Research Progress on Antitumor Effect and Mechanism of Panax quinquefolium Linn.

Yunli TANG, Yao YUAN, Jiangcun WEI, Xiaofang XIE, Cheng PENG*

1.State Key Laboratory of Southwest Traditional Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; 2.Guangxi University of Chinese Medicine, Nanning 530020, China

Abstract Panax quinquefolium Linn., belonging to Panax, Araliaceae, contains a variety of active ingredients.In recent years, many studies have shown that P. quinquefolium Linn.has high value and development prospect in inhibiting colon cancer, lung cancer and breast cancer.Recent advances in studies on chemical components, antitumor effects and mechanisms of P. quinquefolium Linn.are reviewed in the paper.

Key words Panax quinquefolium Linn., Anti-tumor effect, Mechanism of action

1 Introduction

PanaxquinquefoliumLinn., also known as American ginseng, is a rare medicinal material with the effects of nourishing yin, generating fluid and tonifying.P.quinquefoliumLinn., native to United States and Canada, has harsh requirements on growth environment, and it is easy to survive in low latitude and high altitude areas.In the 1980s,P.quinquefoliumLinn.was introduced into China for artificial cultivation and had been successfully planted in Jilin, Liaoning, Beijing, Shaanxi and Shandong provinces.P.quinquefoliumLinn.contains a variety of active components[1], such as amino acids, volatile oils, polysaccharides and saponins, which are the effective components for its antitumor effect.

2 Antitumor effects

2.1 Antitumor effects of extractP.quinquefoliumLinn.and its fruit extract have good inhibitory effect on tumor, and can inhibit the proliferation of colorectal cancer, cell sarcoma S180, lung cancer and other tumor cells.Xieetal.[2]found that the berry extract of freshP.quinquefoliumLinn.had time-dependent(24-96 h)and concentration-dependent(0.1-1.0 mg/mL)inhibitory effects on the growth of human colon cancer SW480 cells.P.quinquefoliumLinn.and its berry extract also inhibited the growth of breast cancer cell MCF-7[3].The water and alcohol extracts ofP.quinquefoliumLinn.inhibited the proliferation of sarcoma S180, lung cancer and lymphocytic leukemia L1210 cells.

After processing at high temperature, low polar saponins, such as ginsenoside Rg3, Rc, Rg_2, Rb_2, Rd,etc., would increase[4-5], which significantly enhanced its anti-tumor effect.The extracts ofP.quinquefoliumLinn.had inhibitory effect on the proliferation of human colorectal carcinoma HCT-116, SW-480 and HT-29 cells before and after steaming.Qietal.[5]found that the steamedP.quinquefoliumLinn.had better inhibitory activity than the raw one on colorectal cancer cells.Wangetal.[6]also proved that the anti-proliferation effect ofP.quinquefoliumLinn.fruit after cooking was enhanced.At the dose of 50 mg/kg, the steamedP.quinquefoliumLinn.berry extract showed significant anti-proliferation activity against human colorectal cancer HCT-116 cells and xenotransplanted tumors in miceinvivo, and the life extension rate of mice reached 100% on the 22ndday of administration, while the survival rate of the positive drug was 60%[7].

2.2 Antitumor effects of saponinsTotal saponins R ofP.quinquefoliumLinn.is the main component of its antitumor activity[6].Panoxadiol has strong toxic and inducing effect on patients with green monkey kidney cancer, and the inhibition rate of malignant tumor at high concentration is about 55%[8].Saponins in protopanoxadiol group also have certain anticancer activities and have strong inhibitory effects on tumor cell proliferation of breast, lung, prostate and pancreatic cancers[9].

The most abundant ginsenoside in the component extract ofP.quinquefoliumLinn.is ginsenoside Rb1, whose intestinal metabolite, ginsenoside Rh2, has been proved to have strong anti-cancer activityinvitro[10].Ginsenoside Rh2 has obvious tumor inhibitory effect on mouse lung carcinoma cells, B16 melanoma cells, rat Morris hepatoma carcinoma cells and prostate cancer cells[11], and inhibits the redifferentiation induced by mouse sarcoma S180 and mouse EAC.Moreover, ginsenoside Rh2 may be used to treat multidrug-resistant cancers, especially in combination with conventional chemotherapy agents.

2.3 Antitumor effects of polysaccharidesA large number of studies have shown that polysaccharides inP.quinquefoliumLinn.play a good inhibitory role in anti-tumor.Maetal.[12]isolated the polysaccharides fromP.quinquefoliumLinn.and studied the effects of the extracted polysaccharides on the growth of hepatoma carcinoma cellsinvitro, confirming that the PPQI and PPQII grades isolated from polysaccharides could inhibit the growth of 7721 hepatoma carcinoma cells and promote their death.Piaoetal.[13]suggested that polysaccharides I, II, III fromP.quinquefoliumLinn.had more obvious inhibitory effect on the proliferation of hepatoma carcinoma cells, andinvitroexperiment results showed that when the mass-volume concentration of panax polysaccharide was increased, the survival rate of carcinoma cells could be effectively reduced to achieve antitumor effect.Zhuetal.[14]found that with the increasing consumption of polysaccharides fromP.quinquefoliumLinn., the weight of tumor cells in the liver of mice decreased significantly, and the tumor immunosuppression rate increased significantly, indicating that the consumption of polysaccharides fromP.quinquefoliumLinn.had significant immunosuppression effect on mouse tumor.Quetal.[15]found that the effect of root saponins polysaccharide inP.quinquefoliumLinn.could effectively inhibit the growth of tumor cells in the spleen of S180 tumor bearing mice.

2.4 Antitumor effect of ureido acidsHuoetal.[16]found that L-amino-acetylarginine(0.125 mmoL/L)at a low concentration had significant promoting effect on normal growth and development of LS174 cells in human body, while high concentration of L-arginine(0.5, 2, 8, 32 mmoL/L)had obvious inhibitory effect on normal growth and development of LS174 cells.Zhangetal.[17]studied the inhibition mechanism of L-arginin on the receptor of chronic hepatocarcinoma cell line QGY27703, and found that L-dodecyl acetylarginine and its receptor at relatively low concentration could effectively promote the normal development and growth of human hepatoma cell line QGY27703.The aromatic conjugated system structure of free tryptophan could produce photosensitive effect, and the photosensitive synergistic effect could be produced by light irradiation, thereby enhancing antitumor activity.

2.5 Adjuvant therapy researchResearch reports show that cancer patients usually take Chinese herbal medicine to treat other cancer-related symptoms, weaken the toxic and side effects of chemotherapy drugs, and enhance the therapeutic efficacy of chemotherapy drugs[18-19].P.quinquefoliumLinn.can cooperate with 5-FU, cisplatin, irinotecan and other chemotherapy drugs to inhibit the growth, development and reproduction of various cancer cells, thus enhancing their effects.Dudaetal.[20]proved thatP.quinquefoliumLinn.had the effect of auxiliary treatment of thymic carcinoma.Some studies proved that 0.5 mg/mLP.quinquefoliumLinn.fruit extract, Rb3 and Re and 1 μg/mL cisplatin inhibited the MCF proliferation rate of breast cancer cells, while Rb1 had no such effect[11].P.quinquefoliumLinn.can reverse the destruction of intestinal barrier caused by cisplatin and reduce its adverse reactions.For a variety of nodular colorectal cancer cells such as SW-480, HCT-116 and HT-29, the administration ofP.quinquefoliumLinn.and its constituents could increase the efficacy of irinotecan as an anticancer drug through synergistic effect, and reduce the therapeutic dose and other related toxic and side effects[22].The combined treatment of steamedP.quinquefoliumLinn.(RAG)with 5-FU had a stronger effect, and the proliferation inhibition rate of colon cancer cells was significantly increased[18].

2.6 OthersFree fatty acid and stearic acid also have antitumor activity.

3 Antitumor mechanism of Panax quinquefolium Linn.

3.1 Impact on cell cycleFlow cytometry(FCM)analysis after PI/RNase staining showed that the unprocessed anticancer components ofP.quinquefoliumLinn.could inhibit the growth of malignant cancer cells in G1 phase.Cell cycle movement analysis showed that panoxadiol could stop its growth cycle in G1 phase in cancer cells, while 5-FU also jointly acted in its S phase or G2/M phase.The combination effect of panoxadiol and 5-FU on different growth cycles of cancer cells has been considered as a possible mechanism to achieve synergistic therapeutic effects.Kingetal.[22]found that polysaccharides and saponins were the main active inhibitors of HCT116 human colon cancer cell proliferation and malignant cell cycle arrest in extracts ofP.quinquefoliumLinn.

3.2 Impact on apoptosisThe molecular binding affinity sites of caspase-3 and other saponin-binding components, the affinity of the binding enzyme and the formation of hydrogen phosphate bond were analyzed in detail by using Surflex-Dock molecular docking method, and the results showed that some enzymes and saponin binding components inP.quinquefoliumLinn.could bind on different molecular binding affinity sites of caspase-3, thus greatly improving the molecular activity of caspase-3 in drugs[17].Through the analysis of molecular binding simulation data, it further confirmed that the use of ginseng isopropanediol and irinotecan showed significant molecular synergistic binding effect by binding to two different molecular sites of caspase-3 enzyme binding protein[2].Chaoetal.[21]reported that L-arginine could induce apoptosis of lung cancer tumor cells through the Arg-NO pathway.

3.3 Impact on signaling pathway and pathway proteinOral administration ofP.quinquefoliumLinn.not only significantly reduces the abnormal activation of EGFR and ErbB2, but also may have high or abnormal expression of epidermal growth factor stimulating receptor(EGFR)in colon malignant tumors.The enhanced anticancer effect of steamedP.quinquefoliumLinn.is related to the inhibition of lipid peroxidation and the regulation of cytochrome P450 signaling pathway related targets[23].A new study has found that there are two more potent esters of anticancer activity, compound K and protopanaxadiol, in the main metabolites of modernP.quinquefoliumLinn., which inhibit the continued growth of malignant colorectal cancer through a variety of immune signaling pathways[24].Rg3 inhibits colorectal cancer through down-regulation of Wnt/β-catenin signaling pathway[25].

3.4 Impact on angiopoiesisAngiogenesis is a key step in tumor growth and metastasis.The inhibitory effect ofP.quinquefoliumLinn.on tumor angiogenesis is related to endothelial cell angiogenesis[26].Endothelial markers such as CD-31 are often used to measure angiogenesis.Guoetal.[27]determined the expression of marker CD31 to calculate microvascular density by establishing a model of subcutaneous xenograft tumor of pancreatic cancer.Studies showed that ginsenoside Rg3 inhibited the growth of subcutaneous xenograft tumor by inhibiting the angiogenesis of subcutaneous xenograft tumor in nude mice.Ginsenoside Rb1 regulates pigment epithelial-derived factors through estrogen receptor β and inhibits capillary morphology of endothelial cells[28].

3.5 OthersPolysaccharides fromP.quinquefoliumLinn.can inhibit malignant tumors by inhibiting and enhancing immunity, inhibiting DNA synthesis of non-anticancer cytokines and inducing combination of anticancer cytokines.Quetal.[15]studied the lymphocyte mitosis and synthesis in tumor spleen of S180 tumor bearing mice and found that polysaccharide fromP.quinquefoliumLinn.could induce the mitosis and synthesis of IL-3 active cell substances in tumor spleen and improve immune function.Zhuetal.[29]conducted clinical detection and experimental analysis on the active effects of polysaccharides fromP.quinquefoliumLinn.on mice, and found that PPQ polysaccharide could effectively inhibit the early growth of malignant tumors in mice, increase the early growth tumor index of thymus gland, liver and spleen, and increase the growth levels of IFN-α, IL-10 and IL-2 in kidney of mice in early stage.Piaoetal.[13]found that panax polysaccharide I, II, III effectively inhibited the DNA and protein synthesis of malignant liver cancer and stem cell tumor.

4 Conclusions

P.quinquefoliumLinn.has been widely used in many countries such as China, and its safety has been gradually confirmed in the theoretical basis of current epidemiological clinical research.It is one of the most economically valuable medicinal materials at present.With the deepening research onP.quinquefoliumLinn., more efforts have been dedicated to anti-cancer effect and mechanism against colorectal cancer and breast cancer, and there are several molecular mechanisms focusing on different signaling pathways.These pathways exist in not only cancer cells, but also endothelial cells and vascular endothelial cells and other non-cancer type environments that cause tissue to become cancerous.Some mechanisms have been discovered, while many more may be unknown, and researches are far from adequate.The antitumor effect and mechanism ofP.quinquefoliumLinn.needs to be further studied, so as to develop new antitumor drugs.