Anticancer effects and potential mechanisms of ginsenoside Rh2 in various cancer types (Review)
- Authors:
- Published online on: February 19, 2021 https://doi.org/10.3892/or.2021.7984
- Article Number: 33
Abstract
Introduction
Cancer is the second leading cause of death globally, responsible for ~9.6 million deaths in 2018 (1). The main forms of cancer treatments are surgery, radiotherapy, chemotherapy and hormone therapy. Adjuvant chemotherapy following surgery has been proven to decrease recurrence and improve patient survival time (2,3). Natural products have been major sources for the active ingredients in numerous medicines. Compared with synthetic products, natural products generally have fewer toxic effects and are less expensive. Ginseng, derived from the rhizome and root of Panax ginseng Meyer (P. ginseng), is a popular herbal medicine that has been used in Asian countries (e.g., China, Japan and Korea) for thousands of years. It is well known for its disease-preventing and therapeutic effects.
Ginsenosides are the main active chemical constituents of P. ginseng. To date, >100 types of ginsenosides have been isolated and identified from P. ginseng (4). Among them, ginsenoside Rh2 (G-Rh2) exhibits various biological activities, such as improvement in learning and memory (5), promotion of immunity (6), and antioxidant (7), anti-inflammatory (8–11), antihyperglycemic (12) and antitumor (13–21) effects. Increasing evidence shows that G-Rh2 exerts antitumor effects in a variety of cancer models, including human lung (22–26), liver (27,28), gastric (29), colorectal (17,18,30,31), breast (32–34), prostate (13,14,35–37) and pancreatic (20) cancer, leukemia (38–41) and ovarian cancer (42–45). The functional mechanisms of G-Rh2 mainly include inducing apoptosis, arresting the cell cycle, inhibiting proliferation, angiogenesis and metastasis, and regulating the tumor microenvironment to promote immunity. Additionally, combining G-Rh2 with chemotherapy drugs can reverse drug resistance and enhance drug sensitivity in various cancer types. These topics will be described later in the review. Therefore, this review provides a systematic summary of the anticancer effects of G-Rh2 in order to facilitate further studies involving G-Rh2.
Chemical properties of G-Rh2
The ginsenosides are classified as 20(S)-protopanaxadiol compounds (including ginsenosides Rb1, Rb2, Rc, Rh2 and Rg3, among others) or 20(S)-protopanaxatriol compounds (including ginsenosides Re, Rg1 and Rg2, among others). G-Rh2 has been found to inhibit the growth of various human cancer cell types, such as lung cancer cells (22–25), liver cancer cells (27,28) and colorectal cancer cells (17,30,31). The chemical formula for G-Rh2 is C36H62O8, and the molecular weight is 622.87; it is a white crystal with strong biological activity. The antitumor activity of ginsenosides is related to factors such as the type of ginsenoside, the substituents, and the number and configuration of sugars. Due to the different spatial structures at the C20 position, there are two stereoisomeric forms of G-Rh2: 20(S)-G-Rh2 and 20(R)-G-Rh2 (Fig. 1). In comparison with 20(R)-G-Rh2, 20(S)-G-Rh2 shows more potent anticancer activity among different cancer cells (35,46). One study reported that the half maximal inhibitory concentration values of 20(S)-G-Rh2 and 20(R)-G-Rh2 in A549 cells were 45.7 and 53.6 µM, respectively (46). Another study compared the effect of 20(S)-G-Rh2 and 20(R)-G-Rh2 on LNCaP, PC3 and DU145 cells. The results showed that 25 µM 20(S)-G-Rh2 inhibited LNCaP proliferation by 70%, PC3 cell proliferation by 40% and DU145 cell proliferation by 20%, while 25 µM 20(R)-G-Rh2 did not affect the proliferation of these cells (35). In addition, cytotoxic potency is generally in the descending order of protopanaxadiol, 20(S)-G-Rh2 and then 20(R)-G-Rh2, indicating structure-related activities in which the compound with less polar chemical structures possesses higher cytotoxic activity towards cancer cells (47). As much of the literature does not indicate whether 20(S)-G-Rh2 or 20(R)-G-Rh2 is used, the term G-Rh2 in this review includes both of these configurations.
Anticancer effects and mechanisms of G-Rh2 in in vitro studies
Previous studies have demonstrated that G-Rh2 exerts significant anticancer activities through multiple molecular mechanisms. The mechanisms are mainly related to cell cycle arrest, apoptosis, proliferation, invasion, metastasis, angiogenesis, autophagy and immunity, which are summarized in Table I and Fig. 2. Although the anticancer activity of G-Rh2 has been widely investigated, the exact molecular mechanisms remain unclear. Based on existing research, the possible mechanisms of action of G-Rh2 are described in this review.
Induction of cell cycle arrest
The cell cycle is a controlled process involved in the growth, differentiation and proliferation of eukaryotic cells (48). Cells that undergo cell cycle arrest lose their ability to replicate and divide. Cyclin-dependent kinase (CDK) inhibitors are crucial for controlling the cell cycle and cell proliferation (49). The CDK inhibitor p21 plays a key role in the G1 phase cell cycle checkpoint (50). G-Rh2 was reported to induce cell cycle G1 phase arrest in MCF-7 cells by increasing p21 levels and decreasing CDK2 and cyclin E-dependent kinase activities (32). In human glioma A172 cells, G-Rh2 induced cell cycle G1 phase arrest by downregulating CDK4 and cyclin E (21). In human lung cancer A549 cells, G-Rh2 induced cell cycle G1 phase arrest by significantly reducing the expression of CDK4 and cyclin D1 (51). Furthermore, G-Rh2 induced cell cycle G1 phase arrest in HL-60 and U937 cells by downregulating the expression of CDK4, CDK6, cyclin D1, cyclin D2, cyclin D3 and cyclin E. G-Rh2-mediated G1 phase arrest and differentiation are closely linked to the regulation of TGF-β production in human leukemia cells (52).
Induction of apoptosis
Apoptosis (programmed cell death) plays an important role in animal development and adult life by eliminating damaged cells (53). The induction of apoptosis in cancer cells can inhibit tumor growth (54). Treatment of colorectal cancer cells with G-Rh2 has been proven to activate the p53 pathway, increasing the expression of the proapoptotic regulator Bax and decreasing the expression of the antiapoptotic regulator Bcl-2 (30). The extrinsic pathway and the intrinsic pathway are two core apoptotic pathways in mammalian cells (55). As shown in Table I, G-Rh2 can induce apoptosis via these two pathways. It was previously shown that G-Rh2 induced apoptosis by downregulating Bcl-2 and survivin and upregulating Bax, cleaved caspase-3 and cleaved caspase-9 in human pancreatic cancer Bxpc-3 cells (20). G-Rh2-triggered intrinsic apoptosis was related to the induced translocation of cytosolic Bak and Bax to the mitochondria, cytochrome c release and caspase-9 activation in HeLa and SW480 cells (56). G-Rh2 may induce apoptosis of Kasumi-1 and U937 leukemia cells via microRNA-21-modulated suppression of Bcl-2 (57). In addition, cotreatment with G-Rh2 and betulinic acid could induce apoptosis of HeLa, A549 and HepG2 cancer cells by enhancing caspase-8 expression, cytochrome c release and Bax translocation (58).
Inhibition of proliferation
Abnormal regulation of cell proliferation is the key cause of cancer development and progression (59). Both activation of oncogenes and the inactivation of tumor suppressor genes can promote the proliferation of cancer cells. Protein kinase B (Akt) is one of the well-known proto-oncogenes, and activated Akt promotes cancer cell proliferation and survival (60). G-Rh2 has been shown to inhibit HeLa and A172 cell proliferation by suppressing the Akt pathway (15,21). Another study revealed that G-Rh2 inhibited the proliferation of HCT116 colon cancer cells by targeting PDZ-binding kinase/T-LAK cell-originated protein kinase and downregulating the expression of p-ERK1/2 and p-histone H3 (17). G-Rh2 inhibits the proliferation of K562 and KG1-α cells by suppressing the expression and activity of HDAC1, HDAC2, and HDCA6, increasing histone H3 acetylation and regulating MAPK/JNK signaling pathways (61). Additionally, G-Rh2 could inhibit cancer cell proliferation by suppressing endoplasmic reticulum (ER) stress (22), by inhibiting the Src/ERK signaling pathway (62) and by targeting microRNA-128 (63).
Inhibition of invasion and metastasis
Metastasis is the main cause of cancer treatment failure and recurrence. During metastasis, the cells become highly plastic or adaptive, similar to stem cells. This change is called epithelial-mesenchymal transition (EMT) (64). G-Rh2 could effectively inhibit tumor metastasis by suppressing EMT. G-Rh2 has been found to inhibit migration and invasion by increasing E-cadherin and suppressing vimentin expression in endometrial cancer cells (65) and oral cancer cells (62). In addition, matrix metalloproteinases (MMPs) play an important role in tumor metastasis, where they can degrade the extracellular matrix and basement membrane (66). G-Rh2 was previously found to effectively inhibit Bxpc-3 cell migration and invasion by downregulating MMP-2 and MMP-9 (20). Moreover, G-Rh2 was reported to significantly reduce the protein levels of VEGF, MMP-2 and MMP-9 in co-cultured lung cancer cells (23) and oral cancer cells (67). Therefore, G-Rh2 may play an inhibitory role in the process of cancer metastasis.
Anti-angiogenesis
Angiogenesis plays an important role in tumor growth and metastasis by providing the necessary nutrients and oxygen (68). TGF-β is a potent angiogenesis inducer in vivo (69). Anti-angiogenic treatment for tumors is considered a promising therapeutic strategy (70). G-Rh2 was reported to inhibit prostate cancer growth by impeding angiogenesis via decreasing the expression of CD31, VEGF, platelet-derived growth factor and CNNM1 in cancer cells (13). Furthermore, G-Rh2 could affect tumor angiogenesis by downregulating JAM expression in tumors (71).
Induction of autophagy
Autophagy is a catabolic process that degrades cytoplasmic constituents and organelles in lysosomes (72). There is increasing evidence that autophagy signaling is closely related to oncogenic signaling. Autophagy may be one of the effective ways to prevent the formation and progression of tumors (72). Selective targeting of autophagy for cancer treatment has attracted considerable attention (73). The autophagy-related genes ATG5, ATG7, LC3B and beclin-1 were upregulated after treatment with G-Rh2 in U937 and K562 cells (74). The formation of autophagosomes involves the conversion from cytosolic LC3-I to the autophagosome-associating form of LC3-II (75). Treatment of U937 and K562 cells with G-Rh2 was found to induce the conversion from LC3-I to LC3-II and downregulate the protein level of p62 (74). G-Rh2 treatment increased autophagy through upregulating autophagy-related proteins Beclin, Atg7 and the ratio of LC3-II to LC3-I in A431 cells (76). Another study reported that G-Rh2 could promote cell autophagy in human retinoblastoma cell lines Y79 and RBL-13 by inactivating the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway (77).
Reverse drug resistance
Drug resistance is the leading cause of failure of cancer chemotherapy. Several studies have suggested that G-Rh2 has a role in reversing drug resistance and improving treatment efficacy. G-Rh2 has been found to reverse oxaliplatin resistance in colon cancer cells through decreasing the expression of P-glycoprotein (78), and to reverse drug resistance in Adriamycin-resistant human breast cancer MCF-7 cells (79). Another study reported that G-Rh2 effectively reversed 5-flurouracil resistance in colorectal cancer cells by regulating MDR1, MRP1, LRP and GST gene expression (80). In addition, G-Rh2 could enhance the antitumor effects of SMI-4a by increasing autophagy in melanoma cells (81) and could enhance the anticancer effects of cisplatin and prolong the survival time of nude mice (43). These reports suggest that G-Rh2 has an adjunctive effect in cancer chemotherapy and can delay the occurrence of drug resistance.
Promotion of immunity
It is well known that certain cancer treatments can temporarily weaken the immune system, and that enhancing the immune response could play an important role in cancer treatment. Ginseng has a long history of improving the immunity of patients in Asia. A growing number of studies indicate that G-Rh2 can improve immunity. One study reported that G-Rh2 enhanced the antitumor immunological response by triggering CD4+ and CD8a+ T-lymphocyte infiltration in B16-F10 melanoma cells derived from xenograft tumor tissues, as well as enhancing the cytotoxicity in spleen lymphocytes (82). Another study found that G-Rh2 could downregulate CASP1, INSL5 and OR52A1, and upregulate CLINT1, ST3GAL4 and C1orf198 expression in MCF-7 cells, indicating that G-Rh2 induces epigenetic methylation changes in genes involved in the immune response and tumorigenesis, thereby contributing to enhanced immunogenicity and inhibiting the growth of cancer cells (33). G-Rh2 suppressed T-cell acute lymphoblastic leukemia (T-ALL) by blocking the PI3K/Akt/mTOR signaling pathway and enhanced immunity in the spleen by downregulating IL-4, IL-6, IL-10, CD3 and CD45, and upregulating IL-2 and INF-γ, and increased the number of natural killer cells (83). These studies indicate that G-Rh2 has the ability to enhance the immune response, which may play a role in the prevention and treatment of cancer.
Anticancer effects and mechanisms of G-Rh2 in in vivo studies
G-Rh2 exhibits anticancer effects in a number of animal models (17,22,36,43,61,83,84). Table II summarizes the anticancer effects of G-Rh2 in in vivo studies. In colon cancer xenograft mouse models, 10 and 50 mg/kg G-Rh2 three times a week via intraperitoneal injection significantly suppressed HCT116 ×enograft tumor growth, and further research indicated that G-Rh2 could downregulate p-ERK1/2 and p-H3 expression by inhibiting TOPK activity in vivo (17). In lung cancer H1299 cell xenograft mouse models, G-Rh2 significantly inhibited lung cancer cell growth by inducing reactive oxygen species (ROS)-mediated ER stress in vivo (22). In leukemia K562 cell xenograft mouse models, treatment with G-Rh2 (20 mg/kg once a day for 3 weeks) significantly inhibited tumor growth in vivo (61). G-Rh2 was found to suppress HepG2 cell xenograft tumor growth (84,85), and the anticancer mechanism of G-Rh2 in HepG2 cells was related to downregulating β-catenin through the activation of glycogen synthase kinase-3β (85). In addition, G-Rh2 has poor oral absorption and low bioavailability. In vivo metabolism and pharmacokinetic studies indicated that oxygenation and deglycosylation were the major metabolic pathways of G-Rh2 (86); the deglycosylation of G-Rh2 led to formation of protopanaxadiol and the oxygenation of G-Rh2, and protopanaxadiol produced two monooxygenated metabolites (86). Another study reported that (24R)-pseudo-ginsenoside HQ and (24S)-pseudo-ginsenoside HQ are the main metabolites of 20(S)-G-Rh2 in vivo, with both of them showing antitumor activity through caspase and VEGF signaling pathways in H22-tumor bearing mice (87). After oral dosing, G-Rh2 was found to be distributed mainly to the liver and gastrointestinal tissues in rats. The bioavailability of G-Rh2 is ~5% in rats and 16% in dogs (88). Thus, modification of the chemical structure of G-Rh2 to increase bioavailability and enhance its pharmacological activity is also one of the current research directions.
Signaling pathway of G-Rh2 in cancer
According to current studies, the anticancer signaling pathway of G-Rh2 remains unclear. It was reported that G-Rh2 suppresses growth of oral squamous cell carcinoma cells by decreasing ROS, MMP-2 and VEGF (67). G-Rh2 inhibits glioma cell growth by targeting microRNA-128 (63) and inhibiting epidermal growth factor receptor (89). G-Rh2 induces leukemia cell differentiation and cell cycle arrest by upregulating TGF-β expression (52) and inducing apoptosis by inducing the release of mitochondrial cytochrome c and the activation of caspase-3 and −9 (90). In neuroblastoma cells, G-Rh2 induces apoptosis via activation of caspase-1 and −3 and upregulation of Bax (91). G-Rh2 suppresses cancer cell migration and invasion by downregulating the expression levels of MMP3 (92) and MMP13 (93), and by regulating CDKN2A-2B gene cluster transcription (84). G-Rh2 exerts anticancer activity in T-cell acute lymphoblastic leukemia cells (94), glioblastoma multiforme cells (95) and osteosarcoma cells (96) by suppressing the PI3K/Akt/mTOR signaling pathway. In addition, G-Rh2-induced DNA damage and autophagy in vestibular schwannoma is dependent on LAMP2 transcriptional suppression (97), and it improves the cisplatin effect in lung adenocarcinoma A549 cells by repressing superoxide generation and PD-L1 expression (98). Based on these reports, we hypothesize that PI3K/Akt/mTOR could be an important signaling pathway for G-Rh2 to exert its activity, which provides some context for further research on G-Rh2. The potential signaling pathways of G-Rh2 in cancer are demonstrated in Fig. 3.
Conclusions
As one of the main active components of ginseng, G-Rh2 has a wide range of pharmacological effects and plays a therapeutic role in numerous diseases. A number of studies have demonstrated that G-Rh2 exerts excellent anticancer activity in vitro and in vivo. G-Rh2 exerts its anticancer activity by inducing apoptosis, autophagy, cell cycle arrest and immunity, as well as by inhibiting proliferation, invasion, metastasis and angiogenesis. In addition, G-Rh2 in combination with specific anticancer drugs can overcome drug resistance and enhance the immune response. In summary, G-Rh2 exerts anticancer effects in vitro and in vivo, and is a promising agent for cancer prevention and treatment.
Acknowledgements
Not applicable.
Funding
No funding was received.
Availability of data and materials
Not applicable.
Authors' contributions
HBZ, SP, HH, EK and JY collected the literature and designed the study. HBZ drafted the manuscript. SKC, ZYR and MK revised the manuscript. ZYR and MK confirm the authenticity of all the raw data. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
All authors declare hat they have no competing interests.
References
|
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Shahab D, Gabriel E, Attwood K, Ma WW, Francescutti V, Nurkin S and Boland PM: Adjuvant chemotherapy is associated with improved overall survival in locally advanced rectal cancer after achievement of a pathologic complete response to chemoradiation. Clin Colorectal Cancer. 16:300–307. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Fujita K, Taneishi K, Inamoto T, Ishizuya Y, Takada S, Tsujihata M, Tanigawa G, Minato N, Nakazawa S, Takada T, et al: Adjuvant chemotherapy improves survival of patients with high-risk upper urinary tract urothelial carcinoma: A propensity score-matched analysis. BMC Urol. 17:1102017. View Article : Google Scholar : PubMed/NCBI | |
|
Lu JM, Yao Q and Chen C: Ginseng compounds: An update on their molecular mechanisms and medical applications. Curr Vasc Pharmacol. 7:293–302. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Hou J, Xue J, Lee M, Liu L, Zhang D, Sun M, Zheng Y and Sung C: Ginsenoside Rh2 improves learning and memory in mice. J Med Food. 16:772–776. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Qian Y, Huang R, Li S, Xie R, Qian B, Zhang Z, Li L, Wang B, Tian C, Yang J, et al: Ginsenoside Rh2 reverses cyclophosphamide-induced immune deficiency by regulating fatty acid metabolism. J Leukoc Biol. 106:1089–1100. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Choi WY, Lim HW and Lim CJ: Anti-inflammatory, antioxidative and matrix metalloproteinase inhibitory properties of 20(R)-ginsenoside Rh2 in cultured macrophages and keratinocytes. J Pharm Pharmacol. 65:310–316. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang XP, Li KR, Yu Q, Yao MD, Ge HM, Li XM, Jiang Q, Yao J and Cao C: Ginsenoside Rh2 inhibits vascular endothelial growth factor-induced corneal neovascularization. FASEB J. 32:3782–3791. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Zhou J, Gao Y, Yi X and Ding Y: Ginsenoside Rh2 suppresses neovascularization in xenograft psoriasis model. Cell Physiol Biochem. 36:980–987. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Choi K, Kim M, Ryu J and Choi C: Ginsenosides compound K and Rh(2) inhibit tumor necrosis factor-alpha-induced activation of the NF-kappaB and JNK pathways in human astroglial cells. Neurosci Lett. 421:37–41. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Bae EA, Kim EJ, Park JS, Kim HS, Ryu JH and Kim DH: Ginsenosides Rg3 and Rh2 inhibit the activation of AP-1 and protein kinase A pathway in lipopolysaccharide/interferon-gamma-stimulated BV-2 microglial cells. Planta Med. 72:627–633. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Wang Y, Wang H, Liu Y, Li C, Qi P and Bao J: Antihyperglycemic effect of ginsenoside Rh2 by inducing islet β-cell regeneration in mice. Horm Metab Res. 44:33–40. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Huang YQ, Huang HX, Han ZD, Li W, Mai ZP and Yuan RQ: Ginsenoside Rh2 Inhibits Angiogenesis in Prostate Cancer by Targeting CNNM1. J Nanosci Nanotechnol. 19:1942–1950. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Tong-Lin Wu T, Tong YC, Chen IH, Niu HS, Li Y and Cheng JT: Induction of apoptosis in prostate cancer by ginsenoside Rh2. Oncotarget. 9:11109–11118. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Shi X, Yang J and Wei G: Ginsenoside 20(S)-Rh2 exerts anti-cancer activity through the Akt/GSK3β signaling pathway in human cervical cancer cells. Mol Med Rep. 17:4811–4816. 2018.PubMed/NCBI | |
|
Wang YS, Lin Y, Li H, Li Y, Song Z and Jin YH: The identification of molecular target of (20S) ginsenoside Rh2 for its anti-cancer activity. Sci Rep. 7:124082017. View Article : Google Scholar : PubMed/NCBI | |
|
Yang J, Yuan D, Xing T, Su H, Zhang S, Wen J, Bai Q and Dang D: Ginsenoside Rh2 inhibiting HCT116 colon cancer cell proliferation through blocking PDZ-binding kinase/T-LAK cell-originated protein kinase. J Ginseng Res. 40:400–408. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Han S, Jeong AJ, Yang H, Bin Kang K, Lee H, Yi EH, Kim BH, Cho CH, Chung JW, Sung SH and Ye SK: Ginsenoside 20(S)-Rh2 exerts anti-cancer activity through targeting IL-6-induced JAK2/STAT3 pathway in human colorectal cancer cells. J Ethnopharmacol. 194:83–90. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Kim MJ, Yun H, Kim DH, Kang I, Choe W, Kim SS and Ha J: AMP-activated protein kinase determines apoptotic sensitivity of cancer cells to ginsenoside-Rh2. J Ginseng Res. 38:16–21. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Tang XP, Tang GD, Fang CY, Liang ZH and Zhang LY: Effects of ginsenoside Rh2 on growth and migration of pancreatic cancer cells. World J Gastroenterol. 19:1582–1592. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Li KF, Kang CM, Yin XF, Li HX, Chen ZY, Li Y, Zhang Q and Qiu YR: Ginsenoside Rh2 inhibits human A172 glioma cell proliferation and induces cell cycle arrest status via modulating Akt signaling pathway. Mol Med Rep. 17:3062–3068. 2018.PubMed/NCBI | |
|
Ge G, Yan Y and Cai H: Ginsenoside Rh2 inhibited proliferation by inducing ROS mediated ER stress dependent apoptosis in lung cancer cells. Biol Pharma Bull. 40:2117–2124. 2017. View Article : Google Scholar | |
|
Li H, Huang N, Zhu W, Wu J, Yang X, Teng W, Tian J, Fang Z, Luo Y, Chen M and Li Y: Modulation the crosstalk between tumor-associated macrophages and non-small cell lung cancer to inhibit tumor migration and invasion by ginsenoside Rh2. BMC Cancer. 18:5792018. View Article : Google Scholar : PubMed/NCBI | |
|
An IS, An S, Kwon KJ, Kim YJ and Bae S: Ginsenoside Rh2 mediates changes in the microRNA expression profile of human non-small cell lung cancer A549 cells. Oncol Rep. 29:523–528. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Chen Y, Zhang Y, Song W, Zhang Y, Dong X and Tan M: Ginsenoside Rh2 inhibits migration of lung cancer cells under hypoxia via mir-491. Anticancer Agents Med Chem. 19:1633–1641. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Cheng CC, Yang SM, Huang CY, Chen JC, Chang WM and Hsu SL: Molecular mechanisms of ginsenoside Rh2-mediated G1 growth arrest and apoptosis in human lung adenocarcinoma A549 cells. Cancer Chemother Pharmacol. 55:531–540. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Chen W, Chu S, Li H and Qiu Y: MicroRNA-146a-5p enhances ginsenoside Rh2-induced anti-proliferation and the apoptosis of the human liver cancer cell line HepG2. Oncol Lett. 16:5367–5374. 2018.PubMed/NCBI | |
|
Chen W and Qiu Y: Ginsenoside Rh2 Targets EGFR by up-regulation of miR-491 to enhance anti-tumor activity in hepatitis B virus-related hepatocellular carcinoma. Cell Biochem Biophys. 72:325–331. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Qian J, Li J, Jia JG, Jin X, Yu DJ, Guo CX, Xie B and Qian LY: Ginsenoside-Rh2 inhibits proliferation and induces apoptosis of human gastric cancer SGC-7901 side population cells. Asian Pac J Cancer Prev. 17:1817–1821. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Li B, Zhao J, Wang CZ, Searle J, He TC, Yuan CS and Du W: Ginsenoside Rh2 induces apoptosis and paraptosis-like cell death in colorectal cancer cells through activation of p53. Cancer Lett. 301:185–192. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Zhu C, Liu F, Qian W, Zhang T and Li F: Combined effect of sodium selenite and Ginsenoside Rh2 on hct116 human colorectal carcinoma cells. Arch Iran Med. 19:23–29. 2016.PubMed/NCBI | |
|
Oh M, Choi YH, Choi S, Chung H, Kim K, Kim SI, Kim DK and Kim ND: Anti-proliferating effects of ginsenoside Rh2 on MCF-7 human breast cancer cells. Int J Oncol. 14:869–875. 1999.PubMed/NCBI | |
|
Lee H, Lee S, Jeong D and Kim SJ: Ginsenoside Rh2 epigenetically regulates cell-mediated immune pathway to inhibit proliferation of MCF-7 breast cancer cells. J Ginseng Res. 42:455–462. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Choi S, Kim TW and Singh SV: 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. 26:2280–2288. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Liu J, Shimizu K, Yu H, Zhang C, Jin F and Kondo R: Stereospecificity of hydroxyl group at C-20 in antiproliferative action of ginsenoside Rh2 on prostate cancer cells. Fitoterapia. 81:902–905. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang Q, Hong B, Wu S and Niu T: Inhibition of prostatic cancer growth by ginsenoside Rh2. Tumour Biol. 36:2377–2381. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Gao Q and Zheng J: Ginsenoside Rh2 inhibits prostate cancer cell growth through suppression of microRNA-4295 that activates CDKN1A. Cell Prolif. 51:e124382018. View Article : Google Scholar : PubMed/NCBI | |
|
Xia T, Wang YN, Zhou CX, Wu LM, Liu Y, Zeng QH, Zhang XL, Yao JH, Wang M and Fang JP: Ginsenoside Rh2 and Rg3 inhibit cell proliferation and induce apoptosis by increasing mitochondrial reactive oxygen species in human leukemia Jurkat cells. Mol Med Rep. 15:3591–3598. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Xia T, Wang J, Wang Y, Wang Y, Cai J, Wang M, Chen Q, Song J, Yu Z, Huang W and Fang J: Inhibition of autophagy potentiates anticancer property of 20(S)-ginsenoside Rh2 by promoting mitochondria-dependent apoptosis in human acute lymphoblastic leukaemia cells. Oncotarget. 7:27336–27349. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Huang J, Peng K, Wang L, Wen B, Zhou L, Luo T, Su M, Li J and Luo Z: Ginsenoside Rh2 inhibits proliferation and induces apoptosis in human leukemia cells via TNF-alpha signaling pathway. Acta Biochim Biophys Sin (Shanghai). 48:750–755. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Chen Y, Liu ZH, Xia J, Li XP, Li KQ, Xiong W, Li J and Chen DL: 20(S)-ginsenoside Rh2 inhibits the proliferation and induces the apoptosis of KG-1a cells through the Wnt/β-catenin signaling pathway. Oncol Rep. 36:137–146. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Nakata H, Kikuchi Y, Tode T, Hirata J, Kita T, Ishii K, Kudoh K, Nagata I and Shinomiya N: Inhibitory effects of ginsenoside Rh2 on tumor growth in nude mice bearing human ovarian cancer cells. Jpn J Cancer Res. 89:733–740. 1998. View Article : Google Scholar : PubMed/NCBI | |
|
Tode T, Kikuchi Y, Kita T, Hirata J, Imaizumi E and Nagata I: Inhibitory effects by oral administration of ginsenoside Rh2 on the growth of human ovarian cancer cells in nude mice. J Cancer Res Clin Oncol. 120:24–26. 1993. View Article : Google Scholar : PubMed/NCBI | |
|
Li N, Lin Z, Chen W, Zheng Y, Ming Y, Zheng Z, Huang W, Chen L, Xiao J and Lin H: Corilagin from longan seed: Identification, quantification, and synergistic cytotoxicity on SKOv3ip and hey cells with ginsenoside Rh2 and 5-fluorouracil. Food Chem Toxicol. 119:133–140. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Kim JH and Choi JS: Effect of ginsenoside Rh-2 via activation of caspase-3 and Bcl-2-insensitive pathway in ovarian cancer cells. Physiol Res. 65:1031–1037. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang C, Yu H and Hou J: Effects of 20 (S)-ginsenoside Rh2 and 20 (R)-ginsenoside Rh2 on proliferation and apoptosis of human lung adenocarcinoma A549 cells. Zhongguo Zhong Yao Za Zhi. 36:1670–1674. 2011.(In Chinese). PubMed/NCBI | |
|
Dong H, Bai LP, Wong VK, Zhou H, Wang JR, Liu Y, Jiang ZH and Liu L: The in vitro structure-related anti-cancer activity of ginsenosides and their derivatives. Molecules. 16:10619–10630. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Harashima H, Dissmeyer N and Schnittger A: Cell cycle control across the eukaryotic kingdom. Trends Cell Biol. 23:345–356. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Roskoski R Jr: Cyclin-dependent protein serine/threonine kinase inhibitors as anticancer drugs. Pharmacol Res. 139:471–488. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Abbas T and Dutta A: p21 in cancer: Intricate networks and multiple activities. Nat Rev Cancer. 9:400–414. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Liu X, Sun Y, Yue L, Li S, Qi X, Zhao H, Yang Y, Zhang C and Yu H: JNK pathway and relative transcriptional factor were involved in ginsenoside Rh2-mediated G1 growth arrest and apoptosis in human lung adenocarcinoma A549 cells. Genet Mol Res. 15:2016. View Article : Google Scholar | |
|
Chung KS, Cho SH, Shin JS, Kim DH, Choi JH, Choi SY, Rhee YK, Hong HD and Lee KT: Ginsenoside Rh2 induces cell cycle arrest and differentiation in human leukemia cells by upregulating TGF-β expression. Carcinogenesis. 34:331–340. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Fuchs Y and Steller H: Programmed cell death in animal development and disease. Cell. 147:742–758. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Plati J, Bucur O and Khosravi-Far R: Dysregulation of apoptotic signaling in cancer: Molecular mechanisms and therapeutic opportunities. J Cell Biochem. 104:1124–1149. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Elmore S: Apoptosis: A review of programmed cell death. Toxicol Pathol. 35:495–516. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Guo XX, Li Y, Sun C, Jiang D, Lin YJ, Jin FX, Lee SK and Jin YH: p53-dependent Fas expression is critical for Ginsenoside Rh2 triggered caspase-8 activation in HeLa cells. Protein Cell. 5:224–234. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Wang X and Wang Y: Ginsenoside Rh2 mitigates pediatric leukemia through suppression of Bcl-2 in leukemia cells. Cell Physiol Biochem. 37:641–650. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Li Q, Li Y, Wang X, Fang X, He K, Guo X, Zhan Z, Sun C and Jin YH: Co-treatment with ginsenoside Rh2 and betulinic acid synergistically induces apoptosis in human cancer cells in association with enhanced capsase-8 activation, bax translocation, and cytochrome c release. Mol Carcinog. 50:760–769. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Evan GI and Vousden KH: Proliferation, cell cycle and apoptosis in cancer. Nature. 411:342–348. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Manning BD and Cantley LC: AKT/PKB signaling: Navigating downstream. Cell. 129:1261–1274. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Liu ZH, Li J, Xia J, Jiang R, Zuo GW, Li XP, Chen Y, Xiong W and Chen DL: Ginsenoside 20(s)-Rh2 as potent natural histone deacetylase inhibitors suppressing the growth of human leukemia cells. Chem Biol Interact. 242:227–234. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang H, Yi J, Kim E, Choo Y, Hai H, Kim K, Kim EK, Ryoo Z and Kim M: 20(S)-Ginsenoside Rh2 suppresses oral cancer cell growth by inhibiting the Src-Raf-ERK signaling pathway. Anticancer Res. 41:227–235. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Wu N, Wu GC, Hu R, Li M and Feng H: Ginsenoside Rh2 inhibits glioma cell proliferation by targeting microRNA-128. Acta Pharmacol Sin. 32:345–353. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Ishay-Ronen D, Diepenbruck M, Kalathur RKR, Sugiyama N, Tiede S, Ivanek R, Bantug G, Morini MF, Wang J, Hess C and Christofori G: Gain fat-lose metastasis: Converting invasive breast cancer cells into adipocytes inhibits cancer metastasis. Cancer Cell. 35:17–32.e6. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Kim JH, Kim M, Yun SM, Lee S, No JH, Suh DH, Kim K and Kim YB: Ginsenoside Rh2 induces apoptosis and inhibits epithelial-mesenchymal transition in HEC1A and Ishikawa endometrial cancer cells. Biomed Pharmacother. 96:871–876. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Deryugina EI and Quigley JP: Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 25:9–34. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang BP, Li B, Cheng JY, Cao R, Gao ST, Huang CJ, Li RP, Ning J, Liu B and Li ZG: Anti-cancer Effect of 20(S)-Ginsenoside-Rh2 on oral squamous cell carcinoma cells via the decrease in ROS and downregulation of MMP-2 and VEGF. Biomed Environ Sci. 33:713–717. 2020.PubMed/NCBI | |
|
Riabov V, Gudima A, Wang N, Mickley A, Orekhov A and Kzhyshkowska J: Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. Front Physiol. 5:752014. View Article : Google Scholar : PubMed/NCBI | |
|
Goumans MJ, Liu Z and ten Dijke P: TGF-beta signaling in vascular biology and dysfunction. Cell Res. 19:116–127. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Fidler IJ and Ellis LM: The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell. 79:185–188. 1994. View Article : Google Scholar : PubMed/NCBI | |
|
Wang Q, Wu MQ, Zhao LH, Yang HK and Lv XH: Effect of ginsenoside Rh2 on transplanted-tumor and expression of JAM in mice. Zhongguo Zhong Yao Za Zhi. 33:2116–2119. 2008.(In Chinese). PubMed/NCBI | |
|
Mizushima N, Levine B, Cuervo AM and Klionsky DJ: Autophagy fights disease through cellular self-digestion. Nature. 451:1069–1075. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Ryan KM: p53 and autophagy in cancer: Guardian of the genome meets guardian of the proteome. Eur J Cancer. 47:44–50. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Zhuang J, Yin J, Xu C, Mu Y and Lv S: 20(S)-Ginsenoside Rh2 Induce the Apoptosis and Autophagy in U937 and K562 Cells. Nutrients. 10:3282018. View Article : Google Scholar | |
|
Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, Adachi H, Adams CM, Adams PD, Adeli K, et al: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 12:1–222. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Liu S, Chen M, Li P, Wu Y, Chang C, Qiu Y, Cao L, Liu Z and Jia C: Ginsenoside rh2 inhibits cancer stem-like cells in skin squamous cell carcinoma. Cell Physiol Biochem. 36:499–508. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Li M, Zhang D, Cheng J, Liang J and Yu F: Ginsenoside Rh2 inhibits proliferation but promotes apoptosis and autophagy by down-regulating microRNA-638 in human retinoblastoma cells. Exp Mol Pathol. 108:17–23. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Ma J, Gao G, Lu H, Fang D, Li L, Wei G, Chen A, Yang Y, Zhang H and Huo J: Reversal effect of ginsenoside Rh2 on oxaliplatin-resistant colon cancer cells and its mechanism. Exp Ther Med. 18:630–636. 2019.PubMed/NCBI | |
|
Zhou B, Xiao X, Xu L, Zhu L, Tan L, Tang H, Zhang Y, Xie Q and Yao S: A dynamic study on reversal of multidrug resistance by ginsenoside Rh(2) in adriamycin-resistant human breast cancer MCF-7 cells. Talanta. 88:345–351. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Liu GW, Liu YH, Jiang GS and Ren WD: The reversal effect of Ginsenoside Rh2 on drug resistance in human colorectal carcinoma cells and its mechanism. Hum Cell. 31:189–198. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Lv DL, Chen L, Ding W, Zhang W, Wang HL, Wang S and Liu WB: Ginsenoside G-Rh2 synergizes with SMI-4a in anti-melanoma activity through autophagic cell death. Chin Med. 13:112018. View Article : Google Scholar : PubMed/NCBI | |
|
Wang M, Yan SJ, Zhang HT, Li N, Liu T, Zhang YL, Li XX, Ma Q, Qiu XC, Fan QY and Ma BA: Ginsenoside Rh2 enhances the antitumor immunological response of a melanoma mice model. Oncol Lett. 13:681–685. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Xia T, Zhang B, Li Y, Fang B, Zhu XX, Xu BC, Zhang J, Wang M and Fang JP: New insight into 20(S)-ginsenoside Rh2 against T-cell acute lymphoblastic leukemia associated with the gut microbiota and the immune system. Eur J Med Chem. 203:1125392020. View Article : Google Scholar : PubMed/NCBI | |
|
Li Q, Li B, Dong C, Wang Y and Li Q: 20(S)-Ginsenoside Rh2 suppresses proliferation and migration of hepatocellular carcinoma cells by targeting EZH2 to regulate CDKN2A-2B gene cluster transcription. Eur J Pharmacol. 815:173–180. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Shi Q, Shi X, Zuo G, Xiong W, Li H, Guo P, Wang F, Chen Y, Li J and Chen DL: Anticancer effect of 20(S)-ginsenoside Rh2 on HepG2 liver carcinoma cells: Activating GSK-3β and degrading β-catenin. Oncol Rep. 36:2059–2070. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Qian T, Cai Z, Wong RN and Jiang ZH: Liquid chromatography/mass spectrometric analysis of rat samples for in vivo metabolism and pharmacokinetic studies of ginsenoside Rh2. Rapid Commun Mass Spectrom. 19:3549–3554. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Qi Z, Chen L, Li Z, Shao Z, Qi Y, Gao K, Liu S, Sun Y, Li P and Liu J: Immunomodulatory effects of (24R)-Pseudo-Ginsenoside HQ and (24S)-Pseudo-Ginsenoside HQ on cyclophosphamide-induced immunosuppression and their anti-tumor effects study. Int J Mol Sci. 20:8362019. View Article : Google Scholar | |
|
Gu Y, Wang GJ, Sun JG, Jia YW, Wang W, Xu MJ, Lv T, Zheng YT and Sai Y: Pharmacokinetic characterization of ginsenoside Rh2, an anticancer nutrient from ginseng, in rats and dogs. Food Chem Toxicol. 47:2257–2268. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Li S, Gao Y, Ma W, Guo W, Zhou G, Cheng T and Liu Y: EGFR signaling-dependent inhibition of glioblastoma growth by ginsenoside Rh2. Tumour Biol. 35:5593–5598. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Xia T, Wang JC, Xu W, Xu LH, Lao CH, Ye QX and Fang JP: 20S-Ginsenoside Rh2 induces apoptosis in human Leukaemia Reh cells through mitochondrial signaling pathways. Biol Pharm Bull. 37:248–254. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Kim YS and Jin SH: Ginsenoside Rh2 induces apoptosis via activation of caspase-1 and −3 and up-regulation of Bax in human neuroblastoma. Arch Pharm Res. 27:834–839. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
Shi Q, Li J, Feng Z, Zhao L, Luo L, You Z, Li D, Xia J, Zuo G and Chen D: 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. 10:1779–1785. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Guan N, Huo X, Zhang Z, Zhang S, Luo J and Guo W: Ginsenoside Rh2 inhibits metastasis of glioblastoma multiforme through Akt-regulated MMP13. Tumour Biol. 36:6789–6795. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Xia T, Zhang J, Zhou C, Li Y, Duan W, Zhang B, Wang M and Fang J: 20(S)-Ginsenoside Rh2 displays efficacy against T-cell acute lymphoblastic leukemia through the PI3K/Akt/mTOR signal pathway. J Ginseng Res. 44:725–737. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Li S, Guo W, Gao Y and Liu Y: Ginsenoside Rh2 inhibits growth of glioblastoma multiforme through mTor. Tumour Biol. 36:2607–2612. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Li C, Gao H, Feng X, Bi C, Zhang J and Yin J: Ginsenoside Rh2 impedes proliferation and migration and induces apoptosis by regulating NF-κB, MAPK, and PI3K/Akt/mTOR signaling pathways in osteosarcoma cells. J Biochem Mol Toxicol. 34:e225972020. View Article : Google Scholar : PubMed/NCBI | |
|
Yang D, Li X and Zhang X: Ginsenoside Rh2 induces DNA damage and autophagy in vestibular schwannoma is dependent of LAMP2 transcriptional suppression. Biochem Biophys Res Commun. 522:300–307. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Chen Y, Zhang Y, Song W, Zhang Y, Dong X and Tan M: Ginsenoside Rh2 improves the cisplatin anti-tumor effect in lung adenocarcinoma A549 cells via superoxide and PD-L1. Anticancer Agents Med Chem. 20:495–503. 2020. View Article : Google Scholar : PubMed/NCBI |
