Anti-cancer effects of Gynostemma pentaphyllum (Thunb.) Makino (Jiaogulan)
© The Author(s) 2016
Received: 30 January 2015
Accepted: 19 September 2016
Published: 27 September 2016
Gynostemma pentaphyllum (Thunb.) Makino (GpM) (Jiaogulan) has been widely used in Chinese medicine for the treatment of several diseases, including hepatitis, diabetes and cardiovascular disease. Furthermore, GpM has recently been shown to exhibit potent anti-cancer activities. In this review, we have summarized recent research progress on the anti-cancer activities and mechanisms of action of GpM, as well as determining the material basis for the anti-cancer effects of GpM by searching the PubMed, Web of Science and China National Knowledge Infrastructure databases. The content of this review is based on studies reported in the literature pertaining to the chemical components or anti-cancer effects of GpM up until the beginning of August, 2016. This search of the literature revealed that more than 230 compounds have been isolated from GpM, and that most of these compounds (189) were saponins, which are also known as gypenosides. All of the remaining compounds were classified as sterols, flavonoids or polysaccharides. Various extracts and fractions of GpM, as well as numerous pure compounds isolated from this herb exhibited inhibitory activity towards the proliferation of cancer cells in vitro and in vivo. Furthermore, the results of several clinical studies have shown that GpM formula could have potential curative effects on cancer. Multiple mechanisms of action have been proposed regarding the anti-cancer activities of GpM, including cell cycle arrest, apoptosis, inhibition of invasion and metastasis, inhibition of glycolysis and immunomodulating activities.
Cancer is the world’s leading cause of death, accounting for 8.2 million deaths in 2012, and it is expected that the annual number of global cancer cases will rise from 14 million in 2012 to 22 million within the next two decades . The isolation and evaluation of anti-cancer agents and lead compounds from natural resources represents a traditional and effective approach for the development of new drugs for the treatment of cancer [2, 3], as exemplified by Paclitaxel, which was derived from Taxus brevifolia [3, 4].
Gynostemma pentaphyllum (Thunb.) Makino (GpM) (Jiaogulan) has been widely used in Chinese medicine for the treatment of various diseases, including hepatitis, diabetes and cardiovascular disease. Modern medical research has shown that GpM exhibits a variety of pharmacological properties, including anti-inflammatory [5–8], antioxidative [9–13], lipid metabolism regulatory [14–18], antiproliferative [19–22], neuroprotective [23, 24] and anxiolytic activities [25–27]. GpM has consequently been widely used for the treatment of hepatitis [15, 28–30], diabetes [11, 30–32], cardiovascular disease [33–35] and cancer [20, 23, 36, 37]. GpM is also widely used as a health supplement in beverages, biscuits, noodles, face washes and bath oils [38–41].
We have conducted a comprehensive review of the literature associated with GpM to provide a summary of recent research towards the anti-cancer activities and mechanisms of action of GpM. We have also searched the PubMed, Web of Science and China National Knowledge Infrastructure (CNKI) databases to identify the material basis for the anti-cancer effects of GpM.
Literature search strategy and exclusion criteria
Strategy in searching PubMed and Web of Science
Web of Science
1 or 2 or 3
4 or 5 or 6
7 or 8 or 9
10 and 11
10 and 12
13 or 14
Strategy in searching CNKI
1, 2 and 3
Chemical components of GpM
Over 230 compounds have been identified as being derived from GpM and can be grouped according to their chemical structures into saponins, sterols, flavonoids, polysaccharides and several other compound classes.
Structures and in vitro anti-cancer activity of identified GpM components
HL-60, Colon 205, Du145, GC-7901, BEL-7402
HL-60, Colon 205, Du145, GC-7901, BEL-7402
HL-60, Colon 205, Du145, GC-7901, BEL-7402
HL-60, Colon 205, Du145, GC-7901, BEL-7402
HL-60, Colon 205, Du145, GC-7901, BEL-7402
HL-60, Colon 205, Du145, GC-7901, BEL-7402
HL-60, Colon 205, Du145, GC-7901, BEL-7402
67.66 ± 3.36 (HL-60), 18.45 ± 0.93 (MCF-7), 34.95 ± 0.93(HT-29), 20.97 ± 1.49 (A549), 27.68 ± 1.58 (SK-OV-3)
>109.2 (HL-60), 42.81 ± 3.60 (MCF-7), 22.06 ± 2.18 (HT-29), 31.45 ± 2.62 (A549), 30.25 ± 1.53 (SK-OV-3)
>107.6 (HL-60), 23.03 ± 1.40 (MCF-7), 46.30 ± 1.08 (HT-29), 21.09 ± 1.18 (A549), 35.62 ± 0.97 (SK-OV-3)
76.63 ± 2.98 (HL-60), 23.62 ± 1.02 (MCF-7), 39.34 ± 1.02 (HT-29), 19.90 ± 1.40 (A549), 19.90 ± 1.49 (SK-OV-3)
7.44 (HL-60), 27.80 (Colon 205), 24.12 (Du145)
0.05 ± 0.01 (A549), 0.25 ± 0.07 (U87)
12.54 ± 0.53 (A549)
34.94 ± 4.23 (A549)
40 ± 0.7 (HepG2)
38 ± 0.5 (HepG2)
41.89 (HCT116), 20.94 (HT-29), 32.61 (MCF-7)
41.40 (HCT116), 19.00 (HT-29), 28.82 (MCF-7)
32.00 ± 1.24 (HepG2)
21.38 ± 1.06 (HepG2)
74.3 ± 1.9 (A549)
18.41 (HT-29), 4.46 (MCF-7), 9.39 ± 0.9 (DI145), 6.93 ± 0.5 (22RV-1)
20.38 (HT-29), 13.51 (MCF-7)
16.14 (HT-29), 8.84 (MCF-7)
38.02 ± 2.98 (MDA-MB-453), 31.62 ± 1.76 (HCT116), 35.48 ± 3.81 (LNCaP), 35.48 ± 6.45 (MCF7)
47.6 (Hep3B), 39.3 (PC-3), 30.6 (A549) HL-60, MCF-7, HT-29, Colon 205, Du145, MDA-MB-435, U87, A549, SK-OV-3, HepG2, SGC-7901, BEL-7402, Huh-7, HA22T, SW620, Eca-109, SAS, L1210, WEHI-3, SW-480, KB/VCR, MCF-7/ADR
65.4 (B16), HT-29, B16, Hela, SW-1116, HepG2
Sterols are composed of 17 carbon atoms across four rings, i.e., three 6-carbon rings and a single 5-carbon ring, with a side chain extending from C17 containing nine or ten carbon atoms (Additional file 1: Table S1). Eighteen sterols were isolated from GpM and fully characterized using a unique method from 1986 to 1990 [61–67]. Briefly, GpM was extracted with CH2Cl2, and the extracted lipids were saponified with 5 % KOH in MeOH. After purification by column chromatography over silica gel, the sterol mixture was acetylated, crystallized and characterized using spectroscopic methods. This process resulted in the isolation of sterols with ergostane, cholestane and stigmastane skeletons. The structures of these 18 sterols are shown in Additional file 1: Table S1. These compounds contained one double bond between C5–C6, C7–C8 or C9–C11, with R2 = H or CH3 and R1 = hydrocarbon chain with 10 carbons, and one double bond or one alkynyl group.
Polysaccharides are major components of GpM, where they are typically conjugated with proteins . The molecular weight of the polysaccharides found in GpM varies from 9000 to 33,000 Da . Several different kinds of polysaccharides have been found in GpM, and the molar ratios of the monosaccharide components of these systems have been reported to vary considerably. For instance, the neutral polysaccharide fraction CGPP mainly consists of mannose, glucose, arabinose, rhamnose, galactose and glucuronic acid with molar ratios of 2.0:2.2:1.3:2.2:1.2:2.5 . Another polysaccharide fraction (NaCl eluted fraction of crude polysaccharides from GpM by DEAE-Sepharose CL-6B chromatography, GMC) consisted of glucose, galactose, mannose and fructose with the molar ratios of 1:2.17:1.25:1.02 . Furthermore, the water-soluble GpM polysaccharide fraction GP-I contains glucose, galactose, mannose, rhamnose and arabinose with molar ratios of 5.3:4.2:3.0:0.7:0.8 . Based on the differences in the possible arrangements of the monosaccharides, various polysaccharides have been isolated from GpM .
Flavonoids are an important class of polyphenol compounds that are widely distributed in fruits and vegetables, where they usually exist in their glycosidic form . In terms of their general structure, flavonoids consist of a 15-carbon skeleton, containing two phenyl rings (A and B) and a heterocyclic ring (C). The carbon structure of these compounds is usually abbreviated as C6–C3–C6. Several flavonoids have been isolated from GpM, including quercetin, rutin, ombuoside , ombuin , isorhamnetin-3-O-rutinoside, isorhamnetin , quercetin-di-(rhamno)-hexoside, quercetin-rhamno-hexoside, kaempferol-rhamno-hexoside and kaempferol-3-O-rutinoside , and the structures of these flavonoids are shown in Additional file 1: Table S2.
Other components of GpM
GpM contains various trace elements (e.g., Cu, Fe, Zn, Mn, Co, Ni, Se, Mo and Sr) , 18 amino acids  (including eight essential amino acids) and various vitamins and proteins, but the relative amounts of these components vary considerably across the different parts of the GpM plant (i.e., leaf, stem and subterranean stem) . Malonic acid , benzyl-O-β-d-glucopyranoside , lutein, vomifoliol, palmitic acid , linolenic acids [81, 82] and carrot glycosides  have also been isolated from GpM. Furthermore, Tsai et al.  reported the isolation of numerous carotenoids and chlorophylls from the carotenoid and chlorophyll fractions of GpM, respectively.
Anti-cancer activities of GpM
In vitro anti-cancer activities of GpM
The in vitro antiproliferative activities of some of the pure compounds and extracts isolated from GpM have been widely reported and the details of these materials are summarized in Table 3. Shi et al.  obtained four dammarane-type triterpene saponins (compounds 3–6) from the aerial parts of GpM, which exhibited moderate cytotoxic activities in vitro against several human cancer cell lines, including HL-60 (human promyelocytic leukemia cells), Colon 205 (human colon cancer cells) and Du145 (human prostate carcinoma cells) cells. Yin et al.  isolated nine dammarane saponins from the methanol extract of the aerial part of GpM, and found that compounds 7, 8 and 9 exhibited inhibitory activities towards the growth of SGC-7901 (stomach cancer cells) and BEL-74020 (hepatocellular carcinoma cells) at a concentration of 100 μM with percentage inhibition values of 21, 93 and 8 %, and 77, 92 and 40 %, respectively.
Almost all of the compounds and extracts isolated from GpM to date have be reported to exhibit noticeable antiproliferative activities with IC50 values ranging from 0.05 to 74.3 μg/mL (Table 3). Compound 16 exhibited potent antiproliferative activities against A549 human lung cancer cells and U87 glioblastoma cells with IC50 values of 0.05 and 0.25 μg/mL, respectively. Compound 15 showed antiproliferative activity against MDA-MB-435 human breast cancer cells with an IC50 value of 3.90 μg/mL, whereas the carotenoid fraction of GpM exhibited the strongest activities of all of the reported extracts with an IC50 value of 1.6 μg/mL against Hep3B human hepatocellular carcinoma cells.
The hydrolysates of the extracts of GpM have also been reported to exhibit anti-cancer activities, together with several other derivatives of the natural products found in GpM. For example, Chen et al.  reported the synthesis of four sulfated derivatives of GPP2, which is a native polysaccharide isolated from GpM. One of the sulfated derivatives prepared by Chen (GPP2-s4) inhibited the growth of HepG2 human hepatocellular carcinoma cells by 46.4 ± 2.8 % at a concentration of 2000 μg/mL. Compared with GPP2, all four sulfated derivatives exhibited stronger antiproliferative activities against HeLa cervical cancer cells at concentrations as low as 100 μg/mL. GP-B1, which is an acidic polysaccharide derived from GpM, significantly inhibited the growth of B16 melanoma cells with an IC50 of 65.4 μg/mL with very little cytotoxicity against normal cells . Moreover, GP-B1 not only significantly inhibited the growth of cancer cells, but also improved cellular immune response by increasing levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-10 (IL-10) and interleukin-12 (IL-12) observed in the serum of melanoma-B16-bearing mice .
In vivo anti-cancer activities of GpM
In vivo anti-cancer activity of identified GpM components
Nude mice: xenografted with human oral cancer SAS cells
65.76 % (tumor size, 20 mg/kg for 28 days)
BALB/c mice: injected with human leukemia WEHI-3 cells
150 % (survival rate, 2 mg/kg for 2 weeks)
175 % (survival rate, 4 mg/kg for 2 weeks)
Nude mice: xenografted with human leukemia HL-60 cells
44 % (tumor size, 20 mg/kg for 28 days)
BALB/c mice: xenografted with murine S180 sarcoma cells
39.57 % (tumor size, 30 mg/kg for 4 days)
BALB/c mice: xenografted with murine colorectal cancer CT-26 cells
75 % (tumor size, 25 mg/kg for 19 days)
55 % (tumor size, 50 mg/kg for 19 days)
26 % (tumor size, 50 mg/kg + 5 mg/kg 5-Fu for 19 days)
Apc Min/+ mice: intestinal neoplasia model
66.06 % (polyps number, 500 mg/kg for 4 weeks)
59.92 % (polyps number, 750 mg/kg for 4 weeks)
Apc Min/+ mice: intestinal neoplasia model
59.32 % (polyps number, 500 mg/kg for 8 weeks)
BALB/c mice: xenografted with murine S180 sarcoma cells
62.77 % (tumor size, 100 mg/kg for 14 days)
59.24 % (tumor size, 200 mg/kg for 14 days)
ICR mice: xenografted with mouse hepatoma H22 cells
62.89 % (tumor size, 50 mg/kg for 10 days)
49.22 % (tumor size, 200 mg/kg for 10 days)
A polysaccharide from GpM inhibited the development of transplanted S180 sarcoma in a dose-dependent manner and increased the phagocytosis of macrophages, as well as increasing the production of NO, IL-1β and TNF-α from the peritoneal macrophages . The neutral polysaccharide fraction CGPP inhibited the growth of H22 hepatocarcinoma cells transplanted into ICR mice . CGPP treatment also led to improvements in the body weight, spleen/thymus index and degree of splenocyte proliferation in tumor-bearing mice . Furthermore, CGPP treatment led to considerable increases in the levels of cytokines, such as IL-2, TNF-α and IFN-γ in tumor-bearing mice, as well as increases in the activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL) . The tumor inhibitory and immunoregulatory effects of CGPP greatly increased the life span of H22 ascites in tumor-bearing mice .
Clinical anti-cancer studies on GpM
Clinical uses of GpM
Patient tumor type
16.44 % (relapse rate)
15.40 % (metastasis rate)
14.23 % (relapse and metastasis rate)
129.56 % (NK cell activity)
157 % (T lymphocyte transformation rate)
78.4 % (IgG levels)
75.1 % (IgA levels)
59.9 % (IgM levels)
128 % (curative rate)
Middle-late gastric cancer
163 % (short term curative rate)
140 % (quality of life)
Mechanisms of action
Cell cycle arrest
Gyps induced cell cycle arrest at the G0/G1 phase SAS human oral cancer cells , WEHI-3 leukemia cells , A549 human lung adenocarcinoma cells , HL-60 human myeloid leukemia cells  and Colo 205 human colon cancer cells . Gyps also induced cell cycle arrest by modulating the expression of several cell cycle regulatory proteins, including cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) [21, 106]. The treatment of SCC-4 human tongue cancer cells with Gyps induced checkpoint kinase 2 (Chk2) expression. This effect subsequently led to the upregulation of p53 and its targets p21 and p16, which led to decreased levels of cyclin D and cyclin E and G0/G1 cell cycle arrest . The treatment of PC-3 human prostate carcinoma cells with flavonoids and saponins isolated from GpM led to cell cycle arrest in the S and G2/M phases in both cases by modulating the expression of cyclins . Furthermore, A549 cells treated with flavonoids from GpM went into cell cycle arrest in the S and G2/M phases, and showed upregulated levels of Cyclin A, Cyclin B, p21 and p53 .
Induction of apoptosis
A large number of studies have shown that GpM exerts its anti-cancer activities by inducing cellular apoptosis through various signaling pathways. Gyps downregulated the anti-apoptotic proteins Bcl-2 and Bcl-xL, and upregulated the pro-apoptotic proteins Bax, Bad and Bak, thereby activating the formation of Bax/Bak pores on the outer mitochondrial membrane [89–91, 107, 108]. Bax/Bak pores allow for the release of cytochrome c and other pro-apoptotic proteins into the cytosol, leading to the activation of initiator caspases-8 and -9, followed by the cleavage of effector caspase-3, which ultimately triggers apoptosis [104–106]. The formation of Bax/Bak pores following Gyps treatment also led to the release of apoptosis inducing factor (AIF) and endonuclease G (EndoG) from the mitochondria [89, 106], following DNA fragmentation and chromatin condensation.
Gyps also induced the production of reactive oxygen species (ROS) [36, 89, 105, 106, 108, 109] and led to increased intracellular Ca2+ concentrations [89–91, 105, 106, 108]. ROS and Ca2+ are both well-studied modulators of the permeability transition pores located on the inner mitochondrial membrane. The opening of these pores leads to an influx of solutes and water into the mitochondrial matrix, causing the outer mitochondrial matrix to swell and rupture, which leads to the release of cytochrome c and apoptosis [89–91, 105–107]. Gyps treatment led to increased levels of DNA-damage-inducible transcript 3 (GADD153), glucose-regulated protein (GRP78), activating transcription factor 6 alpha (ATF6-α) and activating transcription factor 4 alpha (ATF4-α). These increases resulted in endoplasmic reticulum (ER) stress, which could result in the release of Ca2+ from the ER [89–91, 106]. Moreover, Sun et al.  reported increased store-operated Ca2+ entry as another mechanism of action for the activity of Gyps.
Furthermore, Gyps induced dose-dependent DNA damage in SAS cells and reduced the expression of several DNA repair genes, including ataxia telangiectasia mutated, ataxia-telangiectasia and Rad3-related, breast cancer gene 1, 14-3-3σ, DNA-dependent serine/threonine protein kinase and p53, in a time-dependent manner. In this way, Gyps treatment stalled the DNA damage repair process, forcing the cells to undergo apoptosis [109, 111].
Several other components and fractions of GpM have also been reported to induce apoptosis. For instance, flavonoids  and a water extract  from GpM induced apoptosis in tumor cells via the regulation of the Bcl-2 protein family. Furthermore, an ethanolic extract from GpM selectively shifted the intracellular H2O2 concentration to toxic levels in tumor cells because of the increased superoxide dismutase activity of these cells compared with healthy cells .
Inhibition of invasion and metastasis
Gyps suppressed the invasion and migration of SCC4 human tongue cancer cells in a dose- and time-dependent manner by downregulating nuclear factor kappa B (NF-κB) and matrix metalloproteinase-9 (MMP-9) . Gyps also inhibited the invasion and migration of SAS cells, as demonstrated by the results of in vitro wound-healing and Boyden Chamber assays. Treatment with Gyps led to decreases in the levels of several migration- and invasion-associated proteins, including NF-κB, cyclooxygenase-2, extracellular signal-regulated kinase 1/2 (ERK1/2), matrix metalloproteinase-2 (MMP-2), MMP-9, sevenless homolog, Ras, urokinase-type plasminogen activator, focal adhesion kinase and alpha serine/threonine protein kinase . Furthermore, Gyps exhibited anti-migration activities towards SW620 human colon adenocarcinoma cells and Eca-109 human esophageal squamous carcinoma cells . Gyps also inhibited the migration of SW-480 human colon adenocarcinoma cells in vitro at a concentration of 100 μg/mL . This effect was observed in clinical studies. For example, patients with advanced malignant tumors that were treated with GpM formula showed a reduced cancer metastasis rate of 8.5 % compared with 55.2 % in the control group .
One of the hallmarks of cancer cells is deregulated energy metabolism, which can lead to a state known as ‘‘aerobic glycolysis’’ . Targeting glucose metabolism has therefore proven to be a promising avenue for the development of new cancer treatments . GpMix, which is a mixture of triterpenoid saponins from GpM, effectively inhibited the growth of cancer cells in the presence of co-cultivated normal cells . Furthermore, GpMix exhibited both chemopreventive and therapeutic effects towards the formation of intestinal polyps in Apcmin/+ mice (a mouse model of colon cancer). Several key enzymes along the glycolysis pathway, including pyruvate kinase (PK), α-enolase, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), mitochondrial aconitase and ATP synthase-α and -β were found to be downregulated in R6 cells treated with GpMix by proteomic analysis . These findings therefore implied that the inhibition of the glycolysis pathway was involved in the suppression of cell proliferation by GpMix.
GpM also exhibited anti-cancer effects indirectly through its immunomodulating activities. For example, Yang et al.  found that a water-soluble polysaccharide from G. pentaphyllum herb tea (PSGP) indirectly exerted anti-cancer activity against SW-1116 human colorectal adenocarcinoma cells and HT-29 by enhancing the immune response of macrophages with increased TNF-α secretion in a dose-dependent manner. Moreover, GP-B1, the acidic polysaccharide obtained from GpM, not only significantly inhibited the growth of cancer cells, but also improved cellular immune response with increased levels of TNF-α, IFN-γ, IL-10 and IL-12 in the serum of melanoma-B16-bearing mice . The anti-cancer activity of Gyps was attributed to the elevated immune systems of the xenografted mice . Gyps significantly suppressed tumor growth in mice transplanted with Lewis lung cancer cells with tumor weight inhibition rates of 29.8 ± 1.3, 51.4 ± 2.2 and 50.0 ± 1.6 % following intraperitoneal Gyps injections of 10, 20 and 40 mg/kg, respectively. Notably, the immune responses of these mice improved considerably, as demonstrated by increases in their total splenic cell number and the enhanced biological activities of the NK and splenic cells . Clinical studies have also shown that GpM enhanced the activity of NK cells in breast cancer patients , improved the immune function of cancer patients after chemotherapy, increased the T lymphocyte transformation rate and decreased the IgG and IgM levels .
Numerous studies have been published during the last four decades regarding the anti-cancer effects of GpM, including reports focused on (i) the isolation and characterization of its chemical components [121, 122]; (ii) the evaluation of its anti-cancer activities and mechanisms of action [107, 115]; and (iii) studies on its toxicity . Taken together, the results of these reports have demonstrated that GpM has a broad anti-cancer spectrum (against 30 cancer cell lines, Table 3) without any obvious inhibitory effect on normal cell proliferation. However, there are limitations associated with most of these studies.
The standard preparation of Gyps needs to be unified
Gyps consist of a mixture of approximately 189 dammarane-type saponin glycosides. Most of the studies reported to date on GpM have focused exclusively on the use of its fractions, such as Gyps, as well as the use of its extracts. In contrast, there have been very few reports pertaining to the use of single compounds isolated from GpM. For example, in all of the papers published during the last 15 years regarding the anti-cancer mechanisms of GpM there has only been one study involving the use of single compounds. Based on to the lack of chemical consistency in the fractions and extracts of GpM, greater efforts should be taken to explore the anti-cancer activities of single compounds derived from GpM in future studies, where possible. Moreover, none of the Gyps tested in any of the studies reported to date were prepared using a unified procedure, which could have led to completely different chemical component profiles amongst the different samples. Most of these studies also failed to provide essential chemical composition information for their Gyps, such as the exact molecular structure of each saponin, the number of saponins in the mixture, the relative contents of the different saponins in Gyps and a standard HPLC fingerprint [19, 89, 90, 106, 107, 109, 111, 115]. Studies on the chemical structures of the saponins in Gyps are therefore urgently needed, as well as further studies towards the chemical composition and the quantitative analysis of Gyps. These data would allow researchers to develop a deeper understanding of the anti-cancer activities and mechanisms of action of Gyps and facilitate further studies.
Experimental systems need to be closer to the clinical settings
Most of the studies reported to date concerning the anti-cancer activities and mechanisms of action of GpM have been conducted using in vitro cellular systems. This trend could therefore explain why non-specific cell cycle arrest and the induction of apoptosis have been cited, in the majority of cases, as the principal mechanisms of action of GpM [89, 104, 106], with very few reports citing specific molecular targets or enzymatic pathways. In contrast, most of the in vivo studies conducted on GpM, have focused on the use of cancer cell lines implanted into immunodeficient mice [20, 90, 91]. According to this model, cancer cell lines are selected to survive in culture, and tumor-resident cells and proteins that interact with the cancer cells are eliminated to give a phenotypically homogeneous culture . Patient-derived tumor xenograft (PDTX) models have several advantages over cell line xenograft models, such as maintaining the heterogeneity of the tumor and mimicking the microenvironment of human tumors . Humanized-xenograft models can also be created by co-engrafting a sample of a patient-derived tumor together with peripheral blood or bone marrow cells into an immunodeficient mouse, followed by the reconstitution of the murine immune system. Advanced tumor models of this type can be used to study the interactions between xenogenic human stroma and tumor environments in cancer progression and metastasis . Genetically engineered mouse models represent an interesting alternative for evaluating the effects of anti-cancer agents because these animals maintain a competent immune system, allowing for changes in the tumor microenvironment and the tumor itself to be thoroughly evaluated from an early stage . Based on our review of the literature, we believe that further experiments should be performed in a PDTX, humanized-xenograft or genetically engineered mouse model to evaluate the effects of GpM on tumor development with greater clinical accuracy. The latter of these two models would be especially interesting in terms of evaluating the potential immunomodulatory activity of GpM.
In summary, GpM has been investigated extensively as a potent anti-cancer agent against many types of cancers both in vitro and in vivo. The general consensus from the literature is that GpM exerts its anti-cancer activities through multiple mechanisms, including cell cycle arrest, the induction of apoptosis, inhibition of invasion and metastasis, glycolysis inhibition and immunomodulation.
apoptosis inducing factor
alpha serine/threonine protein kinase
acid α-naphthyl acetate esterase
activating transcription factor 4 alpha
activating transcription factor 6 alpha
ataxia telangiectasia mutated
ataxia-telangiectasia and Rad3-related
cyclin-dependent kinase 2
cyclin-dependent kinase 4
cyclin-dependent kinase 6
checkpoint kinase 2
DNA-dependent serine/threonine protein kinase
extracellular signal-regulated kinase ½
focal adhesion kinase
growth arrest and DNA damage-inducible gene 153
Gynostemma pentaphyllum (Thunb.) Makino
glyceraldehydes 3-phosphate dehydrogenase
glucose-regulated protein 78
nuclear factor kappa B
cytotoxic T lymphocytes
tumor necrosis area
tumor necrosis factor-α
tumor total area
urokinase-type plasminogen activator
YL, WL, JH, XY and WM conceived and designed the review. YL, WL, JH, XY and WM wrote the manuscript. All authors read and approved the final manuscript.
This work was supported by Grants from the Science and Technology Development Fund (FDCT) of Macau (Project codes: 034/2015/A1 and 088/2012/A3).
The authors declare that they have no competing interests.
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