Panax ginseng was discovered over 5000 years ago on the hills of Manchuria in China and since then held its place as a highly venerated medicinal plant in Traditional Chinese Medicine (Hemmerly, 1977). The ancient Chinese used it for various health benefits, ranging from overcoming fatigue to treating severe cardiac problems; ancient texts showed that ginseng was valued more than gold and was often reserved for treatment of royalty. The “Shennong Bencao Jing” written around 100 A.D. attributed longevity boosting properties to ginseng and stated that it was good for “enlightening the mind and increasing the wisdom” (Dharmananda, 2002).

The discovery of an American counterpart for this “miracle” plant happened in 1714, due to the efforts of Father Lafitau, a Jesuit priest, working with the Iroquois in Canada. Based on the theory that ginseng might grow wild in the Americas, due to a similarity in climactic conditions with China, Father Lafitau undertook a laborious search for the plant and eventually discovered that it was used as a medicinal herb by the native Indians too (Yun, 2001; Grafton, 2002). The British physicians F. Porter Smith and G. A. Stuart, working in China at the end of the nineteenth century, were among the first to introduce the medicinal qualities of this herb to a Western audience (Dharmananda, 2002). The popularity of ginseng in the western world grew as a “drug weary” population medicated heavily on increasingly toxic chemical compounds started to explore alternative and traditional forms of medicine. Ginseng began to be sold in the form of liquid extracts, capsules, chewing gum, teas, candy, and cigarettes. It was used for treating rheumatism, anemia, insomnia, and various other problems. Some even purchased ginseng products for their alleged aphrodisiac properties. Ginseng fragrances were incorporated in cosmetics and soaps. By 1980s an estimated five to six million Americans were routinely using ginseng products (Carlson, 1986). In fact, the sale of ginseng products in the United States alone was estimated to reach US$83 million in 2010.

In the early 1970s, reports, primarily from China and Korea, started claiming that the herb stimulated protein synthesis, lowered blood sugar and cholesterol levels, regulated rate of metabolism, protected against stress, and could therefore reduce mortality. Asiatic ginseng from eastern Siberia was reportedly used by Soviet cosmonauts and Olympic team trainees to reduce fatigue (Carlson, 1986). During the same period, the Fromm Operation based in Wisconsin funded research on the possibility of using compounds from American ginseng in cancer research (Carlson, 1986). Since then, ginseng’s usefulness in cancer has been shown by extensive pre-clinical and epidemiological studies (Attele et al., 1999; Court, 2000; Bespalov et al., 2001; Yoo et al., 2006). It is also demonstrated that prolonged oral administration of red ginseng extract (RGE) to rats dosed with a carcinogen such as DMBA, urethane, or aflatoxin B1, reduced the incidence and mass of tumors (Yun et al., 1983). Additionally, red ginseng has been shown to improve postoperative survival in patients with stage III gastric cancer (Suh et al., 2002). There is an increasing interest in developing ginseng products as anticancer agents, especially in combination therapy.

The word Panax, first used by the Russian botanist Carl Anton Von Meyer, is derived from the Greek word meaning “all-healing” (Court, 2000). On the other hand, the English word ginseng is derived from the Chinese term “rénshen” which literally means “man root”: a reference to the root’s resemblance to the legs of a human. The Panax genus belongs to the family Araliaceae and consists of at least nine species, including P. ginseng (Asian ginseng), P. quinquefolium L. (Xiyangshen, American ginseng), P. notoginseng (Sanqi), and P. japonicas (Japanese ginseng; Lee and Zhao, 2009). Among them, P. ginseng is the most widely used ginseng and is indigenous to the Far East countries, most notably China and Korea. P. quinquefolium is indigenous to the United States and Canada (Lee and Zhao, 2009). Out of these, P. ginseng C. A. Meyer, P. quinquefolium L, and P. notoginseng have been extensively investigated for their physiological and pharmacological effects on human body.

Ginseng is a perennial herb, 60–80 cm tall. Its root, often 5–6 cm long, is fleshy, bifurcate, aromatic, and grayish white to amber yellow. The surface of root is wrinkled and furrowed, and its taste is sweetish at first, with a somewhat bitter after taste. Ginseng stem is simple, erect, and deep red; its flower is pink; and its fruit, a small berry, is red. The leaves are compound, digitate, oval, and thin. There are a total of five leaflets and the three terminal leaflets are larger than the two lateral ones (Yun, 2001; Coates et al., 2005).

Saponins are glycosides consisting of a sapogenin moiety, which may be a steroid or a triterpene, attached to one or more sugar moieties. Ginseng saponins are generally called ginsenosides and are the main active principals of ginseng. They are often used as a marker for the quality control of ginseng drugs and commercial products. For example, the ginsenoside Rf is unique to Asian ginseng while F11 is found exclusively in American ginseng. Thus the Rf/F11 ratio is used as a phytochemical marker to distinguish American ginseng from Asian ginseng (Li et al., 2000; Assinwe et al., 2003).

The basic structures of ginsenosides are similar, and most ginsenosides consist of a dammarane steroid nucleus with 17 carbon atoms arranged in four rings. Ginsenoside structures are first elucidated by the Shibata group, and named as Rx according to their mobility on TLC plates, with polarity decreasing from index “a” to “h” (Sanada et al., 1974; Liu and Xiao, 1992). According to a Ginseng Evaluation Program led by the American Botanical Council of Austin, Texas, the ginsenosides Rb1, Rb2, Rc, Rd, Re, and Rg1 account for >90% of the total ginsenoside content of the P. ginseng root (Foster, 1996a,b; Chang et al., 2003). Whereas, ginsenosides Rb1, Re, Rd, Rc, Rg1, and Rb3, the six major saponins, make up more than 70% of total ginsenoside content in American ginseng (Wang et al., 2005). Ginsenosides are amphipathic in nature. The hydroxyl (OH) group attached to the steroid backbone in ginsenosides allows interactions between the polar head of the membrane phospholipids and the β-OH group of cholesterol, while the hydrophobic steroid backbone can interact with the hydrophobic side chains of fatty acids and cholesterol. These physicochemical interactions are mostly determined by the numbers and sites of polar hydroxyl groups on each ginsenoside. Based on such properties, ginsenosides with different numbers and sites of hydroxyl groups exhibit diverse activities. Till date, more than 100 ginsenosides have been isolated from Panax species and most of them exhibit four types of aglycone moieties (Liu and Xiao, 1992; Coates et al., 2005). Ginsenosides are classified into the following types based on the steroidal skeleton and number of hydroxyl groups/sugar moieties attached.

Ginseng polysaccharides are water-soluble compounds containing various sugar moieties conjugated to uronic acid and include panaxanes A to U. They are acidic polysaccharides and have been shown to possess immunomodulating and anti-proliferative effects. Recent studies have identified an acidic polysaccharide, referred to as “ginsan,” with immunostimulatory activity (Kim et al., 1998; Shim et al., 2007).

The polyynes are a group of organic compounds with alternating single and triple bonds. In ginseng, these include falcrinol (panaxynol), falcarintriol (panaxytriol), acetic acid, or linolenic acid (Lee and Zhao, 2009).

Besides the compounds mentioned above, some flavonoids and volatile oils also have been isolated and identified from Panax genus (Lee and Zhao, 2009).

Anticancer activities increase with the decrease in the number of sugar moieties in a ginsenoside molecule. Ginsenosides with four or more sugar molecules, such as Rb1 and Rc, show no significant anti-proliferative effects (Yue et al., 2006; Li et al., 2009; Wang et al., 2009a); while Rd with three sugar residues weakly inhibits the growth of cancer cell (Yang et al., 2006; Li et al., 2009). Ginsenosides Rg3 (two sugar residues), Rh2 (one sugar residue), IH-901 (one sugar residue), PPT (no sugar residues), and PPD (no sugar residues) inhibit different types of cancer cells and also enhance the efficacy of conventional chemotherapy agents when given along with them (Hasegawa et al., 1995; Yue et al., 2006; Wang et al., 2007a; Yu et al., 2007). Rh2, 25-OH-PPD, and PPD show 5- to 15-fold relatively stronger anti-proliferative effects than Rg3 (Wang et al., 2007b). Among these compounds, PPD with no sugar residue shows the most potent anticancer activity. Qi et al. (2010) claim that introducing acetyl groups at selected positions increases the anticancer activity of PPD. It has also been suggested that neoglycorandomization might also increase anticancer properties (Langenhan et al., 2005). One might also expect to improve anticancer activity if heteroatoms like nitrogen and sulfur atoms are integrated into the steroid core structure or on the side chain.

Introduction of lipophilic groups in the side chains has been shown to increase anti-proliferative activity (Qi et al., 2010). For example, between the novel ginsenosides 25-OH-PPD and 25-OCH₃-PPD, both isolated from the fruits of P. notoginseng, the latter shows a lower IC₅₀ value in pancreatic cancer cell line (Wang et al., 2009b,c). This type of modification may also improve the pharmacokinetic properties of the compound (Wang et al., 2008b, 2009a,b). A related linear relationship has been observed between Log Ps (also referred to as the lipophilicity) and Log IC₅₀ of ginsenosides (Li et al., 2009). The presence of sugar moieties reduces the hydrophobic character of the compounds and decreases the permeability of the cell membrane. As interaction with the cell membrane decreases, so do the anticancer effects. Thus we see that in general, anticancer activity is inversely correlated to the number of sugar residues; a fact that may be attributed to the cellular uptake capability of the ginsenosides. The cellular uptake ratios of ginsenosides on cancer cells probably decrease with the increase of sugar numbers, due to progressive decrease in hydrophobicity (Ha et al., 2010).

Differences in sugar linkage positions may also influence biological responses. The C-6 substituent differentiates the PPD and PPT groups of ginsenosides structurally. Ginsenoside Rh2 (PPD type) and Rh1 (PPT type), which possess a glucose linkage at C-3 and C-6, respectively, have similar chemical structures, but the anticancer effect of Rh2 is stronger than that of Rh1_. F1 (20-O-glc-PPT) and Rh1 (6-O-glc-PPT) have the same number of sugar moieties and the same molecular weight, with different glucose attachment positions at C-20 and C-6, respectively. In a study on prostate cancer cell lines, F1 showed significantly higher cell inhibition than Rh1 (Li et al., 2009).

With a sugar substitute at C-6, the anticancer activity of ginsenosides is decreased compared to activity with linkages at C-3 or C-20. Molecular modeling and docking experiments confirm that the presence of a sugar moiety at C-6 increases the steric hindrance for these molecules to bind to their target proteins by blocking entrance into the extracellular binding pocket, and thus significantly reducing the anticancer activities of ginsenosides (Chen et al., 2009).

It is known that polar substances interact with phospholipid head groups in the hydrophilic domain of the cell membrane. Ginsenosides interact with the β-OH of the cholesterol in the cell membrane and intercalate themselves into the plasma membrane. This leads to changes in membrane fluidity, and thus affects membrane function, eliciting a cellular response. This ability to insert and orient with the membrane is influenced by the number and site of polar hydroxyl groups. Differences in the number and position of hydroxyl groups influence pharmacological activity. Elimination of the double bond at C-24/25 and addition of hydroxyl or methoxyl at C-25 increases the anticancer potential of ginsenosides. The anticancer activities of 25-OCH₃-PPD, 25-OH-PPD, 25-OH-PPT, PPD, Rh2, and Rg3 have been systematically compared. 25-OCH₃-PPD and 25-OH-PPD show the most potent anti-proliferative, pro-apoptotic, cell cycle regulatory and inhibitory effects of tumor growth in vivo and appear to be promising candidates for further development as novel anticancer agents (Wang et al., 2007b, 2008a,b, 2009a,b).

Dehydration at C-20 increases the bioactivity of ginsenosides (Kang et al., 2006). Rg5 differs from Rg3 only by the presence of a hydroxyl group at C-20 in Rg3 and is approximately four times more effective than Rg3 at inhibiting cell proliferation (Lee et al., 1997; Shin et al., 2006). Rh3, however, is a dehydration product at C-20 of Rh2; both Rh2 and Rh3 induce differentiation of promyelocytic leukemia HL-60 cells, but the potency of Rh2 seems to be higher (Kim et al., 1998).

20(S) and 20(R) forms of ginsenosides are stereoisomers of each other that depend on the orientation of the C-20 hydroxyl in ginsenosides. 20(S)-OH is spatially close to the C-12 hydroxyl of ginsenosides while 20(R)-OH is far. This difference in the stereochemistry produces different pharmacological effects. 20(S)-Rg3 scavenges hydroxyl radicals better than 20(R)-Rg3 (Lee et al., 2008). 20(S)-Rg3 is better aligned with the hydroxyl acceptor group in the ion channels than 20(R)-Rg3, making 20(S)-Rg3 an efficient regulator of voltage-dependent ion channels. Voltage-sensitive ion channels have been shown to play a significant role in the progression of cancer (Jeong et al., 2004; Fiske et al., 2006). In general, the 20(S) compounds have been shown to possess better anti-proliferative effects than their 20(R) counterparts whereas 20(R) compounds such as 20(R)-Rg3 have been shown to inhibit cancer cell invasion and metastasis.

Although a limited effect against cancer is observed, 20(R)-Rh2 inhibits osteoclast formation better than 20(S)-Rh2_. It is possible that the anti-tumor properties of 20(R) ginsenosides are in part mediated through their angiosuppressive activity. These observations imply that the stereostructure of the C-20 hydroxyl may influence the biological and pharmacological effects of ginsenosides (Yue et al., 2006; Qi et al., 2010).

When taken orally, PPD-type ginsenosides are mostly metabolized by anaerobic intestinal bacteria such as Bacteroides, Fusobacterium, Eubacterium, and Provetella to a PPD monoglucoside, compound K, via a step-wise cleavage of the sugar moieties (Lee et al., 2009a). In humans, compound K may be detected in the plasma from 7 h after the intake of PPD-type ginsenosides and in urine from 12 h after the intake. These findings suggest that compound K is the final metabolite of PPD-type ginsenosides (Lee et al., 2009a). Also, compound K exhibits moderate inhibition of the CYP2C9 activity, while PPD and PPT exhibit potent competitive inhibition against CYP3A4 activity (Hasegawa et al., 1996; Tawab et al., 2003).

Growth factors play a critical role in the proliferation of tumor cells. Molecules like EGF, HER2, FGF, vascular endothelial growth factor (VEGF), PDGF, and insulin growth factor (IGF)-1 have been associated with cell proliferation. The suppression of these growth factors or their receptors results in inhibition of tumor growth. For example, the inhibition of EGFR expression and decreased ERK1/2 activity attenuates cell survival and enhances induction of apoptosis in lung and pancreatic adenocarcinoma cells.

Angiogenesis is the process by which new blood vessels are formed from pre-existing structures. It is a crucial step in tumor growth and metastasis by supplying oxygen and nutrients. Ginseng derivatives have been shown to inhibit tumor growth by influencing neovascularization and the angiogenesis-related properties of endothelial cells (ECs; Leung et al., 2007). Ginsenoside Rb1 has been shown to inhibit capillary morphogenesis of ECs by regulating expression of PEDF through the estrogen receptor α (Leung et al., 2007). 20(R)-Rg3 inhibits proliferation, formation of capillary tube, and chemoinvasion of ECs induced by VEGF (Yue et al., 2006). 20(R)-Rg3 also reduces microvascular sprouting in vitro and inhibits neovascularization induced by basic fibroblast growth factor in vivo (Yue et al., 2006). The angiosuppressive effect of 20(R)-Rg3 may be related to the differential regulation of matrix metalloproteinases (MMP-2 and MMP-9) activities (Yue et al., 2006).

Metastases are multiple, widespread tumor colonies established by malignant cells that detach themselves from the original tumor and travel through the body often to distant sites. Some of these invading cells penetrate into a body cavity or the blood, lymph or spinal fluid and then are released forming tumors locally at the site of penetration. Enzymes capable of proteolytic degradation of extracellular matrix and basement membranes have been implicated in tumor progression and metastasis, especially the protease matrix metalloproteinase 9 (MMP-9). Matrix metalloproteinases, a family of zinc-dependent proteases, participate in several steps in tumor progression, including invasion, metastasis, and angiogenesis. Many studies implicate that the aberrant expression of MMP-9 plays an important role in tumor metastasis (Deryugina and Quigley, 2006).

20(R)- and 20(S)-Rg3 possess an ability to inhibit the lung metastasis of tumor cells such as B16-BL-6 melanoma and colon 26M3.1 by inhibition of the adhesion and invasion of tumor cells, and also by anti-angiogenesis activity (Mochizuki et al., 1995). Glucocorticoid receptor-induced downregulation of MMP-9 by panaxadiol (PD) and panaxatriol (PT) appear to be associated with the reduced invasive capacity of HT1080, a highly metastatic human fibrosarcoma cell line (Park et al., 1999).

Mochizuki et al. report that multiple administration of ginsenoside Rb2 after the intravenous inoculation of B16-BL6 melanoma cells results in a significant inhibition of tumor associated angiogenesis leading to suppression of lung metastases. In addition, the authors also show that Rg3 significantly inhibits the adhesion and invasion of B16-BL6 cells into reconstituted basement membranes (Matrigel; Mochizuki et al., 1995). Ginsenoside Rb2 has been reported to inhibit invasion to the basement membrane via MMP-2 suppression in some endometrial cancers such as HHUA and HEC-1-A cells, and can potentially be used as a medication for inhibition of secondary spreading of uterine endometrial cancers (Fujimoto et al., 2001). It is shown that ginsenoside Rg3 inhibits experimental pulmonary metastasis by highly metastatic mouse melanoma B16FE7 cells, by inhibition of the 1-oleoyl-lysophosphatidic acid (LPA)-triggered rise of intracellular Ca²⁺ (Shinkai et al., 1996). In addition, the invasive ability and MMP-9 expression of SKOV-3 cells decreases significantly after treatment with ginsenoside Rg3 (Xu et al., 2008). Compound K is effective in suppressing the expression of MMP-9 and thus inhibiting migration and invasion in metastatic murine colon adenocarcinoma cells (Choo et al., 2008). In another study, the aforementioned ginsenoside has also been shown to inhibit the secretion and protein expression of MMP-9 in astroglioma cells. The inhibitory effect of compound K on MMP-9 expression correlates with decreased MMP-9 mRNA levels and suppression of MMP-9 promoter activity. The compound K-mediated inhibition of MMP-9 gene expression occurs via activator protein-1 (AP-1) because its DNA-binding and transcriptional activities are suppressed by the drug (Jung et al., 2006).

Recently, a study (Yoon et al., 2012) has shown that treatment with the Rd inhibits migration and invasion of the liver cancer cell line HepG2. This is accomplished by reducing the expression of MMP-1, MMP-2, and MMP-7, by blocking MAPK signaling, by inhibition of AP-1 activation, and by inducing focal adhesion formation and decreasing vinculin localization and expression. This leads to a significant anti-metastatic effect. Earlier studies have reported that Rd has negligible anti-proliferative activities (Wang et al., 2007a).

Chronic inflammation is associated with increased cancer risk. The microenvironment provided by inflammatory cells is a crucial contributor in the neoplastic process, fostering proliferation, survival, and migration (Aggarwal and Shishodia, 2006). The inflammatory cells and regulators may facilitate angiogenesis and promote the growth, invasion, and metastasis of tumor cells.

Compound K suppresses the TNF-α-induced activation of nuclear factor kappa-B (NF-κB), expression of MMP-9, migration and invasion of cancerous cells, thus indicating that ginsenosides have the potential to suppress inflammation related metastasis (Choo et al., 2008). American ginseng has been shown to inhibit induced COX-2 and NF-κB activation in MDA-MB-231 and MCF-7 cell line (Peralta et al., 2009). Rg3 suppresses activation of NF-κB inhibiting cancer cell growth in colon cancer cell lines SW620 and HCT116 in a dose-dependent manner (Kim et al., 2010b). Blockage of ROS by NAC/catalase inhibits activation of NF-κB signaling increasing Rh2 induced cell death (Li et al., 2011).

The ginsenoside G-Rp1 dose-dependently inhibits interleukin-1 (IL-1) production (at both mRNA and protein levels) from LPS-treated RAW264.7 cells without altering cell viability. This compound also downregulates IκBα phosphorylation and NF-κB activation, but does not affect the upstream signaling enzymes such as MAPK and p85, a regulatory subunit of PI3K (Kim et al., 2009). PPD-type ginsenosides (G-Rb1 and G-Rb2) exhibit significant inhibition of TNF-α release with IC₅₀ values of 48.0 and 27.9 mM, respectively (Park and Cho, 2009). Strong apoptosis-inducing saponins, Rh1 and Rh2, the main intestinal metabolites of Rg3 have been shown to be inhibitors of proinflammatory TNF-α and IL-1b in LPS/IFN-g-activated BV-2 cells, while increasing the expression of the anti-inflammatory cytokine IL-10 (Jung et al., 2010a,b). The prime targets of G-Rh2 are both the protein kinase A (PKA) pathway and the LPS/IFN-g-induced DNA-binding activity of AP-1, but not the cAMP responsive element binding protein or NF-κB. Both PPD and PPT type ginsenosides inhibit LPS-induced TNFα by blocking the phosphorylation of ERK 1/2, JNK, and c-Jun, as well as blocking NF-κB activation (Wu et al., 2007). RGE from steamed and dried P. ginseng is seen to inhibit Helicobacter pylori-induced MAPK signaling by repressing either nuclear factor NF-κB–DNA-binding activity or release of IL-8 and COX-2 in gastric epithelial cells (Park et al., 2007). RGE also inactivates c-Jun phosphorylation and represses redox-sensitive transcriptional activation, leading to reduced expression of IL-8 and 5-LOX mRNA in gastric mucosal cells (Park et al., 2007).

Rh1 significantly suppresses IFN-γ-induced iNOS promoter activity by inhibiting DNA-binding of several transcription factors, such as NF-κB, IRF-1, and STAT1 (Jung et al., 2010a). Furthermore, Rh1 inhibits the phosphorylation of JAK1, STAT1, STAT3, and ERK, which are upstream signaling molecules for IFN-γ-induced iNOS gene expression. This study also demonstrates that Rh1 inhibits IFN-γ-induced JAK/STAT and ERK signaling pathways and downstream transcription factors, and thereby iNOS gene expression.

Tumor promotion often accompanies an elevated ornithine decarboxylase (ODC) activity, acute inflammation and induction of COX-2 activity. Compound K, when applied topically onto shaven backs of female ICR mice leads to the inhibition of the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced expression of COX-2 and production of prostaglandin E2 (Lee et al., 2005a). The eukaryotic transcription factor NF-κB has been involved in intracellular signaling pathways associated with inflammation and carcinogenesis. Compound K has been seen to inhibit the activation of ERK1/2 and Akt signaling. When compound K is applied topically prior to TPA, expression and activities of ODC are inhibited dose-dependently (Lee et al., 2005a). In addition, compound K given prior to each topical dose of TPA markedly lowered the number of papillomas in mouse skin induced by 7,12-dimethylbenz(a)anthracene. Thus, COX-2 inhibition is an essential mechanistic pathway for tumor inhibition by compound K (Lee et al., 2005a). Rg3 is also shown to inhibit expression of COX-2 in TPA-stimulated mouse skin. Rg3 also exerts potent inhibitory effects on the activation of AP-1 responsible for c-jun and c-fos oncogenic transactivation (Keum et al., 2003). P. notoginseng extracts have been shown to reduce significantly the levels of serum TGF-β1, TNF-α, and IL-6 in a hepatic fibrosis model (induced by carbon tetrachloride) in Sprague-Dawley rats (Peng et al., 2009).

Colorectal cancers are mostly initiated by aberrant activation of the Wnt/β-catenin signaling pathway (Kraus et al., 1994). The ginsenoside Rg3 has been shown to inhibit cell proliferation and viability of cancer cells in vitro by blocking nuclear translocation of the β-catenin protein and hence inhibiting β-catenin/Tcf transcriptional activity. Allelic deletion of the oncogenic β-catenin in HCT116 cells renders the cells more sensitive to Rg3-induced growth inhibition. In a xenograft colon cancer model, Rg3 effectively inhibits the growth of tumors derived from the colon cancer cell line HCT116. Histologic examination revealed that Rg3 inhibits cancer cell proliferation, decreases PNCA expression and diminishes nuclear staining intensity of β-catenin (He et al., 2011).

Hypoxia-inducible factor-1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1α overexpression, which has been associated with increased patient mortality in several cancer types. In both Hep3B cancer and HEK293 immortalized normal cell lines, aqueous extract of Korean red ginseng (KRGW) attenuates the expression of hypoxia-induced genes without apparent cytotoxicity (Choi et al., 2011). Mechanistically, KRGW does not affect the synthesis, degradation, and translocation of HIF-1 in hypoxia. Interestingly, the authors found that KRGW represses the transcriptional activity of HIF-1 by interfering with the dimerization between HIF-1α and aryl hydrocarbon receptor nuclear translocator.

Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a redox-sensitive basic leucine zipper transcription factor involved in the transcriptional regulation of many antioxidant genes. Nrf2 is inhibited in the cytoplasm by the anchor protein Kelch-like ECH-associated protein-1 (Keap1), a cytosolic protein that inhibits Nrf2 signaling by promoting proteasomal degradation of Nrf2. In the presence of oxidative stress or chemical inducers, Nrf2 is released from Keap1 inhibition, translocates to the nucleus, and binds to antioxidant response element (ARE) consensus sequences. Activation of Nrf2 by chemopreventive agents influences expression of anti-oxidative phase-I and phase-II enzymes including heme oxygenase-1 (HO-1), NADPH quinone oxidoreductase-1 (NQO1), and glutathione (Lee and Johnson, 2004). An aqueous extract of wild ginseng has been shown to increase expression of GSTA2, GSTA3, and GSMT2 via an NRF-ARE pathway (Saw et al., 2010). Korean RGE has been shown induce HO-1 by NRF–ARE pathway in rat pheocromocytoma cells (Park et al., 2010b). Ginsenoside Rb1 exhibits protection against 6-hydroxydopamine induced oxidative stress in human neuroblastoma SH-SY5Y cells (Hwang and Hye, 2010).

The human telomerase reverse transcriptase (hTERT), the active subunit of telomerase is activated in cancer cells and prevents telomere shortening, thus inhibiting of apoptotic processes. The inhibition of hTERT is an additional mechanism by which ginsenosides can induce cell death in cancer cells. Compound K is known to inhibit cell proliferation by inducing apoptosis and cell cycle arrest at the G1 phase (Kang et al., 2005). Compound K treatment reduces telomerase activity and downregulates the (hTERT) gene, resulting in the decreased expressions of its protein, and of the c-Myc and Sp1 proteins (transcription factors of hTERT) in U937 leukemia cells (Kang et al., 2006). Also, the hot water extract of Korean red ginseng causes significant inhibition on the growth of U937 leukemia cells which is associated with the inhibition of hTERT expression (Park et al., 2009).

A major difficulty in the treatment of human malignancies is the development of broad anticancer drug resistance by tumor cells. This phenomenon has been termed “multidrug resistance” (MDR). Among all ginsenosides, 20(S)-Rg3 is found to have the most potent inhibitory activity on MDR. Rg3 reverses MDR in drug-resistant human fibrocarcinoma KBV20C cells specifically and effectively in a dose-dependent manner (Park et al., 2005). Several ginsenosides, including 20(S)-Rh2, have been shown to inhibit the transport function of P-glycoprotein and increase sensitivity to cancer chemotherapeutics in resistant cells (Li et al., 2008).