 7, 2012. e41586.

[38]SJ Kim and AK Kim, Anti-breast cancer activity of Fine Black ginseng (Panax ginseng Meyer) and ginsenoside Rg5, J Ginseng Res, Vol. 39, 2015, pp. 125-34.

[39]Y Liu and D Fan, Ginsenoside Rg5 induces apoptosis and autophagy via the inhibition of the PI3K/Akt pathway against breast cancer in a mouse model, Food Funct, Vol. 9, 2018, pp. 5513-27.

[40]J Guinney, R Dienstmann, X Wang, A de Reyniès, A Schlicker, C Soneson, et al., The consensus molecular subtypes of colorectal cancer, Nat Med, Vol. 21, 2015, pp. 1350-6.

[41]J Pan, L Xin, YF Ma, LH Hu, and ZS Li, Colonoscopy reduces colorectal cancer incidence and mortality in patients with non-malignant findings: a meta-analysis, Am J Gastroenterol, Vol. 111, 2016, pp. 355-65.

[42]B Li, J Zhao, CZ Wang, J Searle, TC He, CS Yuan, et al., Ginsenoside Rh2 induces apoptosis and paraptosis-like cell death in colorectal cancer cells through activation of p53, Cancer Lett, Vol. 301, 2011, pp. 185-92.

[43]M Musteanu, L Blaas, M Mair, M Schlederer, M Bilban, S Tauber, et al., Stat3 is a negative regulator of intestinal tumor progression in Apc(Min) mice, Gastroenterology, Vol. 138, 2010, pp. 1003.e5-11.e5.

[44]S Han, AJ Jeong, H Yang, KB Kang, H Lee, EH Yi, et al., Ginsenoside 20(S)-Rh2 exerts anti-cancer activity through targeting IL-6-induced JAK2/STAT3 pathway in human colorectal cancer cells, J Ethnopharmacol, Vol. 194, 2016, pp. 83-90.

[45]PY Yue, DY Wong, PK Wu, PY Leung, NK Mak, HW Yeung, et al., The angiosuppressive effects of 20(R)-ginsenoside Rg3, Biochem Pharmacol, Vol. 72, 2006, pp. 437-45.

[46]H Iishi, M Tatsuta, M Baba, H Uehara, A Nakaizumi, K Shinkai, et al., Inhibition by ginsenoside Rg3 of bombesin-enhanced peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane in Wistar rats, Clin Exp Metastasis, Vol. 15, 1997, pp. 603-11.

[47]S Junmin, L Hongxiang, L Zhen, Y Chao, and W Chaojie, Ginsenoside Rg3 inhibits colon cancer cell migration by suppressing nuclear factor kappa B activity, J Tradit Chin Med, Vol. 35, 2015, pp. 440-4.

[48]CZ Wang, GJ Du, Z Zhang, XD Wen, T Calway, Z Zhen, et al., Ginsenoside compound K, not Rb1, possesses potential chemopreventive activities in human colorectal cancer, Int J Oncol, Vol. 40, 2012, pp. 1970-6.

[49]Q Wu, J Deng, D Fan, Z Duan, C Zhu, R Fu, et al., Ginsenoside Rh4 induces apoptosis and autophagic cell death through activation of the ROS/JNK/p53 pathway in colorectal cancer cells, Biochem Pharmacol, Vol. 148, 2018, pp. 64-74.

[50]A Loboda, MV Nebozhyn, JW Watters, CA Buser, PM Shaw, PS Huang, et al., EMT is the dominant program in human colon cancer, BMC Med Genomics, Vol. 4, 2011, pp. 9.

[51]G Dai, B Sun, T Gong, Z Pan, Q Meng, and W Ju, Ginsenoside Rb2 inhibits epithelial-mesenchymal transition of colorectal cancer cells by suppressing TGF-β/Smad signaling, Phytomedicine, Vol. 56, 2019, pp. 126-35.

[52]JA Hwang, MK Hwang, Y Jang, EJ Lee, JE Kim, MH Oh, et al., 20-O-β-d-glucopyranosyl-20 (S)-protopanaxadiol, a metabolite of ginseng, inhibits colon cancer growth by targeting TRPC channel-mediated calcium influx, J Nutr Biochem, Vol. 24, 2013, pp. 1096-104.

[53]KR Cho and IM Shih, Ovarian cancer, Annu Rev Pathol Mech Dis, Vol. 4, 2009, pp. 287-313.

[54]Z Momenimovahed, A Tiznobaik, S Taheri, and H Salehiniya, Ovarian cancer in the world: epidemiology and risk factors, Int J Womens Health, Vol. 11, 2019, pp. 287-99.

[55]J Li, J Lu, Z Ye, X Han, X Zheng, H Hou, et al., 20(S)-Rg3 blocked epithelial-mesenchymal transition through DNMT3A/miR-145/FSCN1 in ovarian cancer, Oncotarget, Vol. 8, 2017, pp. 53375-86.

[56]X Zheng, Y Zhou, W Chen, L Chen, J Lu, F He, et al., Ginsenoside 20(S)-Rg3 prevents PKM2-targeting miR-324-5p from H19 sponging to antagonize the Warburg effect in ovarian cancer cells, Cell Physiol Biochem, Vol. 51, 2018, pp. 1340-53.

[57]TM Xu, MH Cui, Y Xin, LP Gu, X Jiang, MM Su, et al., Inhibitory effect of ginsenoside Rg3 on ovarian cancer metastasis, Chin Med J (Engl), Vol. 121, 2008, pp. 1394-7.

[58]M Mochizuki, Y Yoo, K Matsuzawa, K Sato, I Saiki, S Tono-oka, et al., Inhibitory effect of tumor metastasis in mice by saponins, ginsenoside-Rb2, 20(R)-and 20(S)-ginsenoside-Rg3, of red ginseng, Biol Pharm Bull, Vol. 18, 1995, pp. 1197-202.

[59]T Liu, L Zhao, Y Zhang, W Chen, D Liu, H Hou, et al., Ginsenoside 20(S)-Rg3 targets HIF-1α to block hypoxia-induced epithelial-mesenchymal transition in ovarian cancer cells, PLoS One, 2014, pp. 9. e103887.

[60]D Liu, T Liu, Y Teng, W Chen, L Zhao, and X Li, Ginsenoside Rb1 inhibits hypoxia-induced epithelial-mesenchymal transition in ovarian cancer cells by regulating microRNA-25, Exp Ther Med, Vol. 14, 2017, pp. 2895-902.

[61]S Deng, CKC Wong, HC Lai, and AST Wong, Ginsenoside-Rb1 targets chemotherapy-resistant ovarian cancer stem cells via simultaneous inhibition of Wnt/β-catenin signaling and epithelial-to-mesenchymal transition, Oncotarget, Vol. 8, 2017, pp. 25897-914.

[62]Y Fu, Z Yin, L Wu, and C Yin, Fermentation of ginseng extracts by Penicillium simplicissimum GS33 and anti-ovarian cancer activity of fermented products, World J Microb Biotechnol, Vol. 30, 2014, pp. 1019-25.

[63]JH Kim and JS Choi, Effect of ginsenoside Rh-2 via activation of caspase-3 and Bcl-2-insensitive pathway in ovarian cancer cells, Physiol Res, Vol. 65, 2016, pp. 1031-7.

[64]I Saricanbaz, E Karahacioglu, O Ekinci, H Bora, D Kilic, and M Akmansu, Prognostic significance of expression of CD133 and Ki-67 in gastric cancer, Asian Pac J Cancer Prev, Vol. 15, 2014, pp. 8215-9.

[65]EH Park, YJ Kim, N Yamabe, SH Park, HK Kim, HJ Jang, et al., Stereospecific anticancer effects of ginsenoside Rg3 epimers isolated from heat-processed American ginseng on human gastric cancer cell, J Ginseng Res, Vol. 38, 2014, pp. 22-7.

[66]HJ Jang, IH Han, YJ Kim, N Yamabe, D Lee, GS Hwang, et al., Anticarcinogenic effects of products of heat-processed ginsenoside Re, a major constituent of ginseng berry, on human gastric cancer cells, J Agric Food Chem, Vol. 62, 2014, pp. 2830-6.

[67]F Aziz, X Wang, J Liu, and Q Yan, Ginsenoside Rg3 induces FUT4-mediated apoptosis in H. pylori CagA-treated gastric cancer cells by regulating SP1 and HSF1 expressions, Toxicol In Vitro, Vol. 31, 2016, pp. 158-66.

[68]L Zhao, Q Lv, Q Xv, J Shao, S Su, F Meng, et al., Ginsenoside Rg3 to regulate the EMT induced by TGF-in gastric cancer, J Clin Oncol, 2017, pp. 35. e23200.

[69]J Huang, K Peng, L Wang, B Wen, L Zhou, T Luo, et al., Ginsenoside Rh2 inhibits proliferation and induces apoptosis in human leukemia cells via TNF-α signaling pathway, Acta Biochim Biophys Sin (Shanghai), Vol. 48, 2016, pp. 750-5.

[70]Q Mao, PH Zhang, J Yang, JD Xu, M Kong, H Shen, et al., iTRAQ-based proteomic analysis of Ginsenoside F2 on human gastric carcinoma cells SGC7901, Evid Based Complement Alternat Med, Vol. 2016, 2016. 2635483.

[71]LA Torre, F Bray, RL Siegel, J Ferlay, J Lortet-Tieulent, and A Jemal, Global cancer statistics, 2012, CA-Cancer J Clin, Vol. 65, 2015, pp. 87-108.

[72]M Maluccio and A Covey, Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma, CA Cancer J Clin, Vol. 62, 2012, pp. 394-9.

[73]SC Lu, Where are we in the chemoprevention of hepatocellular carcinoma?, Hepatology, Vol. 51, 2010, pp. 734-6.

[74]Y Je, FA Schutz, and TK Choueiri, Risk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials, Lancet Oncol, Vol. 10, 2009, pp. 967-74.

[75]YH Huh, S Oh, YR Yeo, IH Chae, SH Kim, JS Lee, et al., Swiprosin-1 stimulates cancer invasion and metastasis by increasing the Rho family of GTPase signaling, Oncotarget, Vol. 6, 2015, pp. 13060-71.

[76]MY Sun, YN Song, M Zhang, CY Zhang, LJ Zhang, and H Zhang, Ginsenoside Rg3 inhibits the migration and invasion of liver cancer cells by increasing the protein expression of ARHGAP9, Oncol Lett, Vol. 17, 2019, pp. 965-73.

[77]C Zhang, L Liu, Y Yu, B Chen, C Tang, and X Li, Antitumor effects of ginsenoside Rg3 on human hepatocellular carcinoma cells, Mol Med Rep, Vol. 5, 2012, pp. 1295-8.

[78]L Zhu, W Zhang, J Wang, and R Liu, Evidence of CD90+CXCR4+ cells as circulating tumor stem cells in hepatocellular carcinoma, Tumor Biol, Vol. 36, 2015, pp. 5353-60.

[79]Q Shi, J Li, Z Feng, L Zhao, L Luo, Z You, et al., Effect of ginsenoside Rh2 on the migratory ability of HepG2 liver carcinoma cells: recruiting histone deacetylase and inhibiting activator protein 1 transcription factors, Mol Med Rep, Vol. 10, 2014, pp. 1779-85.

[80]Z Jia, J Wang, W Wang, Y Tian, W XiangWei, P Chen, et al., Autophagy eliminates cytoplasmic β-catenin and NICD to promote the cardiac differentiation of P19CL6 cells, Cell Signal, Vol. 26, 2014, pp. 2299-305.

[81]H Clevers, Wnt/β-catenin signaling in development and disease, Cell, Vol. 127, 2006, pp. 469-80.

[82]Z Yang, T Zhao, H Liu, and L Zhang, Ginsenoside Rh2 inhibits hepatocellular carcinoma through β-catenin and autophagy, Sci Rep, Vol. 6, 2016. 19383.

[83]L Qu, Y Zhu, Y Liu, H Yang, C Zhu, P Ma, et al., Protective effects of ginsenoside Rk3 against chronic alcohol-induced liver injury in mice through inhibition of inflammation, oxidative stress, and apoptosis, Food Chem Toxicol, Vol. 126, 2019, pp. 277-84.

[84]RS Herbst, D Morgensztern, and C Boshoff, The biology and management of non-small cell lung cancer, Nature, Vol. 553, 2018, pp. 446-54.

[85]AK Palucka and LM Coussens, The basis of oncoimmunology, Cell, Vol. 164, 2016, pp. 1233-47.

[86]FY Xu, WQ Shang, JJ Yu, Q Sun, MQ Li, and JS Sun, The antitumor activity study of ginsenosides and metabolites in lung cancer cell, Am J Transl Res, Vol. 8, 2016, pp. 1708-18.

[87]YJ Kim, WI Choi, BN Jeon, KC Choi, K Kim, TJ Kim, et al., Stereospecific effects of ginsenoside 20-Rg3 inhibits TGF-β1-induced epithelial–mesenchymal transition and suppresses lung cancer migration, invasion and anoikis resistance, Toxicol, Vol. 322, 2014, pp. 23-33.

[88]L Tian, D Shen, X Li, X Shan, X Wang, Q Yan, et al., Ginsenoside Rg3 inhibits epithelial-mesenchymal transition (EMT) and invasion of lung cancer by down-regulating FUT4, Oncotarget, Vol. 7, 2016, pp. 1619-32.

[89]Z Duan, J Deng, Y Dong, C Zhu, W Li, and D Fan, Anticancer effects of ginsenoside Rk3 on non-small cell lung cancer cells: in vitro and in vivo, Food Funct, Vol. 8, 2017, pp. 3723-36.

[90]Q Xie, H Wen, Q Zhang, W Zhou, X Lin, D Xie, et al., Inhibiting PI3K-AKt signaling pathway is involved in antitumor effects of ginsenoside Rg3 in lung cancer cell, Biomed Pharmacother, Vol. 85, 2017, pp. 16-21.

[91]D Park, DK Bae, JH Jeon, J Lee, N Oh, G Yang, et al., Immunopotentiation and antitumor effects of a ginsenoside Rg3-fortified red ginseng preparation in mice bearing H460 lung cancer cells, Environ Toxicol Pharmacol, Vol. 31, 2011, pp. 397-405.

[92]S Hu, JY Yu, LJ Xiong, CP Hu, and YX Zhang, [Research on the mechanism of ginsenoside Rh2 reversing the resistance of lung adenocarcinoma cells to cisplatin], Chinese Med J, Vol. 90, 2010, pp. 264-8. [Article in Chinese].

[93]C Zhang, H Yu, and J Hou, [Effects of 20 (S)-ginsenoside Rh2 and 20(R)-ginsenoside Rh2 on proliferation and apoptosis of human lung adenocarcinoma A549 cells], China J Chinese Mater Med, Vol. 36, 2011, pp. 1670-4. [Article in Chinese].

[94]AJ Deans and SC West, DNA interstrand crosslink repair and cancer, Nat Rev Cancer, Vol. 11, 2011, pp. 467-80.

[95]M Zhao, DD Wang, Y Che, MQ Wu, QR Li, C Shao, et al., Ginsenosides synergize with mitomycin C in combating human non-small cell lung cancer by repressing Rad51-mediated DNA repair, Acta Pharmacol Sin, Vol. 39, 2018, pp. 449-58.

[96]KAO Tikkinen, P Dahm, L Lytvyn, AF Heen, RWM Vernooij, RAC Siemieniuk, et al., Prostate cancer screening with prostate-specific antigen (PSA) test: a clinical practice guideline, BMJ, Vol. 362, 2018. k3581.

[97]S Gillessen, G Attard, TM Beer, H Beltran, A Bjartell, A Bossi, et al., Management of patients with advanced prostate cancer: report of the Advanced Prostate Cancer Consensus Conference 2019 Eur Urol, Vol. 77, 2020, pp. 508-47.

[98]SM Kim, SY Lee, JS Cho, SM Son, SS Choi, YP Yun, et al., Combination of ginsenoside Rg3 with docetaxel enhances the susceptibility of prostate cancer cells via inhibition of NF-κB, Eur J Pharmacol, Vol. 631, 2010, pp. 1-9.

[99]XY Pan, H Guo, J Han, F Hao, Y An, Y Xu, et al., Ginsenoside Rg3 attenuates cell migration via inhibition of aquaporin 1 expression in PC-3M prostate cancer cells, Eur J Pharmacol, Vol. 683, 2012, pp. 27-34.

[100]HS Kim, EH Lee, SR Ko, KJ Choi, JH Park, and DS Im, Effects of ginsenosides Rg3 and Rh2 on the proliferation of prostate cancer cells, Arch Pharm Res, Vol. 27, 2004, pp. 429-35.

[101]JY Park, P Choi, HK Kim, KS Kang, and J Ham, Increase in apoptotic effect of Panax ginseng by microwave processing in human prostate cancer cells: in vitro and in vivo studies, J Ginseng Res, Vol. 40, 2016, pp. 62-7.

[102]C Suárez, JP Rodrigo, A Rinaldo, JA Langendijk, AR Shaha, and A Ferlito, Current treatment options for recurrent nasopharyngeal cancer, Eur Arch Otorhinolaryngol, Vol. 267, 2010, pp. 1811-24.

[103]D Wang, C Wu, D Liu, L Zhang, G Long, G Hu, et al., Ginsenoside Rg3 inhibits migration and invasion of nasopharyngeal carcinoma cells and suppresses epithelial mesenchymal transition, Biomed Res Int, Vol. 2019, 2019. 8407683.

[104]B He, L Qian, and H Jiang, The effect of Rg3 ginsenosides on cellular immune function of nasopharyngeal carcinoma patients with radiotherapy, Acta Univ Med Anhui, Vol. 50, 2015, pp. 1293-6.

[105]CK Law, HH Kwok, PY Poon, CC Lau, ZH Jiang, WC Tai, et al., Ginsenoside compound K induces apoptosis in nasopharyngeal carcinoma cells via activation of apoptosis-inducing factor, Chin Med, Vol. 9, 2014, pp. 11.

[106]Y Liu, Inhibiting effect of ginsenoside Rh2 in vitro on nasopharynx cancer CSCs proliferation, J Hainan Med Univ, Vol. 22, 2016, pp. 5-8.

[107]WQ Chang, Y Lin, D Li, MX Sui, ZM Wang, MH Cui, et al., Experimental study on growth inhibition against anaplastic thyroid carcinoma of animal model by application of ginsenoside Rg1, World Scientific, Singapore, in Proceedings of the 2015 International Conference on Medicine and Biopharmaceutical, 2016, pp. 201-5.

[108]W Qin, P Kang, Y Xu, K Leng, Z Li, L Huang, et al., Long non-coding RNA HOTAIR promotes tumorigenesis and forecasts a poor prognosis in cholangiocarcinoma, Sci Rep, Vol. 8, 2018, pp. 12176.

[109]YP Hu, ZJ Tan, XS Wu, TY Liu, L Jiang, RF Bao, et al., Triptolide induces s phase arrest and apoptosis in gallbladder cancer cells, Molecules, Vol. 19, 2014, pp. 2612-28.

[110]F Zhang, M Li, X Wu, Y Hu, Y Cao, X Wang, et al., 20(S)-ginsenoside Rg3 promotes senescence and apoptosis in gallbladder cancer cells via the p53 pathway, Drug Des Devel Ther, Vol. 9, 2015, pp. 3969-87.

[111]B Ehdaie, SC Smith, and D Theodorescu, Personalized medicine in advanced urothelial cancer: when to treat, how to treat and who to treat, Can Urol Assoc J, Vol. 3, 2009, pp. S232-S6.

[112]H von der Maase, SW Hansen, JT Roberts, L Dogliotti, T Oliver, MJ Moore, et al., Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study, J Clin Oncol, Vol. 18, 2000, pp. 3068-77.

[113]YJ Lee, S Lee, JN Ho, SS Byun, SK Hong, SE Lee, et al., Synergistic antitumor effect of ginsenoside Rg3 and cisplatin in cisplatin-resistant bladder tumor cell line, Oncol Rep, Vol. 32, 2014, pp. 1803-8.

[114]D Saslow, PE Castle, JT Cox, DD Davey, MH Einstein, DG Ferris, et al., American Cancer Society Guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors, CA Cancer J Clin, Vol. 57, 2007, pp. 7-28.

[115]MM Leitao and DS Chi, Recurrent cervical cancer, Curr Treat Options Oncol, Vol. 3, 2002, pp. 105-11.

[116]ZG Yang, HX Sun, and YP Ye, Ginsenoside Rd from Panax notoginseng is cytotoxic towards HeLa cancer cells and induces apoptosis, Chem Biodivers, Vol. 3, 2006, pp. 187-97.

[117]Y Lin, D Jiang, Y Li, X Han, D Yu, JH Park, et al., Effect of sun ginseng potentiation on epirubicin and paclitaxel-induced apoptosis in human cervical cancer cells, J Ginseng Res, Vol. 39, 2015, pp. 22-8.

[118]LD Liang, T He, TW Du, YG Fan, DS Chen, and Y Wang, Ginsenoside-Rg5 induces apoptosis and DNA damage in human cervical cancer cells, Mol Med Rep, Vol. 11, 2015, pp. 940-6.

[119]R Yang, D Chen, M Li, F Miao, P Liu, and Q Tang, 20(s)-ginsenoside Rg3-loaded magnetic human serum albumin nanospheres applied to HeLa cervical cancer cells in vitro, Biomed Mater Eng, Vol. 24, 2014, pp. 1991-8.

[120]P Choi, JY Park, T Kim, SH Park, HK Kim, KS Kang, et al., Improved anticancer effect of ginseng extract by microwave-assisted processing through the generation of ginsenosides Rg3, Rg5 and Rk1, J Funct Food, Vol. 14, 2015, pp. 613-22.

[121]D Goldstein, S Carroll, M Apte, and G Keogh, Modern management of pancreatic carcinoma, Intern Med J, Vol. 34, 2004, pp. 475-81.

[122]AS Strimpakos, KN Syrigos, and MW Saif, The molecular targets for the diagnosis and treatment of pancreatic cancer, Gut Liver, Vol. 4, 2010, pp. 433-49.

[123]W Wang, ER Rayburn, Y Zhao, H Wang, and R Zhang, Novel ginsenosides 25-OH-PPD and 25-OCH3-PPD as experimental therapy for pancreatic cancer: anticancer activity and mechanisms of action, Cancer Lett, Vol. 278, 2009, pp. 241-8.

[124]W Sun, YZ Fan, WZ Zhang, and YG Chun, A pilot histomorphology and hemodynamic of vasculogenic mimicry in gallbladder carcinomas in vivo and in vitro, J Exp Clin Cancer Res, Vol. 30, 2011, pp. 46.

[125]JQ Guo, QH Zheng, H Chen, L Chen, JB Xu, MY Chen, et al., Ginsenoside Rg3 inhibition of vasculogenic mimicry in pancreatic cancer through downregulation of VE-cadherin/EphA2/MMP9/MMP2 expression, Int J Oncol, Vol. 45, 2014, pp. 1065-72.

[126]J Jiang, Z Yuan, Y Sun, Y Bu, W Li, and Z Fei, Ginsenoside Rg3 enhances the anti-proliferative activity of erlotinib in pancreatic cancer cell lines by downregulation of EGFR/PI3K/Akt signaling pathway, Biomed Pharmacother, Vol. 96, 2017, pp. 619-25.

[127]WH Clark, DE Elder, and M Van Horn, The biologic forms of malignant melanoma, Hum Pathol, Vol. 17, 1986, pp. 443-50.

[128]AD Singh, ME Turell, and AK Topham, Uveal melanoma: trends in incidence, treatment, and survival, Ophthalmology, Vol. 118, 2011, pp. 1881-5.

[129]M Cerezo, M Tichet, P Abbe, M Ohanna, A Lehraiki, F Rouaud, et al., Metformin blocks melanoma invasion and metastasis development in AMPK/p53-dependent manner, Mol Cancer Ther, Vol. 12, 2013, pp. 1605-15.

[130]T Shimizu, AW Tolcher, KP Papadopoulos, M Beeram, DW Rasco, LS Smith, et al., The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer, Clin Cancer Res, Vol. 18, 2012, pp. 2316-25.

[131]L Zimmer, U Hillen, E Livingstone, ME Lacouture, K Busam, RD Carvajal, et al., Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition, J Clin Oncol, Vol. 30, 2012, pp. 2375-83.

[132]RD Carvajal, CR Antonescu, JD Wolchok, PB Chapman, RA Roman, J Teitcher, et al., KIT as a therapeutic target in metastatic melanoma, JAMA, Vol. 305, 2011, pp. 2327-34.

[133]X Shan, YS Fu, F Aziz, XQ Wang, Q Yan, and JW Liu, Ginsenoside Rg3 inhibits melanoma cell proliferation through down-regulation of histone deacetylase 3 (HDAC3) and increase of p53 acetylation, PloS One, Vol. 9, 2014. e115401.

[134]L Meng, R Ji, X Dong, X Xu, Y Xin, and X Jiang, Antitumor activity of ginsenoside Rg3 in melanoma through downregulation of the ERK and Akt pathways, Int J Oncol, Vol. 54, 2019, pp. 2069-79.

[135]Z Jiang, Y Yang, Y Yang, Y Zhang, Z Yue, Z Pan, et al., Ginsenoside Rg3 attenuates cisplatin resistance in lung cancer by downregulating PD-L1 and resuming immune, Biomed Pharmacother, Vol. 96, 2017, pp. 378-83.

[136]HY Sun, JH Lee, YS Han, YM Yoon, CW Yun, JH Kim, et al., Pivotal roles of ginsenoside Rg3 in tumor apoptosis through regulation of reactive oxygen species, Anticancer Res, Vol. 36, 2016, pp. 4647-54.

<Previous Article In Issue

Download article (PDF)

Next Article In Issue>

Journal: eFood
Volume-Issue: 1 - 3
Pages: 226 - 241
Publication Date: 2020/05/22
ISSN (Online): 2666-3066
DOI: 10.2991/efood.k.200512.001 How to use a DOI?
Open Access: This is an open access article distributed under the CC BY-NC 4.0 license (http://creativecommons.org/licenses/by-nc/4.0/).

Cite this article

ris enw bib

TY  - JOUR
AU  - Hongwei Chen
AU  - Haixia Yang
AU  - Daidi Fan
AU  - Jianjun Deng
PY  - 2020
DA  - 2020/05/22
TI  - The Anticancer Activity and Mechanisms of Ginsenosides: An Updated Review
JO  - eFood
SP  - 226
EP  - 241
VL  - 1
IS  - 3
SN  - 2666-3066
UR  - https://doi.org/10.2991/efood.k.200512.001
DO  - 10.2991/efood.k.200512.001
ID  - Chen2020
ER  -

download .riscopy to clipboard