Dietary Phytochemicals in Lung Carcinogenesis: Comparison
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Please note this is a comparison between Version 2 by Camila Xu and Version 1 by Chunlin Zhuang.

Chemoprevention is becoming more and more important in lung cancer treatment, especially for dietary chemoprevention, has been paid more and more attention. Dietary phytochemicals mainly include medicinal plants, beverages, fruits, vegetables, spices, etc.

  • dietary phytochemicals
  • lung cancer
  • tobacco carcinogens

1. Introduction

Chemoprevention is becoming more and more important in lung cancer treatment. Epidemiology analysis suggests that lung cancer can be effectively prevented through daily diet adjustments [17][1]. The conventional treatments of lung cancer, such as surgery, radiotherapy, and chemotherapy, can reduce tumor sizes and inhibit the cancer cell growth but cannot cause complete regression. Meanwhile, immunosuppression and the effects of cancer itself lead to low life expectancy after these treatments [18][2]. Chemoprevention by natural or synthetic chemicals through reducing the exposure to tobacco carcinogens could lower the risk [19][3]. Nature offers many safe, effective, and affordable products, usually called “phytochemicals” for various diseases [20][4]. 

In addition, vitamin-rich fruits such as oranges have potential chemoprotective effects on lung cancer [23,24][5][6]. Besides, some dietary natural products such as particular food groups and nutrients have attracted much attention due to their cancer prevention in the past decades. It is worth mentioning that AACR CANCER PROGRESS REPORT 2022 emphasizes that eating at least 30 g fiber and at least 400 g of fruit and vegetables each day could decrease cancer risk in humans. Therefore, the consumption of dietary natural products to prevent lung cancer seems to be an effective strategy. Moreover, lung cancer prevention, especially for dietary chemoprevention, has been paid more and more attention in recent years.

2. Chemoprevention of Lung Cancer by Dietary Phytochemicals

Dietary natural products such as medicine plants, beverages, fruits, vegetables, spices and other plants possess anti-inflammatory, anti-oxidative, anti-proliferative, and cancer inhibitory activities, which have attracted much attention in the past decades. This section focuses on lung cancer chemoprevention properties of these dietary resources and the active compounds in vivo (chemical structures see Table 31).
Table 1.
The representative dietary plants and phytochemicals for lung cancer prevention.
Plants The Structure of Nature Products
Nutrients 15 00491 i001

Tea		 Nutrients 15 00491 i002

Caffeine		 Nutrients 15 00491 i003

EGCG
Nutrients 15 00491 i004

Kava		 Nutrients 15 00491 i005

Dihydromethysticin
Nutrients 15 00491 i006 Nutrients 15 00491 i007

LicA		 Nutrients 15 00491 i008

Glycyrrhizin
Nutrients 15 00491 i009 Nutrients 15 00491 i010

C3G
Nutrients 15 00491 i011

Psoralea corylifolia L.		 Nutrients 15 00491 i012

8-MOP
Grape

Nutrients 15 00491 i013		 Nutrients 15 00491 i014

Resveratrol		 Nutrients 15 00491 i015

EA		 Nutrients 15 00491 i016

DBQ
Citrus

Nutrients 15 00491 i017		 Nutrients 15 00491 i018

5-Demethylnobiletin		 Nutrients 15 00491 i019

Nobiletin		 Nutrients 15 00491 i020

Limonin		 Nutrients 15 00491 i021

Hesperetin
  Nutrients 15 00491 i022

BCX		 Nutrients 15 00491 i023

Hesperidin		 Nutrients 15 00491 i024

Naringenin
Nutrients 15 00491 i025

Tomato		 Nutrients 15 00491 i026

Lycopene
Cruciferous vegetables

Nutrients 15 00491 i027		 Nutrients 15 00491 i028

I3C		 Nutrients 15 00491 i029

PEITC
Cucurbitaceae

Nutrients 15 00491 i030		 Nutrients 15 00491 i031

Cucurbitacin B
Garlic

Nutrients 15 00491 i032		 Nutrients 15 00491 i033

DAS		 Nutrients 15 00491 i034

DADS		 Nutrients 15 00491 i035

DATS
Nutrients 15 00491 i036

Chilli		 Nutrients 15 00491 i037

Capsaicin
Ginger

Nutrients 15 00491 i038		 Nutrients 15 00491 i039

6-shogaol		 Nutrients 15 00491 i040

Zerumbone
Turmeric

Nutrients 15 00491 i041		 Nutrients 15 00491 i042

Curcumin

2.1. Medicine Plants

Medicinal plants have been used in many countries as a source of primary healthcare since ancient times because of their effectiveness and low cost, as well as lesser side effects than many modern treatments [104][7]. Some traditional Chinese medicines are also considered as “drug homologous foods” for developing health products, such as glycyrrhiza, haskap berry, emblica, and psoralea. These “drug homologous foods” are effective in lung cancer prevention.

2.1.1. Glycyrrhiza

In both traditional Ayurvedic and Chinese medicine, Glycyrrhiza glabra L. is commonly referred to as Mulaithi and Yashtimadu, and is used to treat a variety of illnesses. Abundant components are present in Glycyrrhiza glabra L., such as flavanones, chalcones, isoflavans, isoflavenes, flavones, and isoflavones. The flavonoid lipochalcone A (LicA), isolated from Glycyrrhiza uralensis Fisch, is a potent pharmacological agent with a wide spectrum of activities. Among NNK-induced A/J mice, LicA can reverse the expression of NNK-induced miRNA miR-144-3P, miR-20a-5P, miR-29c-3P, let-7d-3p and miR-328-3p, to play a chemical prevention role in lung cancer [29][8]. Glycyrrhizin, a triterpenoid saponin isolated from glycyrrhiza, reversed high level of High Mobility Group Box 1 (HMGB1), which is a protein that regulates nucleosome formation and gene transcription. In addition, glycyrrhizin decreased the activity of JAk/KSTAT signing pathway in PDX mice [30][9]. Glycyrrhizin plus cisplatin or glycyrrhizin alone all reduced the expression of thromboxane synthase (TxAs) and PCNA in nude mice [31,32][10][11]. Proliferative cell nuclear antigen (PCNA) is necessary for DNA synthesis and DNA repair. In conclusion, as potential phytochemical Glycyrrhiza glabra L. has the potential to be a health product. The mechanism of licorice and its extracts or monomers in treating diseases is not completely clear, and it is too early for licorice to enter the clinical frontline as a low toxic, effective and controllable drug. However, as a health product or placebo, it has great commercial potential.

2.1.2. Haskap Berry

Lonicera caerulea L., also known as haskap, is a fruit, commonly planted in Asia, Canada and Eastern Europe. It is also well known by the Japanese aborigines as the “elixir of life”. Haskap berry is rich in ingredients of phenolic acids and flavonoids, especially anthocyanins. Increasing evidence has suggested that haskap berry can prevent the lung tumorigenesis. BEAS-2B cells pre-treatment with the anthocyanin-rich haskap berry extracts significantly reduced 4-[(acetoxymethyl) nitrosamino]-1-(3-pyridyl)-1-butanone (NNKOAc), a precursor of NNK, which could induce DNA damage [105][12]. About 79–92% of the anthocyanin content of haskap berries is composed of cyanidin-3-O-glucoside (C3G). C3G shows significant antioxidant, cardio-protective, anti-inflammatory, neuroprotective, anticancer, and anti-diabetic properties [106][13]. It is documented that NNK-induced A/J mice treated with C3G could markedly decrease the expression of PCNA and Ki-67 in lung tissues [33][14]. In an experiment of C3G plus 5-FU (a commonly used basic chemotherapy drug) in nude mice against lung cancer, the inflammatory cytokine, IL-1β, IL-6 and TNF-α, COX-2, NF-kpa and PCNA was decreased [34][15]. Due to this, haskap berry, especially its major component C3G, may be a promising dietary supplement or nutraceutical for suppressing lung cancer development among high-risk populations. However, this is limited to animal experiments and is still a long way from the clinic. Its future use may still be limited.

2.1.3. Emblic

Phyllanthus emblica L. (PEL), also named emblic, is a medical plant, which has been used extensively in Asia. Investigations have shown that PEL possesses a wide range of phytochemicals including tannins, polyphenols, gallic acid, flavonoids and vitamin C. Bioactivity studies revealed that PEL has a variety of biological activities, including anti-cancer. Wang and others found that the PEL extracts significantly reduced the number of BaP-induced A/J mice lung surface nodes. PEL extracts regulated the IL-1β/miR-i101/Lin28B signaling pathway for lung cancer prevention [35][16]. PEL exhibits anticancer activity against lung cancer, and is worth further study as a possible chemopreventive and anti-invasive agent.

2.1.4. Psoralea

Psoralea, also named Psoralea corylifolia L., is a traditional medicine used in ancient Egypt and China for various ailments such as psoriasis, vitiligo, hair loss, impotence, osteoporosis, etc. Phytochemical studies showed that psoralea mainly contains coumarins, flavones, monoterpenes, chalcones, lipids, resins, and stigmasteroids. 8-methoxsalen (8-MOP) is a furocoumarinisolated from this plant. Laboratory studies showed its effectiveness in chemoprevention of lung cancer Regarding the chemopreventive properties, 8-MOP was demonstrated to inhibit the CYP2A5-mediated metabolic activation of NNK in the mouse lung, leading to the prevention of NNK-induced adenoma [36,37,38][17][18][19]. However, 8-MOP in the diet of post-initiation phase does not prevent mouse lung carcinogenesis [107][20]. This effect is also confirmed in C57BL/6 mice that are induced by NNK [39][21]. In conclusion, 8-MOP is a strong chemopreventive agent for NNK-induced lung tumorigenesis.

2.2. Beverages

2.2.1. Tea

Tea (Camellia sinensis) is a popular beverage worldwide. Most of the tea is consumed in America and green tea is mainly consumed in Asian countries. Tea may help reduce the risk of cardiovascular disease, anti-hypertensive effects, body weight control, antibacterial activity, anti-fibrotic properties, solar ultra violet protection, and neuroprotective power. (-)-epigallocatechin-3-gallate (EGCG) and caffeine are main active components in tea. EGCG, the major catechin found in tea, has the potential to impact a variety of human diseases. A/J mice treatment with EGCG could weaken the elevation of DNMT1 and inhibit lung tumorigenesis triggered by NNK [40][22]. Tea, coffee, and soft drinks are the most important caffeine sources and energy beverages. Caffeine in tea plays an important role in preventing tumorigenesis. It is reported that administration of caffeine could inhibit the developmentof lung adenoma into adenocarcinoma in NNK-induced A/J mice [41][23]. Caffeine 680 ppm significantly lowered the incidence of lung tumors from 47% to 10% in F344 rats [42][24]. Natural polyphenols are organic chemicals thatcontain phenol units in their structures. Polymeric black tea polyphenols (PBPs) are the most abundant polyphenolic component in black tea. Several laboratory studies have confirmed the lung cancer preventive properties of PBPs. Administration of PBPs inhibited cell proliferation rate and the progression of adenoma to adenocarcinoma in adenomas of NNK-induced A/J female mice [43][25]. In addition, PBPs have chemopreventive effects in NNK- and BaP-induced A/J mice possibly via modulation of p38 and Akt to inhibit inflammation and cellular proliferation and to induce apoptosis [44][26]. In addition, PBPs decreased BPDE-DNA adducts and inhibited carcinogen-induced phase-I enzymes of lung lesions in A/J mice [45][27]. Polyphenon E is a green tea polyphenol preparation that contains 65% EGCG, significantly reducing the incidence and multiplicity of adenocarcinoma, similarly to PBPs [41][23]. Polyphenon E plus atorvastatin, or polyphenon E alone both lowered tumor incidence and tumor burden of lung carcinogens. However, atorvastatin alone only decreased tumor burden not tumor multiplicity [46][28]. This means the effects of lung cancer prevention maybe contributed to by polyphenon E [48][29]. NNK-treated mice using green tea containing drinking water (2%) significantly decreased lung tumors per mouse and inhibited the increase of 8-OH-dGuo levels in mouse lung DNA [49][30]. 0.3% green tea extracts also reduced tumor nodes and decreased PD-L1 positive cells in lung tumors of A/J mice [50][31]. White tea extracts also significantly lowered the level of ROS and lipid peroxidation (LPO) [51][32]. Catechin hydrate is a mixture of gallocatechingallate and epigallocatechingallate. Compared with BaP group, catechin hydrate + BaP group reduced Bcl-2, Bax and Capase-3 expression in lung tissues [47][33]. Tea, especially for PBPs, maybe a promising product in the area of health. As one of the beverages that people have the longest contact with in their life, tea has relatively more preventive effects on lung cancer among all the plants that have been studied. However, the exact preventive mechanism of tea is still unclear, but as a food, it is worth more use.

2.2.2. Kava

Kava

Kava is the extract of the roots of Piper methysticum. It has been consumed safely as a beverage in the South Pacific islands for centuries. According to some reports, it has anti-cancer and anti-anxiety effects. Researchers group has carried out continuous chemoprevention studies on kava for lung cancer. The results displayed that dietary kava led to statistically significant lower lung tumor multiplicities in NNK plus BaP-treated A/J mice [55][34]. It is worth mentioning that diets containing kava reduced lung adenomas multiplicity by approximately 99%. Furthermore, daily gavage of kava blocked lung adenoma formation by decreasing DNA damage in lung tissues of O6-methylguanine (O6-mG) [52][35]. Moreover, mice that were fed diets containing kava suppressed lung tumorigenesis in A/J mice via inhibition of cell proliferation, enhancing apoptosis, and also inhibiting the activation of NF-κB [53][36]. In addition, kava and its component methysticin suppressed NF-κB activation in lung adenoma tissues with minimum toxicity [56][37]. However, a three-day kava pretreatment potentiated acetaminophen-induced hepatotoxicity increasing severity of liver lesions, resulting from the cytotoxicity of chalcone compounds in kava [54,57][38][39]. In a clinical trial to evaluate the effects of kava on NNK metabolism, kava increased urinary excretion of total NNAL and reduced urinary 3-methyladenine (3-mA) [101][40].

Dihydromethysticin

Dihydromethysticin (DHM) is one of the active ingredients in kava. DHM had a dose-dependent chemical prevention effect on NNK-induced lung adenoma. DHM could reduce the formation of O6-mG and increase urinary excretion of NNK detoxification metabolites [58][41]. However, another study found that DHM does not affect NNAL formation and does not inhibit NNAL bioactivation. However, DHM remarkably increased O-glucuronidated NNAL in an NNK-induced model [59][42]. Synthetic DHM decreased adenoma multiplicity by 97% in NNK-induced A/J mice, which effects were equal to natural DHM, and it reduced DNA adducts in lung tissues [60][43]. The in vivo structure-activity relationship study found that the unnatural enantiomer of DHM was more potent than the natural enantiomer in NNK-induced A/J mice. More importantly, DHM analogues with high structural similarity show distinct efficacy in reducing NNK-induced DNA damage [61][44]. Moreover, it was determined that the methylenedioxy functional group in DHM that effectively reduced O6-mG adducts formation was critical to the chemopreventive activity and the lactone of DHM could be modified [61,62][44][45]. It was also found that DHM decreased the level of O6-mG in female C57BL/6 mice. However, in the backgrounds of Ahr+/− and Ahr−/−, there is no difference inO6-mG, indicating that AhR is not the upstream target for DHM [64][46]. In a study, DHM was found to suppress the activation of protein A (PKA) pathway induced by NNK [63][47]. Kava and its compounds need more attention to explore their effects in lung cancer. Kava, especially DHM, plays an obvious role in the prevention of lung cancer in mice, but its role in the prevention of lung cancer in patients with a high risk of lung cancer needs to be further studied.

2.3. Fruits

2.3.1. Citrus

5-Demethylnobiletin

Citrus is the most eaten fruit. This fruit is thought to decrease the risk of degenerative diseases and cancer. Active phytochemical constituents of this plant have been revealed so far, namely, limonene, β-caryophyllene, geranial edulinine, ribalinine, 5-demethylnobiletin, and nobiletin. 5-Demethylnobiletin is a unique citrus flavonoid with various beneficial bioactivities. Song et al. first confirmed that dietary intake of 5-demethylnobiletin remarkably inhibited tumorigenesis in NNK-induced mice, and this effect possibly was due to the metabolites of 5-demethylnobiletin in lung tissues [65][48].

Nobiletin

Nobiletin, a major component of citrus polymethoxy flavones, has anti-cancer effects [108][49]. Nobiletin inhibited CYP enzymes involved in the metabolic activation for preventing lung cancer [66][50]. In NNK-treated mice, oral nobiletin significantly suppressed lung tumorigenesis and decreased tumor volume [67][51].

Other Compounds

Limonin is a dietary phytochemical, which has been reported to possess many biological activities. Limonin supplements significantly decreased lipid peroxidation, serum marker enzymes and inflammatory cytokine levels in BaP-treated mice, and increased the nonenzymatic and enzymatic antioxidant levels, showing an effective lung cancer prevention [68][52]. β-Cryptoxanthin (BCX) is an oxygenated carotenoid and abundant in oranges, peaches, and pumpkins. BCX inhibited lung tumorigenesis through the down-regulation of α7-nAChR/PI3K signaling in NNK-induced A/J mice [69][53]. In addition, in the same lung cancer model, dietary intake of BCX restored the expressions of lung SIRT1, p53, and RAR-β, and decreased the levels of phosphorylate AKT and lung IL-6 mRNA to increase the survival probability in NNK-induced A/J mice [70][54]. Hesperetin and naringenin are the most abundant flavonoids in citrus fruits and possess various effects on different diseases. Hesperetin possesses a wide array of pharmacological effects which include cancer prevention [109][55]. Both hesperetin and naringenin effectively suppressed lung carcinoma and the associated preneoplastic lesions in a BaP-induced model by decreasing the expression of NF-kB, PCNA and CYP1A1 [71,110][56][57]. Moreover, hesperidin attenuates mitochondrial dysfunction during BaP-induced lung carcinogenesis in mice [72][58]. Citrus is one of the most commonly eaten fruits in daily life. According to the current literature the role of lung cancer prevention is currently documented only in animal experiments, and there is no literature to support the effects of low doses. Therefore, in life, for the purpose of preventing lung cancer, it can be appropriate to eat more of this fruit.

2.3.2. Tomatoes

Tomatoes are a good source of health-promoting phytochemicals, including phenolic compounds, lycopene, vitamins and glycoalkaloids. Lycopene is a naturally occurring carotenoid in tomatoes, tomato products and other red fruits as well as vegetables. Among smokers, dietary intake of lycopene has a strong connection with the risk of lung cancer. Rakic et al. found that dietary lycopene effectively inhibited chronic bronchitis and preneoplastic lesions in a ferret model of cigarette smoke (CS)-induced lung cancer. Moreover, lycopene feeding suppressed the accumulation of total cholesterol. Besides, dietary lycopene increased mRNA expressions of critical genes related to the reverse cholesterol transport (RCT) in the lung [73][59]. Similarly, lycopene is protective against NNK/CS induced lung lesions and pulmonary cholesterol homeostasis through the restoration of the impaired RCT [74][60]. Lycopene supplementation could inhibit α7 nicotinic acetylcholine receptor’s expression in NNK-induced mice. Moreover, it attenuated the mortality and pathological lesions in the lung [75][61]. The lycopene was converted to apo-10′-lycopenoids, which dose-dependently decreased the lung tumor multiplicity in NNK-induced A/J mouse model [76][62]. Similarly, anti-carcinogenic and antioxidant functions of apo-10′-lycopenoids were mediated by inducing phase II detoxifying/antioxidant enzymes as well as activating the expression of Nrf2 [111][63]. Apo-14′-lycopenoic acid is the lycopene eccentric cleavage product. Apo-10′-lycopenoic acid and apo-14′-lycopenoic acid decreased cigarette smoke extract-induced ROS production, 8-OH-dGuo formation and COX-2 expressions [112][64]. All these nicotine-induced structural changes in lungs of offspring mice were prevented by supplementing the mother’s diet with tomato juice [113][65]. Tomatoes can be eaten as either fruit or vegetable, and based on the current literature, there seems to be no risk of toxicity when consumed in moderation. In a word, tomato as a common fruit offers health benefits in daily life.

2.3.3. Grape

The grape contains various phenolic compounds, flavonoids and stilbenes. Many components in grapes have chemopreventive effects on lung cancer. For example, resveratrol is an important phenolic component in grapes. It has been reported that resveratrol exhibited a 27% reduction in tumor multiplicity, resulting in a 45% decrease in tumor per mice in NNK-induced A/J mice [77][66]. Resveratrol also prevented BaP-induced CYP1A1 expression [78][67]. Ellagic acid (EA) is produced by hydrolysis of ellagitannins, which is present in fruit berries and grapes. It has been reported that EA decreased ATP levels, reduced HIF-1α and activated AMP-activated protein kinase (AMPK) in lung tissues [114][68]. EA down-regulated the level of cancerous inhibitor of protein phosphatase 2A (CIP2A) in tumor-bearing mice [115][69]. 2,6-dimethoxy-1,4-benzoquinone (DBQ) was isolated from Vitis coignetiae (crimson glory vine, also named yamabudo in Japan). Yamabudo-juice or DBQ showed chemopreventive effects on lung tumors in NNK-induced mice. Investigation of the anti-tumorigenic mechanisms of yamabudo juice and DBQ indicated they reduced methyl DNA adducts and accelerated DNA repair. In addition, yamabudo juice and DBQ could suppress the signaling of Akt, Erk and Stat3 [79][70]. Grape seed proanthocyanidins (GSPs) are promising phytochemicals that have anti-inflammatory and anti-cancer effects [116][71]. Researchers proved GSPs inhibited the growth of lung tumor xenografts in nude mice; this effect was connected with the reduction of Bax, capase-3 [80][72]. Moreover, GSPs also reduced radiation damage to normal lung tissues and also regulated the expression of Ki-76, p53,Il-6 and TNF-α [117][73]. In short, grapes can be more used in life for whatever aim. Grapes are a common fruit and are also used as raw materials for wine. Grapes did not seem to have much of a protective effect against lung cancer, which may be partly due to the way resveratrol was administered. As a fruit, however, there seems to be no harm in eating more of it in daily life.

2.4. Vegetables

2.4.1. Cruciferous Vegetables

Phenethyl Isothiocyanate

Cruciferous vegetables have been traditionally consumed in the human diet as fresh and preserved vegetables, vegetable oils, and condiments since ancient times. 2-Phenethyl isothiocyanate (PEITC) is a natural product found in cruciferous vegetables. Various biological activities of PEITC have been explored. PEITC can induce detoxifying enzymes such as GST. Additionally, it can inhibit CYP450 involved in metabolic activation of carcinogens [118][74]. In the matter of lung cancer prevention, treatment with PEITC inhibited lung carcinogenesis in NNK-exposed mice [119,120][75][76]. PEITC could inhibit NNK-induced lung tumors by suppressing metabolic activation of NNK and inhibiting α-hydroxylation of NNAL in lung tissues of male F344 rats [81][77]. Moreover, dietary PEITC decreased the incidence of alveolar atypical and the expression of COX-2 and PCNA [82][78]. In a clinical trial, the NNK metabolic activation ratio was reduced after PEITC treatment in 82 smokers [102][79]. Similarly, Boldry et al. reported the effect of PEITC on the metabolism of carcinogen 1,3-butadiene in current smokers. The results revealed PEITC treatment is protective in respect of the detoxification of 1,3-butadiene in cigarette smokers [103][80]. Other compounds, including sulforaphane and sulforaphane-N-acetylcysteine, have been documented the chemopreventive efficacy on lung cancer. Dietary sulforaphane-N-acetylcysteine significantly reduced the incidence of lung tumors. Furthermore, the malignant lung tumor multiplicity was significantly reduced with dietary sulforaphane and sulforaphane-N-acetylcysteine in NNK-induced A/J mice by decreasing PCNA and capase-3 [121][81].

Indole-3-Carbinol

Indole-3-carbinol (I3C) is a constituent in Brassica vegetables. I3C is reported to reduce the tumor multiplicity and the level of tumor-associated signature proteins, such as apolipoprotein A-1, a-antitrypsin precursor and transferrin [83][82]. In NNK induced A/J mice, I3C decreased tumor burden and size by inhibiting PI3K/Akt signaling [84][83]. Given dietary I3C, in NNK plus BaP-treated mice, I3C showed a dose-dependent inhibition of lung tumor per mouse. Furthermore, I3C restrained the expression of PCNA, p-Akt as well as the number of Ki-67–positive cells [85][84]. Moreover, I3C has also been reported in combination with other compounds to prevent lung cancer. For example, a given combination of PEITC-N-acetylcysteine (NAC) and I3C could effectively reduce tumor multiplicity in NNK plus BaP induced A/J mice. The combination treatments could reduce the activation of Akt and NF-kB in lung tumor tissues that were pretreated with cigarette smoke (CSC) condensate [122][85]. In addition, previous research indicates that the mixtures of I3C and silibinin are much stronger than the individual compounds in A/J mice [123][86]. The cruciferous plant family is one of the most studied in the field of lung cancer prevention. However, it seems to have no effect on cancer treatment. It may be used in combination with chemoradiotherapy drugs in the future to reduce the side effects of chemoradiotherapy drugs to a certain extent.

2.4.2. Cucurbitaceae

Cucurbitacin B

The major crop species of cucurbitaceae family are cucumber, melon and watermelon. The chemical constituents of cucurbitaceae mainly include terpenoids, glycosides, alkaloids, saponins, tannins, etc. Cucurbitacin B (CuB) is one of the major terpenoids in cucurbitaceae plant. CuB could suppress both DNMTs and histone deacetylase as well as inhibit tumor incidence and multiplicity in A/J mice [86][87]. Meanwhile, Hua et al. confirmed the protective effect of CuB on lung function. CuB effectively improved the pulmonary gas exchange function, reduced pulmonary edema, and inhibited the inflammatory response by reducing the level of TNF-α and IL-6 in lung tissues [124][88].

2.5. Spices

2.5.1. Garlic

Garlic (Allium sativum L.), belonging to genus allium in the Liliaceae family, is native to central Asia and is widely cultivated around the world. It has been used to heal various diseases, including leprosy, cancer, constipation, asthma, and fever. Garlic has abundant bioactive chemical compounds, such as diallyl sulfide (DAS), diallyl disulfide (DADS) and diallyl trisulfide (DATS). All of these compounds have been reported to have the effects of anti-carcinogenesis [125][89]. Several studies have revealed the chemoprevention of DAS in lung cancer. Hong et al. found that DAS significantly lowered the incidence of lung tumors and the tumor multiplicity in A/J mice that carcinogens induced. DAS also inhibited the metabolism of NNK in lung microsomes [87][90]. Oral DAS also decreased tumor marker enzymes and recovered antioxidant enzymes, SOD and CAT in mice [90][91]. Investigation by Kong et al. revealed that oral DAS partially could reverse parts of the mitochondrial metabolic pathways, global methylation and transcriptomic changes [88][92]. Moreover, DAS inhibited CYP enzymes activation for inhibiting the bioactivation of NNK in A/J mice of lung tissues [89][93]. DAS inhibited pulmonary adenoma formation and increased glutathione S-transferase [126][94]. DATS and DADS induced apoptosis by increasing DNA fragmentation and activating C-Jun N-terminal kinase (JNK), up-regulating p53, and down-regulating Bcl-2 expression [127][95]. In DATS treated lung cancer cells it was found that Bax and Bak proteins are critical targets [128][96]. Garlic oil is thought to be bioactive in garlic. Researchers group recently screened the inhibitory effects of garlic oil on NNK treated A/J mice. The results displayed that garlic oil increases the level of the phase II drug-metabolizing enzymes for inhibiting the NNK-induced lung cancer [7][97].

2.5.2. Chilli

Capsaicin, a component of red chilli and red pepper, has been found to have various effects, including anti-cancer. Capsaicin could inhibit the process of lung carcinogenesis by inducing apoptosis, increasing DNA fragmentation, up-regulating the expressions of p53, Bax and decreasing the level of Bcl-2 in BaP-induced in Swiss albino mice [92][98]. Capsaicin also reversed BaP-induced increase of extracellular matrix components and proteases [93][99]. Capsaicin induced apoptosis in lung cancer cells was mediated via the TRPV6 receptor as well as inversed oxidative stress in mice administered with BaP [94,129][100][101]. Moreover, capsaicin decreased lung mitochondrial lipid peroxidation in Bap-induced lung cancer Swiss albino mice. More importantly, capsaicin augmented the activities of enzymic and non-enzymic antioxidants, citric acid cycle enzymes and respiratory chain enzymes to near normalcy [130][102]. Previous studies have also found that capsaicin supplementation in lung cancer bearing mice considerably prevented the increaseof TNF-α, IL-6, COX-2 and NF-κB [91][103].

2.5.3. Zingiber

Ginger, the rhizome of Zingiber officinalis, is one of the most widely used species in Asia. Phytochemical studies revealed that ginger is rich in chemicals including 6-shogaol, β-Elemene, Zerumbone and so on. Zerumbone, presented in subtropical ginger Zingiber zerumbet Smith, is reported to have anti-cancer properties. In the process of lung cancer induced by NNK, administration of Zerumbone restrained the multiplicity of lung adenomas through inhibition of proliferation and induction of apoptosis. These effects mainly resulted from suppression of NF-κB, HO-1 expression in lung tissues [95][104]. 6-shogaol is a major component of dry ginger. It increases cAMP concentration, limits NF-κB signaling and produces pro-inflammatory cytokines in activated CD4 cells to attenuate house dust mite antigen mediated lung inflammation in mice [131][105].

2.5.4. Turmeric

Curcumin is a constituent present in Curcuma longa L. (turmeric) rhizome. It has been used as a spice for cooking in Asia for many years. It has been reported that curcumin has chemopreventive effect on lung cancer. The average number of tumor nodules present in the lungs of the Swiss albino mice induced by BaP was significantly higher than in mice that received both a 2% curcumin diet and BaP. Furthermore, a curcumin diet lowered BaP-induced activation of NF-κB, MAPK signaling and COX-2 transcription in lung tissues of A/J mice [96][106]. Similarly, dietary curcumin reduced BaP-induced DNA adduct, oxidative damage and inflammation [132][107]. In a word, a series of spices such as garlic, ginger, pepper and turmeric is present in daily diets and living habits, but their smell is strong and will be disliked by some people. Moreover, it is not certain whether excessive consumption will have toxicity.

2.6. Other Plants

Flax has a long history of use as a food, medicine, and textile fiber. Chikara et al. found that flaxseed consumption could protect against both NNK and BaP induced lung tumor formation in A/J mice lung tissues. The effects mainly include upregulating the expression of phase II enzymes and downregulating the expression of proinflammatory cytokines [97][108]. Houttuynia cordata Thunb (HCT) is a commonly used herbal medicine in Asian countries, with anti-inflammatory and anti-bacterial effects. In BaP-induced A/J mice, HCT extracts activated the Nrf2-HO-1/NQO-1 signaling pathway. It also has the function of relieving intracellular ROS generation to attenuate DNA damage and inflammation induced by BaP stimulation [98][109]. Camptosorus sibiricus Rupr (CSR) is a commonly used herbal medicine which has anti-tumor effects. CSR extracts prevented lung tumorigenesis by acting against ROS and DNA damage in BaP-induced A/J mice [99][110]. Fermented brown rice and rice bran have chemopreventive effects on carcinogenesis in the colon, liver and stomach. For lung cancer prevention, both fermented brown rice and rice bran inhibited NNK-induced pulmonary tumorigenesis in A/J mice. This effect is mainly through reducing the expression of mRNA levels of CYP4502A5 [100][111].

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