food therapy and health care

ARTICLE DOI: 10.12032/FTHC202002002

12 | no.2 | vol.1| February 2020 | Food Therapy and Health Care

Food Therapy and Health Care

Research Progress of Tea Functional Components in the Prevention and Treatment of Lung Cancer

Hao Wu1, Qin-You Ren1, Xing Tang2, Hui Zhang1, Can-Jun Zhao1, Jian-Gang Yang1, Lan-Hui Zhang1, Ao-Yu Shi1, Bi-Zhu Geng1, Jin Zheng1*

1Department of traditional Chinese medicine, the Second Affiliated Hospital of Air Force Military Medical University, Xi'an 710038, China. 2Xi'an brain disease hospital of traditional Chinese Medicine, Xi'an 710038, China.

*Corresponding to: Jin Zheng. Department of traditional Chinese medicine, the Second Affiliated Hospital of Air Force Military Medical University, Xi'an 710038, China. E-mail: [email protected].

Highlights

In this paper, the functional components of tea, the basic theory of traditional Chinese medicine, the mechanism of functional components against lung cancer, and expert opinions are reviewed. Information data and traditional Chinese medicine are discussed in order to explore the theory and direction of tea prevention and treatment of lung cancer from the point of view to the inside, from the shallow to the deep, and the combination of Chinese and Western medicine.

Traditionality

The etiology and pathogenesis of phlegm, blood stasis, heat knot and dampness obstruction in lung collaterals of lung cancer have great significance in treating lung cancer according to the effect of tea invigorating the spleen and eliminating dampness, promoting blood circulation and unblocking collaterals, clearing away heat and detoxification and dispersing knots.

DOI: 10.12032/FTHC202002002 ARTICLE

Food Therapy and Health Care | February 2020 | vol.2 | no.1 | 13

AbstractThe incidence and mortality of lung cancer rank first among all malignant tumors, so the prevention and treatment of lung cancer has become a worldwide concern. Tea is one of the most popular healthy drinks in the world. A large number of studies have shown that tea polyphenols, theophylline, tea pigments, theanine, tea polysaccharides and other functional components in tea can promote apoptosis of cancer cells, inhibit proliferation and division of cancer cells, and regulate the expression of tumor-related gene protein through strong antioxidant activity, inhibiting the activity of key enzymes and blocking signal transduction to prevent and treat the occurrence, development and metastasis of lung cancer. In this study, the application of tea in the prevention and treatment of lung cancer was elaborated through the traceability, basic components, basic theory of traditional Chinese medicine, anti-lung cancer mechanism, expert opinions and so on, in order to provide direction for the prevention and treatment of tea and lung cancer.Keywords: Tea, Lung cancer, Functional components, Traditional Chinese medicine, Research progress

Abbreviations:

TCM, traditional Chinese medicine; ASCO, American Society of Clinical Oncology; WHO, World Health Organization; EGCG, epigallocatechin gallate; EGC, epigallocatechin; ECG, epigallocatechin gallate; PPAR-γ, Proliferator-activated receptor-γ; COX-2, cyclooxygenase-2; MTT, metabolic activity; VEGFR, vascular endothelial growth factor receptor; PI3K, phosphatidylinositol kinase; Cx43, connexin 43..

Competing interests:

The authors declare that there is no conflict of interest.

Citation:

Hao Wu, Qin-You Ren, Xing Tang, et al. Research Progress of Tea Functional Components in the Prevention and Treatment of Lung Cancer. Food Therapy and Health Care 2020, Online.

Submitted: 14 October 2019, Accepted: 21 November 2019, Online: 28 January 2020.



Introduction

Lung cancer, also known as bronchial lung cancer, the annual report of cancer progress in 2018 that published by the American Society of Clinical Oncology(ASCO) in the latest Journal of Clinical Oncology in the 2018: In 2018, there will be 18.1 million new cancer cases worldwide, and 9.6 million people will die of cancer. About 2.1 million are lung cancer and 1.8 million are death, which accounting for the first incidence and mortality of all malignant tumors [1]. It seriously that affects human life and health all over the world. Therefore, the prevention and treatment of lung cancer has become the focus of attention all over the world. Finding effective methods and drugs to alleviate cancer symptoms, prolonging survival and improving the quality of life has become the main research direction. Tea is one of the most popular healthy drinks and its consumption ranks second in the world. Tea drinking has become a daily habit of people in China, Europe, the United States, Japan and other countries and regions. It has been extensively studied because of its good efficacy and anti-cancer mechanism. On October 27, 2017,through Preliminary arrangement and reference of the list of carcinogens published by the International Cancer Research Institute of the World Health Organization (WHO), tea was found in one of the three categories. There is no sufficient human or animal data on human carcinogenicity, but experimental studies have found that tea has a direct inhibitory effect on cancer cells. On the other hand, tea can improve human immunity to achieve anti-cancer effect [2].Therefore, it is important to summarize the relationship between the research on tea and anti-cancer therapy. This paper evaluates the relationship between tea and lung cancer by researching and analyzing the origin, classification, component analysis and expert opinions of tea.Discusses the mechanism of tea prevention and treatment of lung cancer through experimental and animal studies so as to provide ideas for clinical and experimental research of prevention and treatment of lung cancer in the later stage.

1. Traceability and Classification of Tea

China is the origin and cultural development of tea. Tea’s name first appeared in the "Shennong’s Classic of Materia Medica",which said : "Shennong tastes hundreds of herbs and gets seventy two poisons a day, which can be relieved by tea." It is recorded that a few leaves floated into the pot when Shennong was cooking water in the field, which causing its water yellowing.

Drinking the liquid in the mouth, Shennong felt thirst quenched and the mind refreshed. Based on Shennong's experience of tasting hundreds of herbs in the past, it can be judged that it is a kind of medicine. This is the most common saying about the origin of tea drinking in China. Its origin is recorded in the Classics of Tea by Lu Yu of Tang Dynasty, which states that "tea for drinking is originated from Shennong, heard from Duke Zhou of Lu, rised in Tang Dynasty, and flourished in Song Dynasty". At present, tea is classified into angiosperm, dicotyledon, primitive perianth, theales and camellia in the botanical classification system. According to the classification method of Chinese Tea Classics compiled by Chen Zongmao, Vice-Chairman of International Tea Association, tea is classified into green tea, black tea, oolong tea, white tea, yellow tea and dark tea. In Europe, tea is divided into three categories: green tea, black tea and oolong tea. According to the fermentation degree of tea , it can be divided into non-fermented tea, pre-fermented tea and post-fermented tea in Japan.

2. Basic Components of Tea

Tea contains a variety of chemical components [4].There are more than 500 known compounds have been isolated and identified, including more than 450 organic compounds and no less than 15 inorganic mineral elements. The fresh tea leaves contain about 22% - 25% dry matter, among which organic compounds account for 15% - 21% of the fresh weight. Its mainly including phenolic substances (20% - 35%), protein (20% - 30%), carbohydrates (20% - 25%), fat (8%), alkaloids (2% - 5%), organic acids (3%), amino acids (1% - 4%), pigments (1%), vitamins (0.6% - 1.0%), aromatic substances (0.005% - 0.03%) and enzymes. Inorganic minerals account for about 5% of the total dry matter in tea, which mainly include calcium, iron, phosphorus, fluorine, iodine, zinc, selenium, copper, magnesium, manganese, platinum and germanium. About 50% of them are potassium oxides and 15% are phosphorus oxides and phosphate. According to the functional components of tea, it is mainly divided into natural organic compounds such as tea polyphenols, tea polysaccharides, tea theophylline, tea pigments and tea-based acids. Among them, tea polyphenols, tea polysaccharides and theophylline are the most important components. At present, the main research on tea is in epidemiology, in vitro, in vivo and animal experimental study of extract, clinical review study, etc. Its main functions are anti-oxidation, anti-allergy, anti-ulcer, preventing cancer and anti-cancer, eye-catching, improving intestinal immunity and so on.



3. Theoretical Study of Traditional Chinese Medicine

Tea is bitter, sweet and slightly cold, belonging to heart, spleen, liver and lung meridian. It is first seen in Shennong’s Classic of Materia Medica as a drug [5],which said : "Shennong tastes hundreds of herbs and gets seventy two poisons a day, which can be relieved by tea." It has the functions of refreshing, clearing away heat and toxin, relieving summer heat, eliminating food and phlegm, promoting body fluid to quench thirst, activating blood circulation and stopping diarrhea with bright eyes. Among them, flower tea can promote the growth of Yang Qi in the human body and send out cold evils .Green tea can promote body fluid to quench thirst, clear heart to remove irritation, detoxify and sober up, stop diarrhea and dehumidification. Black tea can invigorate the spleen and stomach, induce diuresis to reduce edema. Oolong tea can refresh the mind, eliminate fatigue, promote fluid production and diuresis. White tea can clear away heat and moisten lung, calm liver and benefit blood, clear away heat and detoxifie toxins. Yellow tea can refresh the mind, eliminate food and resolve stagnation. Dark green tea has the functions of strengthening the intestines and stopping astringency, clearing away heat and promoting diuresis. There is a record of " new drink formula substituting tea " in Wang Tao's Medical Secrets of an Official in Tang Dynasty. Wang Huaiyin's Prescriptions from Great Peace Imperial Grace Pharmacy of Song Dynasty said, " Chinese Onion & Bean Tea Prescription is made of scallion, light soybean sauce, Schizonepeta, peppermint, gardenia and gypsum. The dregs are removed by water frying, with the tea powder added to the water and boiled in four or five boiling times. Then Divide the mixture into two parts and take one at a time. This is commonly used for the treatment of headache and fever." That is, treat disease with tea prescription. Song Chenzhi's “New Guidebook to the Elder's Health Preservation” records that Four Shun San is used for relieving exogenous febrile disease in four seasons of the older.Tangerine powder can promote to digest in summer, ect. It can be seen that traditional Chinese medicine has certain experience in treating diseases with herbal tea since ancient times. According to the main symptoms of lung cancer such as cough, expectoration, shortness of breath and spontaneous sweating, the “Textual Research for Medical Prescriptions” prompts that once the defensive Qi is deficient, it is not enough to fix the body fluid, then it seeps through itself, which is the cause of spontaneous

perspiration. Atractylodes macrocephala and Astragalus membranaceus often used in combination with Fangfeng because those can replenish qi, but those with sweet taste can't reach the surface quickly. Li Dongyuan said that Astragalus combined with fangfeng works well,these phenomenons are called as the mutual restraint and mutual assistance between two drugs. Spontaneous sweating is different from sweating caused by invasion of exogenous pathogens. The sweating caused by invasion of exogenous pathogens is due to the exuberance of external evils. The spontaneous sweating caused by miscellaneous syndromes is due to the lack of positive Qi in the body. The deficiency and excess of type of syndromes are different, their purging and tonifying therapies also vary from each other. That means Yupingfeng san(Jade Screen Powder) has a good effect on spontaneous sweating caused by deficiency of lung qi. According to Detailed Analysis of Warm Deseases, the method of taking Sangju drink to treat cough in four seasons,which can be used as tea substitute. On the other hand, the pathogenesis and pathological mechanism of lung cancer are turbid phlegm, blood stasis, heat knot and dampness blocking the lung collaterals, so it is of great significance to treat lung cancer with tea according to the effect of tea of invigorating the spleen and removing dampness, activating blood and dredging collaterals, clearing away heat, detoxifying and dispersing the collaterals.

4. Study on the Prevention and Treatment of Lung Cancer by Tea Functional Components

According to the functional components of tea, i t is mainly divided into tea polyphenols, tea polysaccharides, tea alkaloids, tea pigments, tea based acids and other natural organic compounds. Jin Ziyi [6], Professor of Nanjing University of traditional Chinese medicine, through meta-analysis of the relationship between tea drinking and lung cancer in mainland China, Hong Kong and Taiwan found that the incidence of lung cancer among tea drinkers was lower than those people who don’t drink tea (or = 0.66,95% CI: 0.49-0.89), which positively correlated with the number of years of tea drinking and had a protective effect on lung cancer in green tea drinkers. Kubik[7] through the analysis of the risk factors of lung cancer in women concluded that black tea can significantly reduce the risk of lung cancer in non-smoking women (or = 0.66,95% CI: 0.47-0.94).The more years of tea drinking, the lower the risk of lung cancer. Tea drinking can inhibit and reduce the risk of various types of lung cancer. Yoshiyuki [20] found that the higher tea intake in Okinawa in where the lower the risk of lung cancer,



especially the risk of lung squamous cell carcinoma through studied the relationship between tea drinking and lung cancer in Okinawa, Japan, from 1988 to 1991. It is conclued that tea drinking has a protective effect on the occurrence of lung cancer. At present, it has been found that tea ingredients have a definite effect on the prevention and occurrence of lung cancer, but retrospective epidemiological studies [40]and the research of specific components and mechanisms of anti lung cancer are relatively scarce. The author of this paper intends to analyze the research progress of different ingredients in the prevention and treatment of lung cancer through in vivo experiment, in vitro experiment, anti-lung cancer mechanism and so on.

4.1 Tea polyphenolTea polyphenol (TP) is a kind of phenolic substance rich in multi meridians in tea, which mainly have four types of including catechins (flavanols), anthoxanthin (flavonoids and flavonols), anthocyanins (anthocyanidin and leucoanthocyanidin), phenolic acids and depsides. It accounts for 18-36% of the dry weight of tea, of which catechins account for 80%. Catechins mainly include epigallocatechin gallate (EGCG), epigallocatechin (EGC), epigallocatechin gallate (ECG) and so on. At present, it is believed that tea polyphenols through antioxidation, clean up the oxygen radical, regulate and control the formation, development and metastasis-related genes of tumor, inhibit and kill the proliferation of tumor cells or increase the sensitivity of anti-lung cancer drugs to achieve the purpose of prevention and treatment of lung cancer (Figure 1). Li[8]analyzed the dose-response relationship between EGCG feeding on non-small cell lung cancer H1155, H661 and A427 (human lung cancer derived

cell lines) nude mice and the prevention and treatment of lung cancer .It mainly measured the growth of xenografts in nude mice and the level of EGCG in plasma and tissues, with observed for 45 days . The results showed that the tumor weight of EGCG fed on mice was significantly reduced (57%) compared with that of the control group, and the cells of h1155, H661 and a427 in nude mice were restrained obviously. The main mechanism may be that EGCG can inhibit lung cancer by inducing ROS, DNA oxidative damage and apoptosis. Hudlikar’ team [9] studied and analyzed the effect of tea polyphenols extracted from black tea on the incidence, diversity and delayed period of lung cancer in mice. Through the study and observation of lung lesions after the carcinogenesis of lung cancer model, analyzing the inflammation, cell proliferation, tumor markers, mitogen activated protein kinase (p38MAPK), protein kinase B (Akt) and their phosphorylation forms in the lesion site at 4, 10 and 18 weeks after the carcinogenesis.It was found that black tea polyphenol can significantly reduce the diversity of tumor surface and micro nodules. The tumor markers and inflammatory factors were also significantly reduced. The mechanism may be that tea polyphenols can down regulate NNK induced cell proliferation by phosphorylation of p38 and Akt and inhibit inflammatory secretion to achieve the purpose of treating lung cancer. The team of Zhou [10]established the lung cancer mice model induced by NNK fed with EGCG. After 19 weeks of observation, they examined the expression of lung tissue related protein genes and elucidated the role of miRNA in EGCG's inhibition of A/J mice 'tobacco carcinogenic lung cancer by using genomic methods. They believed that EGCG could inhibit lung cancer by inducing miRNA to regulate gene expression through its antioxidant activity and specific protein binding to regulate cell function. Hessien[11] studied the direct inhibitory effect of tea extract on NSCLC in vitro. By observed by detecting cell proliferation rate, metabolic activity (MTT) and apoptosis to showed the relationship between tea polyphenols and H460 lung cancer cell line.The results showed that tea polyphenols not oniy can reduce the activity of H460 cell line, but also enhance the degree of cisplatin reducing the activity of lung cancer cell line. The mechanism may be related to that tea polyphenols can up regulate the expression of p53, Caspase-3, down regulate the expression of Bcl-2, and promote cell death. Okabe et al [12] explored the effect of EGCG on the expression of 588 genes in human lung cancer PC-9 cell line.It was found that the expression of Nik, DAPK1, rhoB and SKY were down regulated, while the expression of retinoic acid receptor

Figure 1 Molecular structure formula of tea polyphenolEpicatechin: R1=R2=H Epigallocatechin: R1=H;R2=OH Epicatechin gallate: R1=Galloyl;R2=H Epigallocatechin gallate: R1=Galloyl;R2=OH



α1 was up regulated after EGCG treatment. The results showed that EGCG mainly inhibited the activity of NF-KB by inhibiting the Nik / IKK signal pathway, so as to down regulate the expression of Nik gene, which is the main means of prevention and treatment of lung cancer. Huang[13]studied the treatment of highly metastatic human lung cancer cell line A549 with tea polyphenols in vitro and found that tea polyphenols mainly reduced the concentration of Ca2 + and the level of connexin 43 (Cx43) in lung cancer cells, which blocked A549 cells from G0 / G1 phase, affected their DNA synthesis, and thus inhibited cell proliferation. According to the analysis of current research results, because the particularity of lung cancer cells that can resist the stimulation of tumor drug apoptosis, the mechanism of tea polyphenols[25-27]in the prevention and treatment of lung cancer has developed from blocking cell cycle, inhibiting cell proliferation, inducing apoptosis to regulating related genes and proteins, blocking related signal pathways, etc. The specific mechanisms are as follows.1. Tea polyphenols can directly inhibit tumor and enhance the drug sensitivity of tumor cells;2. Tea polyphenols can affect DNA synthesis of tumor cells, block cell cycle at G0 / G1 phase and inhibit tumor cell proliferation;3. Tea polyphenols can directly strengthen the anti-oxidation effect of the body and inhibit tumor formation;4.By up regulating the expression of p53, caspase-3 and other genes, tea polyphenol can down regulate the process and binding of Bcl-2, Nik, DAPK1, rhoB, SKY, NF-KB and other genes, so as to promote the apoptosis of lung cancer cells and achieve the purpose of treating lung cancer.

4.2 Tea polysaccharidesTea polysaccharide(TPS) is an acid glycoprotein extracted from tea and combined with protein. It is

mainly composed of glucose, arabinose, galactose, xylose, etc (Figure 2). At present, it is believed that the main functions of tea polysaccharide are to reduce blood lipid, resist oxidation and improve immunity. The mechanism of anti-lung cancer may be to improve the immunity of the body, enhance NK cell activity, promot the production and secretion of tumor necrosis factor by macrophages and so on. Park and his partners [14]treated nude mice infected with melanoma by intraperitoneal injection of tea extract polysaccharide. After 14 days of treatment, the lung tumor colonies were observed. The results showed that tea polysaccharide could significantly inhibit lung metastasis through its anti-tumor activity. The main mechanism may be to stimulate the production of cytokines in macrophages, inhibit the growth and metastasis of tumor by macrophages and NK cells, so as to achieve the effect of inhibiting lung metastasis. Yi's team[15]separated tea extract into nanoparticles through nanoparticle technology and used chemotherapy methods to determine its nanoparticles, they found that it mainly includes tea polysaccharides.It was found that tea polysaccharide could directly stimulate the secretion of white hormone-6 and TNF -α in macrophages of mice and enhance the immune response and immune stimulation of mice though vivo experiments.A549 cells were cultured with tea polysaccharide and adriamycin in vitro, and the cell survival rate was detected by MTT method.The results showed that tea polysaccharide promoted the absorption of adriamycin, decreased the dosage of adriamycin, and enhanced the inhibition of adriamycin on lung A549.According to the analysis of current results, the prevention and treatment mechanism of tea polysaccharide on lung cancer is mainly as follows: 1.Tea polysaccharide can promote macrophages to secrete inflammatory factors to stimulate the immune response and increase the activity of immune cells so as to inhibit the proliferation of tumor cells;2.Tea polysaccharide can promote the apoptosis of lung cancer cells by increasing the sensitivity of chemotherapeutics, which leads to the purpose of prevention and treatment of lung cancer.

4.3 tea polybasicAlkaloids in tea are one of the important chemical constituents in tea. They mainly include caffeine, theophylline and theobromine. Caffeine accounts for about 2%-4% of the dry weight of tea. Its main functions are excitated, cardiotonic, diuretic and so on. Wang [17] studied the effect of tea caffeine combined with cisplatin on human lung adenocarcinoma SPC-A-1 cells by detecting the toxic effect and survival rate

Figure 2 Molecular structure formula of tea polysaccharide



of cisplatin on cells in vitro.The results showed that caffeine could significantly enhance the anti-cancer effect of cisplatin on lung adenocarcinoma SPC-A-1 cells in vitro. Its mechanism may be primarily caffeine damage checkpoint response to feedback of the cell cycle regulation and shorten the cells of cisplatin induced G2 / M phase of stagnation, thereby inhibiting DNA repair, prompting DNA damage of tumour cells get into the cell proliferation cycle and apoptosis.Tsai [18] tested the inhibitory effect of caffeine combined with cisplatin on high-p185 cell line in vitro and the cell survival rate by MTT method to study the chemical sensitization effect of caffeine on high-p185 cell line of human lung cancer.The results showed that caffeine could inhibit cell G2/M phase arrest and mitosis, destroy DNA in lung cancer cells and block their replication and transcription, which can treat lung cancer. According to the current research results, the main mechanisms of alkaloids in tea to prevent and treat lung cancer are as follows: 1. Alkaloids in tea can directly enhance the cell sensitivity of related chemotherapeutic drugs and promote cell apoptosis to achieve the purpose of treating lung cancer; 2. Achieve the purpose of anti-cancer by directly destructing cell DNA and blocking cell mitosis. Generally speaking [19], currently the study of alkaloids in tea is principally in vitro, but less in vivo. The main reason is that when theophylline acts in vivo, it needs blood concentration at least 20 times the maximum tolerance of human body, so there are few reports about it.

4.4 tea pigmentTea pigments are a kind of water-soluble phenolic pigments extracted from tea,which including catechins, theaflavins, thearubigins, theabrownins, etc. Their functions are primarily anti-lipid oxidative, anti-tumor and enhancing immunity. At present, it is believed that the mechanism of tea pigments in preventing and treating lung cancer is mainly to regulate cell proliferation cycle, induce apoptosis, regulate cell signaling molecules and inhibit cell-related enzymatic activity. Mao[21]studied the effect of tea pigments extracted from white tea on human lung adenocarcinoma cell lines A549 and H520 in vitro and detected cell survival rate and related gene protein expression by bronchoalveolar lavage and MTT method. The results showed that the mechanism of the direct and specific cytotoxicity of tea pigments to lung adenocarcinoma cells was negated and it might induce lung cancer cell apoptosis by inducing caspase-3 activation and inhibiting the signaling pathways of Induction of peroxisomes, including Proliferator-activated receptor-γ(PPAR-γ) and 15-lipoxygenase

(15-LOX). By studying the effects of thearubigins and theaflavins on lung cancer HT460 cells in vitro, Imran and others [22]found that tea pigment can block lung cancer HT460 cells directly in G2/M phase, and its mechanism may be up-regulation of cyclin-dependent kinase inhibitors or down-regulation of cyclin and protein-dependent kinase to achieve the purpose of treating lung cancer. Rawangkan etal [23] through studied the expression level of PD-L1 on the cell surface of non-small cell lung cancer cell lines by tea pigments experiment in vitro found that PD-L1 was the highest in lc-ai and lu99 cells, the middle in A549 and h322 cells, and the very low in h1703 and H1299 cells,which independent of cancer cells. The mechanism may be that tea pigments can inhibit the expression of PD-L1 in lung cancer cells and enhance the anti-tumor immunity to achieve the purpose of anti-lung cancer by inhibit PD-L1 gene by inhibiting the phosphorylation of Akt/STAT1. In vivo experiments have found that tea pigments can significantly reduce the level of PD-L1 protein in NNK-induced lung cancer in mice. Therefore, it is believed that tea pigments can inhibit the expression of PD-L1 in lung cancer cells, enhance the anti-tumor immunity and it have significant anti-cancer activity. JUN [24]and others studied the apoptotic mechanism of catechins on A549 lung cancer cells in vitro. MTT assay was used to measure the cell survival rate and RT-PCR was used to measure the related genes. The results showed that catechins may inhibit the synthesis of Bcl-xL protein by inhibiting the expression of Bcl-xL gene in cells, thus reducing the inhibition of apoptotic mechanism and inducing target cell apoptosis. Zhong [28] etal studied the mechanism of catechin inhibiting the proliferation of lung cancer cells. The cell viability and cycle of lung cancer cells treated with catechin were analyzed through in vitro experiments. The results showed that catechin could regulate the expression of C-MYC and LIN-28 gene regulatory proteins at the levels of gene and protein by regulating let-7a-1 and let-7g signaling pathways in lung cancer cells. After treatment with catechin, the number of lung cancer cells in G2/M phase increased, while the number of S phase cells decreased. It was concluded that catechin could inhibit the proliferation of lung cancer cells to achieve the effect of anti-lung cancer. According to the analysis of the present results, the main mechanisms of catechin [29-30] inhibiting lung cancer are as follows: 1. Tea pigment can inhibit lung cancer cell proliferation or induce apoptosis by directly regulating cyclin and related enzymes blocks cells in G2/M phase; 2. Tea pigment induce activation of apoptotic mechanism through related regulation of gene expression of lung cancer-related mRNA genes



can promote apoptosis; 3.Tea pigment can prevent and cure lung cancer by regulate related signal pathway, enhance immunity, reduce the activity of lung cancer cells and regulate the expression of related genes and proteins.

4.5 TheanineTheanine is a unique component of free amino acids in tea, mainly glutamate γ-ethyl amide, which has antioxidant, antihypertensive and antineoplastic effects. Its mechanism may be directly inhibiting the proliferation of cancer cells or inhibiting cell metastasis (Figure 3). Mendel [31] etal tested the survival rate of lung cancer, colon cancer and breast cancer cells by observing theanine in vitro experiment. The results showed that theanine had inhibitory effect on lung cancer, colon cancer and breast cancer cells, but it had no inhibitory effect on normal cells. The mechanism may be that theanine directly inhibited the nuclear fragmentation of lung cancer cells, consolidated and densely stained and formed apoptotic bodies, thus promoting the apoptosis of lung cancer. Liu [32] and others fed rabbits with theanine.Then cultured serum for in vitro and in vitro growth experiments to observe the effect of theanine on A549 lung adenocarcinoma cells. The results showed that theanine could significantly inhibit the proliferation of A549 lung cancer cells. The mechanism may be that theanine could inhibit the proliferation of endothelial cells and inhibit the formation of endothelial tubules by down-regulating the expression of vascular endothelial growth factor (VEGF) and CD3 protein, which can sequentially promote cell apoptosis and inhibit the proliferation and metastasis of lung cancer cells. Fujii [33]and his team found that theanine could significantly inhibit the proliferation of lung cancer cells in vitro experiment. Its mechanism may be to down-

regulate the downstream targets of NF-kappa B and vascular endothelial growth factor receptor (VEGFR) while promote the expression of Caspase-3 and p53 proteins to promote the apoptosis of lung cancer cells. According to the analysis of current results[34-35], the prime mechanisms of Theanine in preventing and treating lung cancer are as follows: 1. Theanine can directly act on the nucleus to promote cell apoptosis; 2. Theanine can inhibit the proliferation and angiogenesis of cancer cells by regulating the expression of related genes and proteins such as vascular endothelial growth factor and nuclear factor-kappa B.

4.6 Other extractsTea extract is a substance extracted from various components of tea. Beane etal[36] through studied the airway gene expression of high-risk smokers with precancerous lesions found that most of them were up-regulated by p53 and mTOR signaling pathways, while the pathways related to exogenous biometabolism, glutathione and retinol were reduced. Beane named this "damage area".The results showed that the airway tissue had a significant improvement after drinking tea extract, which may be related to the reduction of p53 and mTOR signal pathway expression and the "damage area". Izdebska’s team[37] studied the effect of tea extract on the protective autophagy of lung cancer A549. They observed the changes of cell structure and detected cell sensitivity and cell mortality to shown the effect of tea extract on lung cancer A549 after treatment in vitro. The results showed that tea extract directly increased the number of acidic vesicle organelles, promoted the formation of autophagic dots, blocked the protective autophagy of cells, enhanced the ability of death induction of dead cells. Lu and others[38] studied the effect of tea extract-induced annexin-1 (Annexin-1) on inhibiting the proliferation of lung cancer cells by inhibiting cyclooxygenase-2 (COX-2). The results showed that the proliferation of lung cancer cells was reduced significantly. The mechanism may be that tea extract increased anti-inflammatory activity by inducing Annexin-1, inhibited the expression of COX-2 and prostaglandin (PGE2) and inhibited its related receptors blinding that can promote the metastasis, growth and proliferation of lung cancer cells, thus giving rise to the purpose of treating lung cancer. According to the analysis of current results[39], the main mechanisms of tea extracts in preventing and treating lung cancer are as follows: 1. Tea extracts playing a preventive role by regulating the expression of genes related to high-risk lung cancer; 2. Tea extracts promoting apoptosis by inhibiting the protective autophagy of lung cancer cells; 3. Tea

Figure 3 Mmolecular structure formula of Theanine



extracts inhibiting the expression of tumor-related proteins by inducing anti-inflammatory mechanism, thereby inhibiting cell metastasis and proliferation.

5. Mechanism of tea against lung cancer

Lung cancer is one of the malignant tumors with the highest mortality. Because of the drug resistance and insensitivity to chemotherapeutic drugs, the 5-year survival rate of lung cancer I and II is 30-40%, while that of advanced lung cancer is only 5%. Therefore, it is particularly vital to study the mechanism of lung cancer prevention and treatment. At present, the prevention and treatment mechanism of tea on lung cancer[41-43]principally includes the following points. 1. Tea can induce cell growth cycle arrest of lung cancer cells. For instance, tea polyphenols can promote high expression of PTEN protein and block activation of tumor metastasis and proliferation of PI3K/Akt signal transduction pathway through the activity of phosphatidylinositol kinase (PI3K) and the expression level of vascular endothelial growth factor, so that G1 cycle can be processed by lung cancer cells and the growth and metastasis of lung cancer cells can be inhibited, thus achieving the purpose of prevention and treatment of lung cancer. 2. Tea Induce apoptosis of lung cancer cells.It is mainly through activating the surface-related molecules of lung cancer cells by external factors, which leads to the formation of apoptotic bodies in the cells and thus promotes apoptosis. For example, overexpression of Bcl-2 gene in cancer patients can inhibit the apoptotic mechanism and lead to cancer. Tea polyphenols and tea pigments can down-regulate the overexpression of Bcl-2 gene, resulting in the decrease of anti-apoptotic proteins and the increase of pro-apoptotic proteins leading to cell apoptosis to prevent and treat lung cancer. 3.Tea can regulate the expression of related gene. Tea polyphenols and theophylline can directly regulate the cell cycle-related proteins and enzymes through the expression of p53 gene. The reason is that DNA damage in the nucleus can not be replicated and cell cycle is blocked at G0/G1, G1/S and G2/M phase to prevent and treat lung cancer. 4.Tea can inhibite angiogenesis of tumors. Tumor angiogenesis is one of the ways of growth and metastasis of tumors. Among them, VEGF can induce angiogenesis and promote the growth and metastasis of lung cancer cells. While the secretion and proliferation of lung cancer cells can secrete a large amount of VEGF to further promote the proliferation and metastasis of lung cancer cells. Theanine and tea polyphenols can inhibit angiogenesis by inhibiting the expression of vascular

endothelial growth factor gene for the purpose of prevention and treatment of tumors. 5. Tea can reverse the drug resistance of lung cancer cells. After multi-cycle chemotherapy, the effect of chemotherapy is less effective on account of the resistence of cells. Tea polyphenols, tea pigments and tea polysaccharides can reverse the chemotherapeutics of the drug resistance of lung cancer by reducing the cell sensitivity of lung cancer cell-related chemotherapeutics.

6. Expert opinion

Drinking tea has become one of the most widely consumed healthy beverages around the world, so the research on tea is rising all over the world. Professor Jiang Heyuan, Tea Research Institute of Chinese Academy of Agricultural Sciences, believes that tea, with antioxidant properties can prevent and cure cancer by inhibiting the proliferation, differentiation and metastasis of tumors. But the premise of exerting the anti-cancer effect of tea is to insist on drinking tea scientifically and taking healthy functional ingredients of tea reasonably. Professor Li Jiezhong[45]studied 649 cases of primary lung cancer in Shanghai before 1992-1994 and 675 Shanghai household registered women randomly. He found that drinking tea among non-smoking women could prevent the occurrence of multiple cancers, including lung cancer. Therefore, drinking tea properly could prevent the occurrence of various types of cancers. The cancer center of the Chinese Academy of Medical Sciences[46] assessed the risk of tea drinking and lung cancer among 103010 male employees and retirees in Kailuan general hospital from 2006 to 2015, with a median follow-up of 8.91 years. It was found that there was no correlation between tea drinking and lung cancer. Mendilaharsu[47] studied the correlation between lung cancer and tea drinking in Uruguay. There were 427 cases of lung cancer and 428 other hospitalized patients observed. It was found that drinking black tea or drinking a large amount of tea (two or more cups per day) reduced the risk of lung cancer, which was more significant in early stage of lung squamous cell carcinoma and small cell lung cancer. By studying the relationship between black tea and coffee in Singapore and the risk of lung cancer, Seow[48] found that coffee may increase the risk of lung cancer, while black tea can significantly reduce it in smokers. So smokers are encouraged to drink black tea appropriately. By studying the relationship between tea consumption and lung cancer in Okinawa, Japan, from 1988 to 1991, Yoshiyuki[20] found that the higher the intake of tea in Okinawa, Japan, the lower the risk of lung cancer, especially the risk of lung squamous



cell cancer. Through a study of 200 lung cancer patients in Hong Kong, China, and their control group, Tewes[49] found that the risk of lung cancer in tea drinking was significantly increased, which may be due to the mutation of cells caused by low-dose and long-term tea mutagens, leading to the occurrence of lung cancer. Pasquet [50] analyzed the correlation between coffee and tea and the potential risk of lung cancer in 1130 lung cancer patients and 1483 control groups in Montreal, Canada, and used logistic regression analysis to analyze the frequency, average daily quantity, duration and cumulative quantity. It was considered that there was no correlation between tea and coffee consumption and the risk of lung cancer, which might be affected by the type of tea drinking , tea time, tea temperature and other bad habits.Through the research and analysis of the correlation between tea and lung cancer from 12 articles published in PubMed database after 2011, Yuan[51] concluded that tea polyphenols, tea pigments and other functional components in tea had a definite effect on inhibiting and reducing the risk of lung cancer, yet there was no relevant big data support for tea at present.So it was suggested that tea extracts should be used for drinking.According to the current large data and related literature studies on the risk of tea and lung cancer, it is considered that tea or tea functional components are related to the occurrence of lung cancer. Tea functional components can significantly reduce the incidence of lung cancer, which has been proved many times in vitro, vivo and animal experiments. However, the relationship between tea and lung cancer has been controversial in epidemiological studies. The professor who hold the view tea is related to lung cancer suggested that patients should drink tea reasonably in terms of tea temperature, drinking habits and tea types. For example,tea with low temperature can significantly reduce the damage of tea components,green tea contains a great deal of tea polyphenols,black tea contains more tea pigments and drinking tea during the day can obviously reduce discharge of the esophagus compared with drinking tea at night. It is hope that the application of tea functional components can be speeded up. Both of them expect to continue the further research of the larger and more accurate databases.

7. Conclusion and prospest

In conclusion, through the analysis of the correlation between functional components of tea such as tea polyphenols, tea polysaccharides, tea theophylline, tea pigments, Theanine and the mechanism of prevention and treatment of lung cancer, it is concluded that

many components of tea can inhibit the proliferation, differentiation and metastasis of lung cancer cells by inducing cell growth cycle arrest, resulting in apoptosis of lung cancer cells, regulating related gene expression, inhibiting tumor angiogenesis and reversing drug resistance of lung cancer cells. The mechanism of tea polyphenols, alkaloids and tea pigments is more studied than that of tea polysaccharides, theanine and alkaloids. The mechanism of anti-lung cancer of tea is explored through in vivo, vitro and animal experiments of tea functional components, but the specific pathways, concrete mechanisms and related signaling pathways are less studied. Therefore, further studies on the particular mechanism of anti-lung cancer of tea can be carried out in the future. At present, the mechanism of anti-lung cancer of tea ingredients is primarily single in component, pathway and mechanism. There are few studies on the combination of multi-components, multi-genes and multi-pathways. Hence, the study of regulation and influence between tea ingredients and multi-genes and multi-pathways of anti-lung cancer can be strengthened. Currently there are two aspects of the correlation analysis between tea and lung cancer risk. Some experts consider that drinking tea can significantly reduce the incidence of lung cancer. On the other hand, the specialists believe that there is no data and relevant evidence to support the occurrence of and lung cancer and drinking tea. Consequently the risk assessment of tea and lung cancer needs further study. In a word, the efficacy of tea functional ingredients is definite in the treatment of lung cancer , and the study on the correlation between various factors of drinking tea and lung cancer still needs a large sample and a multi-regional joint research. It still needs further efforts to find out which form of tea functional ingredients can be used in clinical practice. Tea originated in China, developed in China and went to the world, which is the pride of every offspring of China. Therefore, how to better play the role of tea in the prevention and treatment of lung cancer is a long way to go.

References

1. Clinical Cancer Advances 2018: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology.

2. Lu G, Liao J, Yang GY, et al. Inhibition of adenoma progression to adenocarcinoma in a 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis model in A/J mice by tea polyphenols and caffeine. Cancer Res 2006, 66: 11494-11501.



3. Wang W, Guo YL. Research p rogress in mechanisms of functional components in tea on lung cancer. Chinese Traditional and Herbal Drugs 2017, 48: 3654-3659.

4. Sun BL, Pan YH. Isolation and Bioactivities of Main Functional Components in Tea. Asian Journal of Chemistry 2014, 26: 2191-2198.

5. Chen ZM. Anticancer effects of tea: past, present and future. Chinese tea 2009, 31: 4-7.

6. Jin H, Ren Q. A Meta-analysis on tea drinking and the risk of lung cancer in Chinese population. Zhonghua liuxingbingxue zazhi 2012, 33: 857-861.

7. Kubik A. Interactions between smoking and other exposures associated with lung cancer risk in women: diet and physical activity. Neoplasma 2007, 54: 83-88.

8. Huang J, Chen S. Green tea polyphenol induces significant cell death in human lung cancer cells. Tropical Journal of Pharmaceutical Research May 2017, 16: 1021-1028.

9. Hudlikar A, Venkadakrishnan V, Kaushal R, et al. Chemoprevention of lung cancer by polymeric black tea polyphenols (PBPs): Preclinical evaluation of potential molecular targets. European an Journal of cancer 2016, 54: S69-S69.

10. Zhou H, Chen JX, Yang CS, et al. Gene regulation mediated by microRNAs in response to green tea polyphenol EGCG in mouse lung cancer. BMC Genomics 2014, 15: S3.

11. Hessien M, El-Gendy S. Growth Inhibition of Human Non-Small Lung Cancer Cells H460 By Green Tea and Ginger Polyphenols. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents 2012, 12: 383-390.

12. Okabe S, Fujimoto N, Sueoka N, et al. Modulation of gene expression by (-)-epigallocatechin gallate in PC-9 cells using a cDNA expression array. Biol Pharm Bull 2001, 24: 883-886.

13. Huang J, Chen S, Shi Y, et al. Epigallocatechin gallate from green tea exhibits potent anticancer effects in A-549 non-small lung cancer cells by inducing apoptosis, cell cycle arrest and inhibition of cell migration. Journal of buon 2017, 22: 1422-1427.

14. Park HR, Hwang D, Suh HJ, et al. Antitumor and antimetastatic activities of rhamnogalacturonan-II-type polysaccharide isolated from mature leaves of green tea via activation of macrophages and natural killer cells. Int J Biol Macromol 2017, 14: 179-186.

15. Yi S J , Wa n g Y Z , H u a n g Y J , e t a l . Te a Nanoparticles for Immunostimulation and Chemo-

Drug Delivery in Cancer Treatment. J Biomed Nanotechnol 2014, 10: 1016-1029.

16. Nie SP, Xie MY. A review on the isolation and structure of tea polysaccharides and their bioactivities. Food hydrocolloids 2012, 25: 144-149.

17. Wang YP, Shu LC, Xiao H. Enhancement of the anticancer activity of cisplatin combined with caffeine and phenobarbital in vitro, Chin J Lung Cancer 2001, 4: 181-185.

18. Tsai CM, Perng RP, Chen MH, et al. Greater enhancement of chemosensitivity by caffeine in high-p185neu-expressing human non-small-cell lung cancer cell lines. J Natl Cancer Inst 1994, 86: 1018-1020.

19. L e l o A , B i r k e t t D J , R o b s o n R A , e t a l . Comparative pharmacokinetics of caffeine and its primary demethylatedmetabolites paraxanthine, theobromine and theophyline in man. Br J Clin Pharmacol 1986, 22: 177-182.

20. Keiichiro G. Tea consumption and lung cancer risk: a case-control study in Okinawa, Japan. Japanese journal of cancer research 1995, 86: 1027-1034.

21. Jenny T, Mao WX, Nie T, et al. White Tea Extract Induces Apoptosis in Non–Small Cell Lung Cancer Cells: the Role of Peroxisome Proliferator-Activated Receptor-γ and 15-Lipoxygenases.Cancer prevention 2010, 3: 1132-1140.

22. Imran A, Butt MS, Xiao H, et al. Inhibitory effect of black tea (Camellia sinensis) theaflavins and thearubigins against HCT 116 colon cancer cells and HT 460 lung cancer cells. Journal of food biochemistry 2019, 43: 69-71.

23. Rawangkan A, Iida Kl. Green tea catechin, EGCG, enhances antitumor immunity by down-regulation of PD-L1 expression in non-small human lung cancer cell lines. Cancer 2017, 77: 2665-2669.

24. Sonoda JI, Ikeda R, Baba Y, et al. Green tea catechin, epigallocatechin-3-gallate, attenuates the cell viability of human non-small-cell lung cancer A549 cells via reducing Bcl-xL expression. Cancer 2014, 8: 59-63.

25. Kenichi Y. Identification of epigallocatechin-3-gallate in green tea polyphenols as a potent inducer of p53-dependent apoptosis in the human lung cancer cell line A549. Toxicology in Vitro 2009, 23: 834-839.

26. Qing YL, Yang Y,ShengJ, et al. Effects of green tea extract on lung cancer A549 cells: Proteomic identification of proteins associated with cell migration. Proteomics 2009, 9: 757-767.

27. Banerjee, Sarmistha, Manna, et al. Black tea



polyphenols restrict benzopyrene-induced mouse lung cancer progression through inhibition of Cox-2 and induction of caspase-3 expression In Asian Pacific Journal of Cancer Prevention 2006, 7: 661-666.

28. Zhong ZW, Dong Z. Inhibition of proliferation of human lung cancer cells by green tea catechins is mediated by upregulation of let-7. Exoerimental medicine 2012, 4: 267-27.

29. Sadava E, Whitlock S. Kane. The Green Tea Polyphenol, et al. Epigallocatechin-3-gallate Inhibits Telomerase and Induces Apoptosis in Drug-Resistant Lung Cancer Cells. Biochemical and Biophysical Research Communications 2007, 360: 233-237.

30. Oya Y, Mondal A. Down-regulation of histone deacetylase 4,-5 and-6 as a mechanism of synergistic enhancement of apoptosis in human lung cancer cells treated with the combination of a synthetic retinoid, Am80 and green tea catechin. Journal of biomedical nanotechnology 2017, 42: 7-16.

31. Friedman M, Mackey BE, Kim HJ, et al . Structure-activity relationships of tea compounds against human cancer cells. J Agric Food Chem 2007, 55: 243-253.

32. Liu Q, Duan H, Luan J, et al. Effects of theanine on growth of human lung cancer and leukemia cells as well as migration and invasion of human lung cancer cells. Cytotechnology 2009, 59: 211-217.

33. Fujii S, Inai K. Tumorigenicity study of L-theanine administrated orally to mice. Food Chem 2008, 110: 643-646.

34. Lai CY, Kerr CL. The Green Tea Polyphenol EGCG Potentiates the Antiproliferative Activity of c-Met and Epidermal Growth Factor Receptor Inhibitors in Non-small Cell Lung Cancer Cells. Clinical cancer research 2009, 15: 4885-4894.

35. Lai CY, Huang CC, Kerr CL.et al. Genetic Polymorphism of catechol-O-methyltransferase Modulates the Associa t ion of Green Tea Consumption and Lung Cancer. Eur J Cancer Prev 2019, 28: 316-322.

36. Beane JE, Hijazi K. Airway gene expression a l t e ra t ions a s soc ia t ed wi th lung cance r chemoprevention using green tea extract. Cancer 2012, 72: 1607.

37. Anna, Marta Hałas. Green tea extract induces protective autophagy in A549 non-small lung cancer cell line. Postepy Hig Med Dosw 2015, 31; 1478-84.

38. Lu QY, Jin YS, Mao JT. Green tea inhibits

cycolooxygenase-2 in non-small cell lung cancer cells through the induction of Annexin-1. B iochemica l and B iophys i ca l Resea rch Communications 2012, 427: 725–730.

39. Laurie VA, Miller SC. Phase I Study of Green Tea Extract in Patients with Advanced Lung Cancer.Cancer and Chemotherapy Pharmacology 2005, 55: 33-38.

40. Jin P, Zhu F. Study on effective substances of tea for chemoprevention of lung cancer based on principal component analysis.Journal of Chinese medicinal materials 2013, 36: 948-952.

41. Clark YM. Chemoprevention of lung cancer by tea. Molecular nutrition & food research 2006, 20: 144-151.

42. Wang LF, Zhang XW. Tea consumption and lung cancer risk: A meta-analysis of case-control and cohort studies.Nutrution 2014, 30: 1122-1127.

43. Mao JT. White Tea Extract Enhances The Ability Of Human Bronchoalveolar Lavage Cells To Induce Apoptosis In Nonsmall Cell Lung Cancer Cells. Cancer 2011, 183: 5068.

44. Jing HY. Anticancer effect and mechanism of tea. Chinese tea 2018, 12: 1-8.

45. Zhong L, Goldberg MS, Gao YT, et al . A population-based case-control study of lung cancer and green tea consumption among women living in Shanghai, China. Epidemiology 2001, 12: 695-700.

46. Wei LP, Li N, Wang G, et al. Tea consumption and the risk of lung cancer in Chinese males: a prospective cohort study. Chinese journal of preventive medicine 2018, 52, 511-516.

47. Mendilaharsu M, De Stefani E, Deneo-Pellegrini H, et al. Consumption of tea and coffee and the risk of lung cancer in cigarette-smoking men: a case-control study in Uruguay. Lung cancer 1998, 19: 101-75.

48. Wei JS, Aizhen J, Jian MA, et al. Intake of tea and tea flavonoids, coffee and caffeine in relation to risk of lung cancer - the Singapore Chinese Health Study. AACR Annual Meeting 2017, 23: 1-5. Cancer Research 2017, 77:5318-5318.

49. Tewes L, Koo T, Meisgen, et al. Lung cancer risk and mutagenicity of tea. Environmental Research 1990, 52: 22-23.

50. Pasquet R, Karp I, Siemiatycki J, et al. The consumption of coffee and black tea and the risk of lung cancer. Ann Epidemiol 2016 , 26: 757-763.

51. Jian M. Green tea and prevention of esophageal and lung cancers. Mol Nutr Food Res 2011, 55: 886–904.

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