Ginseng - An Anticancer Agent

In East Asian countries, Ginseng has been used as a folk medicine for thousands of years, mainly as a general tonic and adaptogen, maintaining the body's resistance to adverse conditions and maintaining homeostasis. It is also used as an antiageing and to improve general vitality and physical and sexual functions. Ginseng and ginsenosides are beneficial for immunity, cancer, diabetes, CNS functions, and other diseases.

Anticarcinogenic Function of Ginseng

Ginseng is one of the promising candidates for cancer prevention and treatment. Consumption of Ginseng lowers the risk of cancers of the stomach, lung, liver, pancreas, ovary, colon, and oral cavity. Ginseng polysaccharides show antitumour activity through the modulation of innate immunity. Ginsenosides Rg3 and Rh2, found in Ginseng extract, are recognized as major active anticancer saponins. The anticarcinogenic effects of Ginseng are based on diverse mechanisms, including cell cytotoxicity and differentiation, antitumour promotion in inflammation-induced tumours, prevention of metastasis and inhibition of angiogenesis, synergistic effect on chemotherapy agents, and decreasing multidrug resistance (MDR).

Effect of Ginseng on Tumour Cell Cytotoxicity and Differentiation

Saponin and non-saponin compounds of ginseng show cytotoxic activities against various cancer cells. Ginsenoside Rh2, one of the major active components of Ginseng, inhibits proliferation, induces apoptosis in cancer cells, and sensitizes drug-resistant breast cancer cells to paclitaxel (chemotherapy drug). Studies show that ginseng extract induces apoptosis and decreases telomerase (An enzyme that makes cancer cells immortal) activity in cancer cells, including leukaemia. Ginsenosides Rg3 and Rh2 inhibit the proliferation of prostate cancer cells by modulating mitogen-activated protein (MAP) kinases. Ginsenoside Rh2 significantly inhibits the viability of breast cancer cells at G0/G1 phase cell-cycle arrest. Rh2 markedly increases albumin secretion and alkaline phosphatase activity, whereas it decreases alpha-fetoprotein secretion and gamma-glutamyl transpeptidase in hepatocellular carcinoma. Furthermore, Rh2 almost completely inhibits telomerase activity with the parallel induction of cell differentiation. Rg3 inhibits the proliferation of colorectal cancer cells. Panaxydol, a polyacetylene compound isolated from Ginseng, inhibits the proliferation of cancer cells and induces differentiation of the human hepatocellular carcinoma by increasing the expression of tumour-suppressor genes p21 and pRb while reducing the inhibitor of differentiation. In addition, acetylpanaxydol and panaxydolchlorohydrin show cytotoxicity against lymphoid leukaemia. These studies suggest that ginseng constituents, such as ginsenoside Rh2 and panaxydol inhibit cancer cell proliferation and induce cell differentiation making more mature forms of normal cells.

Antitumour Activity of Ginseng in Inflammation-Induced Tumour Promotion

Tumour promotion is closely related to inflammation, and compounds with strong anti-inflammatory activity possess antitumour promoter activity. Ginsenoside Rg3, found in Ginseng, is the most effective anti-inflammatory agent. Ginseng extract decreases the expression levels of cyclo-oxygenase-2 (COX-2) and Inducible nitric oxide synthase (NOS), which are indicators of inflammation related to tumour promotion in cancer cells. In addition, treatment with Ginseng extract induces apoptosis of leukaemia cells mediated by inhibiting anti-apoptotic proteins Bcl-2 and Bcl-XL. Ginseng progressively downregulates the expression of telomerase reverse transcriptase by inhibiting the expression of proto-oncogene c-Myc.

Antimetastatic Effect and Inhibition of Angiogenesis

Ginseng extract, mainly Ginsenoside Rg3, inhibits tumour invasion and metastasis without impairing cell growth and proliferation of tumour cells. The inhibitory effect is due to the inhibition of tumour-induced angiogenesis and decreased invasive ability. Ginsenoside Rg3 significantly inhibits the growth and angiogenesis of ovarian cancer when used alone or combined with cyclophosphamide (A chemotherapy drug). Studies show that low-dose Cyclophosphamide combined with Rg3 produces significant antiangiogenic effects without toxicity and improves the living quality and survival time. This regimen also has the advantage of a lowered susceptibility to drug resistance. Another ginsenoside, Rb1, also has similar anticancer properties. Studies demonstrate several novel mechanisms of these ginsenosides that have potential as anticancer and antiangiogenic agents.

Anticarcinogenic and Synergistic Effect of Ginseng in Combination with Chemotherapy

Studies conducted to evaluate the chemopreventive potential of ginseng show marked reduction not only in tumour incidence but also in cumulative tumour frequency at the initiation phase of tumorigenesis. Studies show that long-term oral administration of ginseng extract inhibits incidence and proliferation of tumours. Ginsenosides Rg3 and Rg5 demonstrate a significant reduction in lung cancer, whereas ginsenoside Rh2 tends to decrease the incidence of lung cancer. Ginseng extract inhibits lung adenoma and decreases the frequencies of chromosomal aberrations and micronuclei. Another study shows that Rh2 has an antiproliferative effect on lung adenocarcinoma with cell cycle arrest at the G-1 phase. Ginseng suppresses colon carcinogenesis with inhibition of cell proliferation, acting on aberrant crypt foci in the colon mucosa. Ginseng also shows an anticarcinogenic effect on the development of liver cancer and has both preventive and curative properties. Ginsenoside Rh2 inhibits cell growth at low concentrations, induces apoptosis at high concentrations, and acts either additively or synergistically with chemotherapeutic drugs on cancer cells, such as breast cancer cells' response to chemotherapy drug paclitaxel. Ginseng extract, mainly Panaxadiol (PD), enhances the anticancer effects of chemotherapy drug 5-fluorouracil (5-FU) in colorectal cancer cells by inducing apoptosis. The enhancement of the S-phase arrest and the increased susceptibility to apoptosis are synergistic effects of PD on 5-FU.

Ginseng Helps Reduce Multidrug Resistance

The extensive laboratory, preclinical, and epidemiological studies have shown the protective influence and the complementary therapeutic potential of Ginseng for cancer treatment. Studies evaluate the potential beneficial effects of Ginseng on chemoprevention and complementary therapy of cancer. One of the major obstacles in cancer treatment is acquiring broad anticancer drug resistance by cancer cells. This phenomenon called multidrug resistance (MDR) is a major problem in cancer chemotherapy. It is correlated with the overexpression of P-glycoprotein (Pgp) in the plasma membrane of resistant cells. Ginseng extract has a moderate inhibitory effect on the drug efflux pump in MDR lymphoma due to ginsenosides Rg1, Re, Rc, and Rd. Ginsenoside Rg3, among several ginseng components, has the most potent inhibitory activity on MDR fibroblast carcinoma. Treatment of drug-resistant cancer cells with Rg3 specifically inhibits drug accumulation and further increases the life span of resistant leukaemia patients. Another study shows that ginsenoside metabolites Rh2, PPD, and PPT significantly enhance the cytotoxicity of mitoxantrone (MX) to breast carcinoma and may be potential inhibitors of breast cancer resistance protein (BCRP) in breast cancer cells, which overexpress BCRP. Studies also suggest that ginseng significantly reduces the risk of gastric cancer.

Conclusion

As a well-known herbal immune modulator, hundreds of studies have extensively reported the anti-cancer or chemo-preventive effects of Ginseng. The anti-cancer effects of Ginseng are mainly through the improvements in cell-mediated immunity consisting of cytotoxic T cells and NK cells. At the same time, other mechanisms such as oxidative stress, apoptosis, and angiogenesis are also involved. A comprehensive review dealing with anti-cancer effects from the immunological point of view would be vital in the near future.