Ham et al. [5] showed that Rg3 up-regulated tumor-related genes through alteration of epigenetic methylation levels, thereby inhibiting the growth of breast cancer cells. Rg3 down-regulated hypermethylated TRMT1L, PSMC6 and NOX4, and up-regulated methylated ST3GAL4, RNLS and KDM5A. Yang et al. [6] found that ginsenoside Rg3 inhibited the proliferation of colorectal cancer SW-480 cells by down-regulating the transcriptional activity of C/EBP beta NF-kappaB. Sun et al. [7] found that ginsenoside Rg3 inhibited the proliferation of Lewis lung cancer (LLC) cells by reducing ROS and down-regulating the expression of cyclin and cyclin dependent kinase. Shan et al. [8] showed that ginsenoside Rg3 can inhibit malignant melanoma by inducing G0/G1 cell cycle arrest, reducing histone deacetylase 3 (HDAC3) and up-regulating p53 acetylation. In a further study, Shan et al. [9] pointed out that ginsenoside Rg3 prevented the growth of melanoma through deactivation of EGFR/MAPK pathway mediated by decreased FUT4/LeY expression. In pancreatic cancer, ginsenoside Rg3 enhanced erotinib-induced apoptosis by increased the expression levels of caspase-3, 9 and cleaved PARP, and reduced the expression levels of p-EGFR, p-PI3K, and p-AKT. Therefore, ginsenoside Rg3 could enhance the role of erotinib on proliferation suppression and apoptosis induction via down-regulating the EGFR/PI3K/AKT pathway [10].

Li et al. [11] found that ginsenoside Rh2 induced cell cycle arrest by down-regulated cyclin dependent kinase 4 and cyclin D, and significantly reduced the level of phosphorylated AKT. Therefore, ginsenoside Rh2 inhibited proliferation of

human A172 glioma cell by regulating CDK4/CyclinD complex and AKT. In lung cancer H1299 cells, Ge et al. [12] found that ginsenoside Rh2 induced ROS mediated endoplasmic reticulum stress-dependent apoptosis, and up-regulated the expression of activated transcription factor 4 (ATF4), CCAAT/enhanced binding protein homologous protein (CHOP), and caspase-4, thereby inhibiting cell proliferation. Yong et al. [13] proved that ginsenoside Rh2 significantly inhibited the proliferation of nasopharyngeal carcinoma CSCs in vitro, promoted apoptosis, and reduced the expression of IL-6. Gao et al. [14] indicated that ginsenoside Rh2 inhibited the growth of prostate cancer cells by inhibiting microrna-4295, which activates the cell cycle inhibitor p21 (CDKN1A).

Ginsenoside Rp1 is a new ginsenoside derived from ginsenoside Rk1. Kim et al. [15] found that ginsenoside Rp1 can up-regulate apolipoprotein apo-a1 in colorectal cancer LoVo cells, strongly inhibiting cell proliferation and promoting cell apoptosis. Zhang et al. [16] found that ginsenoside Rd can inhibit the proliferation and induce apoptosis of breast cancer cells, and inhibit the Akt/mTOR/P70S6 kinase signaling pathway.

Sun et al. [7] found Rg3 induced apoptosis of Lewis lung cancer (LLC) cells by regulating apoptosis-related proteins, such as Bcl-2, Bax, PARP-1, and lysed caspase-3. Dai et al. [17] demonstrated that the combined use of ginsenoside Rg3 and gefitinib can up-regulated the pro-apoptotic protein Bax and down-regulated the anti-apoptotic protein Bcl-2, thereby activating caspase-3 and promoting the apoptosis of non-small cell lung cancer (NSCLC) cells. Aziz F.’s et al. [18] pointed out that ginsenoside Rg3 up-regulated the expression of specific protein 1 (SP1) and down-regulated heat shock factor 1 (HSF1) to inhibit the expression of brown alginase transferase IV (FUT4), and activated caspase-3, -8, -9 and PARP to promote the apoptosis of gastric cancer cells. Li et al. [19] found that ginsenoside Rg3 reduced the protein expression of Bcl2 and repressed PI3K/AKT/mTOR signaling pathway in human osteosarcoma cell lines (mg-63, u-2os and saos-2), and increased the expression of lysed caspase3. Therefore, Rg3 induced apoptosis of human osteosarcoma cell lines. In addition, ginsenoside 20(S) -Rg3 can also induce apoptosis of ovarian cancer HO-8910 cells through suppression of the PI3K/Akt pathway. Concordantly, Wang et al. [20] found that 20(S)-ginsenoside Rg3 reduced the activity of ovarian cancer HO-8910 cells in dose- and time-dependent manners, and induced apoptosis. Apoptosis induction was due to down-regulation of phosphatidylinositol 3-kinase (PI3K)/Akt family protein and apoptosis-inhibiting protein (IAP) family protein, and up-regulation of the expression of caspase-3 and caspase-9.

Duan et al. [21] found that ginsenoside Rh4 can promote apoptosis of breast cancer McF-7 cells by down-regulating Bcl-2, up-regulating Bax, and activating caspase-8, -3 and PARP. Another study indicated that Rh4 increased the accumulation of reactive oxygen species (ROS), thereby activating the JNK-p53 pathway [22]. Reactive oxygen scavenging agents, JNK and p53 inhibitors can significantly reduce Rh4-induced apoptosis, suggesting that Rh4 can trigger apoptosis by activating the ROS/JNK/p53 pathway in colorectal cancer cells.

Li et al. [23] confirmed that in colorectal cancer HCT116 and SW480 cells, ginsenoside Rh2 can induce the caspase-mediated apoptosis of colorectal cancer cells. Rh2 activated the p53 pathway, significantly increasing the level of pro-apoptotic protein Bax and reducing the level of anti-apoptotic protein Bcl-2. It was reported that ginsenoside Rh2 inhibited the proliferation of gastric cancer SGC-7901 Side Population cells in a dose-dependent manner. Rh2 arrested cells at G1/G0 phase, followed by stimulation of apoptosis through up-regulation of Bax and down-regulation of Bcl-2 [24]. Wu et al. [25] found that ginsenoside Rh2 induced apoptosis of prostate cancer DU145 cells by up-regulating the expression of PPAR-delta, which was related to the up-regulation of p-STAT3 and induction OF ROS/ superoxide.

Ginsenoside F2 is the potential bioactive metabolite of main ginsenosides. Mao [26] indicated that Ginsenoside F2 induced ROS accumulation, decreased mitochondrial transmembrane potential (MTP), stimulated the release of cytochrome c, and induced caspase-dependent apoptosis. The regulation of ASK-1/JNK pathway also contributed to apoptosis. Results suggested that Ginsenoside F2 induced apoptosis by inducing ROS accumulation and activating ASK-1/JNK signaling pathway.

The effect of ginsenosides on autophagy is controversial. Reportedly, ginsenoside 20(S)-Rg3 (a type of Rg3 ginsenosides stereo isomer) inhibited autophagic flux by suppression of late-stage autophagosome maturation or degradation and eventually induced apoptosis in cervical cancer cells [5]. However, Zhang Y et al. [27] found that that ginsenoside Rg3 induced autophagy so as to inhibit breast cancer tumor growth in tumor-bearing mice, and its mechanism was associated with P13K/AKT/mTOR pathway, Rg3 decreased P62 levels, increased generation of LC3-II cleaved from LC3-I. Zheng et al. [28] showed that 20 (S)-ginsenosides Rg3 induced autophagy in ovarian cancer SKOV3 cells by increasing the levels of LC3-II, Atg5, and Atg7.

Lv et al. [29] found that smith-4 can inhibit the phosphorylation of AKT/mTOR and reduce the activity of AKT/mTOR pathway to promote autophagy, while ginsenoside Rh2 can enhance this autophagy activity in vivo and in vitro to enhance the anti-melanoma efficacy of smith-4. Liu et al. [30] found that ginsenoside Rh2 promoted autophagy and apoptosis of K562 cells. Rh2 ginsenosides reduced the expression of HDAC6, promoted acetylation of Hsp90, and increased the expression of LC3-I, LC3-II, Beclin 1. Sarkar et al. [31] showed that increasing the acetylation of Hsp90 and decreasing the expression of Hsp90 would both cause autophagy and apoptosis of cells.

Wu et al. [22] et al. investigated the role of ginsenoside Rh4 in colorectal cancer cells (Caco 2, HCT116 cell) on growth inhibition, and they found that Rh4 promoted autophagy of colorectal cancer cells by activating ROS/JNK/p53 pathway. Rh4 promoted intracellular reactive oxygen species (ROS), which led to JNK phosphorylation and further promotes the p53 phosphorylation. Phosphorylated p53 increased the Beclin 1 levels, which can further increase the expression of Atg-7 and LC3-Ⅱ so as to promote the autophagy, optimization inhibition of colon cancer cells growth.

Chung et al. [32] found that in breast cancer MCF-7 cells, Rg2 can bind to glucocorticoid receptor (GR) as a glucocorticoid-like cellular mechanism. Rg2 increased p53 levels by transcriptional activation of GR, which activated the tuberous sclerosis complex 1 (TSC1) and TSC2, then phosphorylated AMPK and subsequently inhibited the mTOR pathway, and increased autophagy. Rg2 increased the levels of p-p53, p-AMPK, Atg-7, and LC3-II, while decreased the levels of p62.

Liu et al. [33] proved that ginsenoside Rg5 had a strong anti-tumor effect in human breast cancer cells. Rg5 promoted autophagy by inhibiting P13K/AKT/mTOR pathway, which decreased P62 levels, increased by Atg5, Atg7, Atg12, and accelerated the LC3-I to LC3-II transformation to promote autophagy.

CK, the metabolite of ginsenoside, can increase the phosphorylation level of AMPK and reduce the phosphorylation level of mTOR, thereby promoting autophagy and promoting apoptosis. Chen et al. [34] found that CK treatment up-regulated the expression of Beclin 1 in non-small-cell cancer cells, induced generation of LC3-II cleaved from LC3-I, and decreased the P62 levels.

It has been found that Chemokine CXC receptor 4 (CXCR4) plays an important role in metastasis by acting on the chemokine ligand CXCL12. [36] Chen et al. [37] demonstrated that ginsenoside Rg3 inhibited CXCR4 expression and CXCL12 (CXCR4 ligand) induced chemotaxis in cultured MDA-MB-231 cell, a highly metastatic cell line of breast cancer, thus inhibiting cancer cell migration. Pan et al. [38] found that ginsenoside Rg3 can inhibit the growth and metastasis of ovarian cancer cells by down-regulating the expression of VEGF mRNA and protein, reducing microvascular density and blocking angiogenesis. XU et al. [39] found that ginsenoside Rg3 can significantly inhibit the metastasis of ovarian cancer. The inhibitory effect was partly due to reduction of MMP-9 expression, which promoted the ovarian cancer SKOV3 cells to invade.

Lee et al. [40] investigated the effects of ginsenoside 20(S)-Rg(3) in colorectal cancer SW620 cells, and found that ginsenoside 20(S)-Rg(3) inhibited the expression of fatty acid synthetase and histone H4, thus inhibiting the metastasis of SW620 cells.

The epithelial-mesenchymal transition (EMT) is a physiological and pathological phenomenon, characterized by the loss of typical epithelial characteristics and the acquisition of mesenchymal traits. [41] Studies have revealed that EMT contributes to cancer progression, invasion and migration in various types of cancer [42] [43]. In the process of EMT, the expression of E-cadherin, a membrane protein mediating the tight junction between epithelial cells, is downregulated, and the expression of connexin between mesenchymal cells, such as N-cadherin and vimentin, is upregulated. [44] Tian et al. [45] found that Rg3 significantly up-regulated the mRNA levels of the E-cadherin, and down-regulated the mRNA levels of Snail, N-cadherin and Vimentin in NSCLC cells (A549, H1299 and H358 cells), thereby effectively preventing EMT process in dose- and time-dependent manners. Kim et al. [46] found that 20(R)-Rg3 inhibited the EMT by suppressing E-cadherin and vimentin expression in TGF-ß1-activated lung cancer A549 cells. Ting et al. [47] found that ginsenoside 20(S)-Rg3 potently blocked hypoxia-induced EMT of ovarian cancer cells in vitro and in vivo. They confirmed that 20(S)-Rg3 reduced the expression of hypoxia-inducible factor 1a (HIF-1a) by activating the ubiquitin-proteasome pathway to promote HIF-1a degradation. Decreased HIF-1a suppressed Snail transcription, leading to up-regulation of E-cadherin (the epithelial cell-specific marker) and down-regulation of vimentin (the mesenchymal cell-specific marker) under hypoxic conditions.

Transforming growth factor (TGF)-β1 was found to be the main inducer of ETM [48] [49]. Ginsenoside Rg1, is one active and abundant components in ginseng, which has exerts anticancer properties [50] [51] [52] [53]. Yu et al. [54] found that TGF-β1 could induce the expression of vimentin and decrease the expression of E-cadherin, which could make human liver cancer HepG2 cells behave as mesenchymal phenotype and significantly enhance the invasion and migration of cells. When treated with ginsenoside Rg1, Rg1 increased the expression of E-cadherin and inhibited the expression of the mesenchymal phenotype marker vimentin, showing a typical epithelial morphology. Therefore, ginsenoside Rg1 inhibited the invasion and migration of hepatocellular carcinoma HepG2 cells in vitro by inhibiting EMT. Concordantly, Dan et al. [55] found that treatment with ginsenoside Rg1 for 48 h in ovarian cancer cell SKOV3, the EMT morphology change induced by hypoxia was partially reversed. Rg1 recovered the expression of E-cadherin and attenuated expression of vimentin by regulating NF-KB pathway.

Ginsenoside Rd is a kind of procyanidins found in ginseng ginseng saponin. Wang et al. [56] found that Rd treatment increased expression of Smad2 by down-regulating microRNA (miR)-18a in cultured 4T1 cells and in tumors grown from inoculated 4T1 cells. Smad2, a direct target of miR-18a, significantly induced attenuation of migration in 4T1 cells.

Yoon et al. [57] showed that ginsengside inhibited migration and invasion of human hepatocellular cancer HepG2 cells by inhibiting ERK and MAPK signaling pathways, which reduced the expression of MMP-1, MMP-2 and MMP-7.

Guan et al. [58] found that Rh2 reduced the invasiveness of glioblastoma cells in a dose-dependent manner by inhibiting AKT mediated MMP13 activation, assessed by wound healing test and Transwell assay. Jung et al. [59] showed that Rh1 inhibited the mRNA expressions of MMP-1, -3 and -9 in human malignant gliomas cells (U87MG and U373MG). Rh1 also inhibits promoter activity of MMP-1, -3, and -9. Further studies showed that Rh1 played an important role in inhibiting MAPK and PI3K/Akt signaling pathways and downstream transcription factors. Han et al. [60] found that ginsenoside 20(S)-Rh2 effectively inhibited the phosphorylation of signal transducers and transcriptional activator 3 (STAT3), as well as the expression of matrix metalloproteinases (MMPs), including MMP-1, -2, and -9, thereby inhibiting the metastasis of colorectal cancer cells.

Phi et al. [61] found that ginsenoside Rb2 inhibited CSC properties and EMT of HT29 SW620 cells, thereby inhibiting the transfer of CRC cells in vivo, which was achieved by inhibiting EGFR and its downstream signal pathways, SOX2 and Snail. Liu et al. [62] demonstrated that Rb1 downregulated the expression of miR-25, resulting in overexpression of E-cadherin transcriptional activator EP300, thus increasing E-cadherin level and inhibiting the hypoxia-induced EMT process in ovarian cancer SKOV3 and 3AO cells. Ginsenoside Rp1, a new type of ginseng saponin, was showed to play an anticancer role by inhibiting the adhesion of tumor cells and the formation of blood vessels, and by strongly inhibiting the cell activity and metastasis process. Park et al. proved that Rp1 inhibited human umbilical vein endothelial cells (HUVECs) tube formed, blocked HCT15 and A549 cell viability, and strongly inhibited the pulmonary metastasis of B16-F10 melanoma cells [63].

CK (20-O-β-d-glucopyranosyl-20(S)-protopanaxadiol) is an active metabolite that are synthesized by intestinal bacteria after oral administration of ginsenosides Rb1, Rb2, Rc and Rd. [64] It was found that CK increased the level of epithelial marker molecule Ecadherin, and reduced the level of mesenchymal markers N-cadherin and vimentin in MCF-7 cells, indicating that CK inhibited the EMT process in MCF-7 cells [65]. The activation of PI3K/Akt signalling pathway may promote the occurrence of EMT in most tumour cells [66] [67]. Studies showed that CK inhibited the EMT in MCF-7 cells, which may be due to inhibition the activation of PI3K/Akt pathway [68], since it was clarified that CK could inhibit EMT by reducing the level of p-AKT [65]. Peng et al. [69] found that CK decreased N-cadherin and increased E-cadherin in liver cancer HepG2 cells, indicating that CK inhibited the EMT process. Suppression of ERK and Akt signaling pathways was involved in this pharmacologic action.

Wang et al. [70] [71] reported that ginsenoside Rg3 sensitized hypoxic lung cancer cells to cisplatin via blocking of NF-κB mediated EMT and stemness [72], and Rg3 also reduced the toxicity induced by cisplatin. Lee et al. [73] found that Rg3 enhanced the sensitivity of colon cancer cells to cisplatin by reducing the basal level of nuclear factor erythroid 2-related factor2-mediated heme oxygenase-1/NAD(P)H quinone oxidoreductase-1, and prevented normal tissue damage by scavenging cisplatin-induced intracellular ROS. Jiang et al. [10] showed that Rg3 attenuated cisplatin resistance and increased chemosensitivity in lung cancer by down-regulating PD-L1 and resuming immune. Tang et al. [74] found that Rg3 could strengthen the cytotoxicity of 5-Fluorouracil and oxaliplatin against orthotopic xenografts in vivo in colorectal cancer by downregulating the levels of B7-H1 and B7-H3, predictors of adverse clinical outcomes in CRC. Jiang et al. [75] found Ginsenoside Rg3 enhances the anti-proliferative activity of erlotinib in pancreatic cancer cell lines by downregulation of EGFR/PI3K/Akt signaling pathway. Lee [59] et al. found that ginsendoside Rg3 sensitize TRAIL-induced cell death by via CHOP-mediated DR5 upregulation in human hepatocellular carcinoma cells.

Deng et al. [76] proved that ginsenoside Rb1 exerted strong cytotoxicity to tumor stem cells. Rb1 and its metabolites can effectively inhibit the growth of ovarian cancer stem cells, promoting cells more sensitive to clinical-related doses of chemotherapeutic drugs, such as cisplatin and paclitaxel. The mechanism is that by suppressing the Wnt/β-catenin signaling and EMT. Studies delivered by Nakata indicated that ginsenoside Rh2 combined with cisplatin can enhance the therapeutic effect in ovarian cancer, since Rh2 sensitized ovarian cancer cell to cisplatin in vitro and in vivo [77]. The membrane transporter MDR-1, located on the lipid rafts of the plasma membrane, and increased MDR-1 activity is an important contributor to multidrug resistance. Yun et al. [78] found that ginsenoside Rp1 repressed MDR-1 activity by redistributing lipid rafts, which reversed resistance to anti-tumor drugs, including doxorubicin. Chian found that GS-Rd significantly sensitized A549/DDP cells to therapeutic drugs by inhibiting NRF2 which could develop multidrug resistance [79]. Zheng K et al. [28] found that ginsenoside Ro potentiates 5-Fu cytotoxicity via delaying CHEK1 (checkpoint kinase 1) degradation and downregulating DNA replication process, resulting in the delayed DNA repair and the accumulation of DNA damage.