Cell Biological Mechanism in Anticancer Activities of Ginsenosides

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1		Luan Luong Chu	--	1817	2023-02-20 07:31:20	\|
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This entry is adapted from the peer-reviewed paper 10.3390/molecules28031437

Ginsenosides are major bioactive compounds present in the Panax species. Ginsenosides exhibit various pharmaceutical properties, including anticancer. Ginsenosides, a triterpenoid glycoside, are major constituents extracted from Panax ginseng (Pg), P. notoginseng, P. quinquifolium, and another species belonging to the Panax genus, P. vietnamensis.

ginsenosides Panax species endophytes

1. Introduction

Natural bioactive compounds and traditional medicines have great importance in the treatment of prevalent human diseases and health care. Bioactive compounds mainly include various valuable metabolites, such as stilbenes, flavonoids, terpenoids, polyketides, and alkaloids ^[1]^[2]. These molecules show multifunctional properties, such as anticancer, antioxidant, antimicrobial, antifungal, and antiviral activities. They also exhibit many beneficial effects on the treatment of neurological, cardiovascular and metabolic, immunological, inflammatory, and related diseases ^[3]. According to the World Health Organization, approximately 19 million people were newly diagnosed with cancer in 2020, with a total of 10 million cancer-related deaths. the top five cancer diseases, such as lung cancer, female breast cancer, colorectal cancer, stomach cancer, and liver cancer, are speeding up to rank among the top dangerous reasons for the death rate of humankind. Therefore, the investigation and development of approaches for producing a novel anticancer agent have been highly required in human life. Among a lot of natural bioactive compounds, ginsenosides from Panax species have been reported to have a wide variety of pharmacological and biological activities, including anticancer activity. Approximately 200 ginsenosides have been identified from the leaves, roots, flower buds, roots, and berries of Panax species in recent years ^[4]. Although ginsenoside has multifunctional properties, it has been considerably attended to the regulation of cancer cell metabolism in vitro and in vivo ^[5].

The most powerful tool for treating cancer is chemotherapy. Chemotherapy is widely used to treat cancer at all stages of progression in the various cancer cell lines ^[6]. the extraction from plants and chemical synthesis are two traditional approaches to produce anticancer drugs. These methods are limited because of their disadvantages. While the former method is time-consuming and based on seasonable weather, the latter approach often requires unexpected purity, high reaction pressure, and high temperatures with the use of the harmful reagent ^[7]. Moreover, the immune response is activated by using chemically synthesized anticancer drugs. the immune response has a negative effect on healthy patients ^[8]. Thus, simple, safe, and efficient approaches are strongly required for the production of anticancer drugs. Enzymatic reactions are able to produce the specific reaction and a simple alternative; however, it is too expensive. Although the generation of the cofactor has been developed through single-vessel recycling reactions, enzymatic reactions are not easy to produce on a large-scale ^[9]^[10]. Moreover, endophytes, which colonized inside plant tissues without displaying signs of disease symptoms, showed the ability to produce enzymes for natural compound biosynthesis, resulting in the method being recognized as safe with a qualified presumption of safety ^[11]. While endophytic bacteria and fungi are also concerned with a promising novel resource product, engineered microorganisms are used as cell factories for the production of bioactive compounds. Whole-cell microorganisms not only show the ability to catalyze reaction efficiency, but also exhibit a low consideration for environmental problems. Whole-cell biocatalysts are becoming the most preferred approach for the industrial production of anticancer medicine ^[12]. Moreover, microbial production provides eco-friendly and efficient approaches for the development of anticancer drugs ^[13]^[14].

2. Ginsenosides: Classification and Cell Biological Mechanism in Anticancer Activities

Ginsenosides, a triterpenoid glycoside, are major constituents extracted from Panax ginseng (Pg), P. notoginseng, P. quinquifolium, and another species belonging to the Panax genus, P. vietnamensis ^[15]^[16]. In spite of the fact that all tissues of ginseng contain ginsenosides, the root is known as a major source of accumulating total ginsenosides. It was demonstrated that there are a lot of factors that impact on the total ginsenosides in the Panax species, including the age of the ginseng, plant growth promotion, plant–pathogen interaction, and collection and extraction methods. According to their chemical structure, ginsenosides are divided into four groups: (1) protopanaxadiol (PPD) group consisting of Ra1, Rb1, Rc, Rd, R1, and compound K (CK). the sugar moiety attaches at β-OH of C-3 and/or C-20 in PPD compounds; (2) protopanaxatriol (PPT), consisting of Re, Rf, Rg1, and Rh1. PPT has a sugar moiety that binds to α-OH of C-6 and/or β-OH of C-20; (3) the ocotillol group, including majonoside R2, vinaginsenoside R1, and pseudoginsenoside F11. This group processes a five-membered epoxy ring at C-20; (4) oleanane ginsenoside group consisting of a pentacyclic triterpene skeleton, such as Ro and R_OA (Table 1) ^[17]^[18]. On the other hand, ginsenosides are also classified into two groups based on the percentages of the total ginsenoside content in each Panax species. While a major ginsenoside has been determined to account for over 80% of total ginsenoside content, minor ginsenosides have been present in low concentrations in wild and red ginseng (Figure 1). the major ginsenosides, such as Rb1, Rb2, Rc, Rd, Re, Rg1, and R1, can be digested into minor ginsenosides by hydrolyzing the multiple sugar moieties. Although the presence of sugar moieties increases the stability and solubility properties of compounds, these residues lead to a decrease in the permeability of the cell membrane. Therefore, the minor ginsenosides, such as F1, F2, Rg2, Rg, Rh2, and CK, have higher anticancer activities than the major ginsenosides ^[19]. Ginsenoside Rg3 and Rh2, which possess two and one sugar moieties, respectively, show potent apoptotic and antiproliferative activities ^[20]. However, ginsenosides, which possess three or more sugar residues, including Rd, Rc, and Rb1, show little or no sign of antiproliferative activity ^[21]. Moreover, many minor ginsenosides show great biological and pharmacological activities. the novel minor 5,6-didehydroginsenoside Rg3 from Pg showed a significant effect on anti-inflammatory activity ^[22]. CK has been shown to have antidiabetic, antitumor, anti-inflammatory, and hepatoprotective activities ^[23]. A new derivative of ginsenoside from P. notoginseng, 25-OCH₃-PPD, not only inhibited various types of cancer cell lines, such as pancreatic, breast, and lung cancer, but also exhibited nongenotoxic properties for antitumor treatment ^[24]. Noticeably, differences in the position of sugar linkers and hydroxyl groups give direction to biological activities. It has been demonstrated that the available sugar moieties at C-6 of ginsenosides have less anticancer activity than linkages at C-3 or C-20 of ginsenosides. the moieties at C-6 of ginsenosides decrease the interaction between these compounds and their binding proteins by blocking the way into the binding pocket. For example, ginsenoside Rh2 exhibits stronger potency in anticancer activity than Rh1 ^[25]. In addition, the interaction between ginsenoside and β-OH of the cholesterol in the cell membrane is affected by the number and size of the hydroxyl group, and due to polar compounds, this could change membrane fluidity and function ^[26].

Figure 1. Biological activities and cellular mechanisms versus cancer of ginsenosides. CDK: cyclin-dependent kinase; IAP: inhibitory apoptotic protein; VEGF-A: vascular endothelial growth factor A; FGF-2: fibroblast growth factor 2; PI3K/AKT: protein kinase B signaling pathway; TSP-1: inhibitors thrombospondin-1; IGF-1: insulin-like growth factor-1; TNF-α: tumor necrosis factor-α; MMP: matrix metalloproteinase; NF-κB, nuclear factor κB.

Table 1. Classification and cell biological mechanism in anticancer activities of four types of ginsenosides.

Structure	Name	R1	R2	R3	R4	Cellular Mechanisms	Ref.
Protopanaxadiol (PPD) Type
	Ra1	Glc²-Glc	-	Glc⁶-Ara(p)⁴-Xyl	-	Not reported
	Rb1	Glc²-Glc	-	Glc⁶-Glc	-	Inhibition of invasion and migration	^[17]^[21]
	Rb2	Glc²-Glc	-	Glc⁶-Ara(p)	-	Inhibition of metastasis and proliferation	^[17]
	Rc	Glc²-Glc	-	Glc⁶-Ara(f)	-	Anti-proliferative activity	^[19]
	Rd	Glc²-Glc	-	Glc	-	Inhibit proliferation; Inhibit angiogenesis	^[4]
	Rg3	Glc²-Glc	-	H	-	Repression of cell proliferation and induce apoptosis	^[20]^[25]
	Rh2	Glc	-	H	-	Modulation of cell cycle; Regulation of inflammatory response molecules	^[20]^[27]
	F2	Glc	-	Glc	-	Inhibit proliferation	^[4]
	CK	H	-	Glc	-	Modulation of growth factors and regulation of transcription factors; Induce apoptosis	^[5]^[23]
Protopanaxatriol (PPT)-type
	Re	OH	Glc²-Rha	Glc	-	Not reported
	Rf	OH	Glc²-Glc	H	-	Cell cycle arrest and apoptosis	^[19]
	Rg1	OH	Glc	Glc	-	Induce apoptosis; Repression of cell proliferation	^[4]^[21]
	Rg2	OH	Glc²-Rha	H	-	Induce apoptosis; Repression of cell proliferation	^[4]
	Rh1	OH	Glc	H	-	Regulation of gene coding for metalloproteinase; Repression of cell proliferation	^[5]^[28]
	F1	OH	H	Glc	-	Modulation of death receptor	^[29]
	Notoginsenoside R1	H	Glc²-Xyl Glc	Glc	-	Regulation of inflammatory response molecules	^[19]
Ocotillol-type
	Majonoside R2	OH	Glc²-Xyl	-	-	Not reported
	Vinaginsenoside R1	OH	Ac-Glc²-Rha	-	-	Not reported
Oleanolic acid type
	R_O	GlcUA-Glc	-	-	Glc	Not reported
	R_OA	GlcUA-Glc	-	-	Glc⁶-Glc	Not reported

Ac: acetyl; Ara(p): α-L-glucopyranosyl; Ara(f): α-L-arabinofuranosyl; Glc: β-D-glucopyranosyl; Rha: α-L-rhamncpyranosyl.

Ginsenosides exhibited various pharmacological activities, such as antimicrobial, antiaggregant, antioxidant, prevention of cardiovascular disease, and improving immune function ^[30]. Ginsenoside has been used as a source for the cosmetic and food industries. However, it is the most famous compound as an anticancer agent. While major ginsenosides have no significant or only weak antiproliferative and antiangiogenic activities, minor ginsenosides exhibit strong anticancer activities and cause cell death ^[19]^[21]. Minor ginsenosides have a significant inhibitory effect on cell proliferation and differentiation. the possible cell biological mechanisms of action of ginsenosides based on the existing research are listed as follows: effect on proliferation and differentiation, regulation of cell cycle and p53/p21/murine double minute-2 pathways, modulation of cell death (Bcl-2, Bcl-xL, inhibitory apoptotic protein (IAP), caspases, and death receptors), modulation of growth factor and protein kinase, inflammatory response molecules, and effects on DNA damage (Figure 1) ^[19]^[21]. As an example, Rh2 has been shown to inhibit the proliferation of MCF-7 human breast cancer cells via inducing a G1 arrest in cell cycle progression, which is associated with the enzyme expression of the cyclin-dependent kinase (CDK) inhibitor protein p21 ^[27]. Rh2 also inhibits cell growth and induces apoptosis of human leukemia (HL-60) cells via the tumor necrosis factor-α (TNF-α) pathway. Similarly, Rh2 and Rg3 repress cell proliferation and induce apoptosis in HL-Jurkat cells by increasing a mitochondrial reactive oxygen species (ROS) ^[25]. Moreover, Rg5 inhibits cell proliferation in retinoblastoma cells by downregulating BCL2 expression in the protein kinase B (PI3K/AKT) signaling pathway ^[31]. In addition, Rh1 was the most effective at causing differentiation of F9 teratocarcinoma stem cells by binding to a glucocorticoid receptor. Rh1 also exhibits the ability to inhibit the proliferation, migration, and invasion of colorectal cancer cell lines. the inhibition was achieved by the repression of matrix metalloproteinase 1 (MMP1) and expression of metalloproteinase 3 (MMP3) expression level ^[28]. Ginsenoside F1 enhances natural killer (NK) cell cytotoxicity in cancer immunosurveillance by insulin-like growth factor-1 (IGF-1) treatment ^[29]. Noticeably, CK not only increases the mRNA levels of angiogenic inhibitors thrombospondin-1 (TSP-1), -1 MMP-1, and metalloproteinase-2 (MMP2), but also decreases the mRNA levels of angiogenic factors vascular endothelial growth factor A (VEGF-A) and fibroblast growth factor 2 (FGF-2) in 3T3-L1 adipocytes. Furthermore, CK shows the ability to inhibit and migrate human glioblastoma U87MG and U373MG cells via an arrested cell cycle progression at the G0/G1 phase ^[23]. Moreover, 25-OCH₃-PPD has significant effects on decreasing the survival and inhibiting the proliferation of human prostate and breast cancer cell lines ^[24]. Thus, ginsenosides likely have therapeutic potential for the treatment of various cancer diseases.

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1. Introduction

2. Ginsenosides: Classification and Cell Biological Mechanism in Anticancer Activities

References