Dietary Phytochemicals as Potential Chemopreventive Agents against Tobacco-Induced Lung Carcinogenesis.

Lung cancer is the second most common cancer in the world. Cigarette smoking is strongly connected with lung cancer. Benzo[a]pyrene (BaP) and 4-(N-methyl-N-nitrosamine)-1-(3-pyridyl)-butanone (NNK) are the main carcinogens in cigarette smoking. Evidence has supported the correlation between these two carcinogens and lung cancer. Epidemiology analysis suggests that lung cancer can be effectively prevented through daily diet adjustments. This review aims to summarize the studies published in the past 20 years exploring dietary phytochemicals using Google Scholar, PubMed, and Web of Science databases. Dietary phytochemicals mainly include medicinal plants, beverages, fruits, vegetables, spices, etc. Moreover, the perspectives on the challenges and future directions of dietary phytochemicals for lung cancer chemoprevention will be provided. Taken together, treatment based on the consumption of dietary phytochemicals for lung cancer chemoprevention will produce more positive outcomes in the future and offer the possibility of reducing cancer risk in society.

The Impact of One-week Dietary Supplementation with Kava on Biomarkers of Tobacco Use and Nitrosamine-based Carcinogenesis Risk among Active Smokers.

Tobacco smoking is the primary risk factor for lung cancer, driven by the addictive nature of nicotine and the indisputable carcinogenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as well as other compounds. The integration of lung cancer chemoprevention with smoking cessation is one potential approach to reduce this risk and mitigate lung cancer mortality. Experimental data from our group suggest that kava, commonly consumed in the South Pacific Islands as a beverage to promote relaxation, may reduce lung cancer risk by enhancing NNK detoxification and reducing NNK-derived DNA damage. Building upon these observations, we conducted a pilot clinical trial to evaluate the effects of a 7-day course of kava on NNK metabolism in active smokers. The primary objective was to compare urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL plus its glucuronides, major metabolites of NNK) before and after kava administration as an indicator of NNK detoxification. Secondary objectives included determining kava's safety, its effects on DNA damage, tobacco use, and cortisol (a biomarker of stress). Kava increased urinary excretion of total NNAL and reduced urinary 3-methyladenine in participants, suggestive of its ability to reduce the carcinogenicity of NNK. Kava also reduced urinary total nicotine equivalents, indicative of its potential to facilitate tobacco cessation. Plasma cortisol and urinary total cortisol equivalents were reduced upon kava use, which may contribute to reductions in tobacco use. These results demonstrate the potential of kava intake to reduce lung cancer risk among smokers.

Desensitization to chemical and food sensitivities by low-dose immunotherapy ascertained by provocation neutralization is associated with reduced influx of calcium ions into lymphocytes.

Background Food and chemical sensitivities have detrimental effects on health and the quality of life. The natural course of such sensitivities can potentially be altered through various types of allergen-specific immunotherapy, including low-dose immunotherapy. The molecular mechanism by which low-dose immunotherapy causes desensitization has not thus far been elucidated. While resting lymphocytes maintain a low cytosolic calcium ion concentration, antigen receptor signaling results in calcium ion influx, predominantly via store-operated calcium channels. We therefore hypothesized that desensitization by low-dose immunotherapy is associated with reduced influx of calcium ions into lymphocytes. The aim of this study was to test this hypothesis. Methods Intracellular lymphocytic calcium ion concentrations were assayed in a total of 47 patients, following incubation with picogram amounts of the test allergens, using a cell-permeable calcium-sensing ratiometric fluorescent dye and fluorescence spectroscopy, both at baseline and following successful provocation neutralization treatment with low-dose immunotherapy. Results Low-dose immunotherapy was associated with a reduction in lymphocytic intracellular calcium ion concentration following treatment of: 23 % for metabisulfite sensitivity (p<0.0004); 12 % for salicylate sensitivity (p<0.01); 23 % for benzoate sensitivity (p<0.01); 30 % for formaldehyde sensitivity (p<0.0001); 16 % for sensitivity to petrol exhaust (p<0.003); 16 % for natural gas sensitivity (p<0.001); 13 % for nickel sensitivity (p<0.05); 30 % for sensitivity to organophosphates (p<0.01); and 24 % for sensitivity to nitrosamines (p<0.05). Conclusions Low-dose immunotherapy may affect baseline levels of intracellular calcium in lymphocytes, supporting the premise that allergens affect cell signaling in immune cells and provocation neutralization immunotherapy helps to promote more normal immune cell signaling.

[Changes in Wnt pathway inhibiting factors in nitrosamine-induced esophageal precancerosis lesions and effect of gexia zhuyu decoction].

OBJECTIVE: To discuss the changes in Wnt pathway inhibiting factors in esophageal precancerosis lesions induced by methyl benzyl nitrosamine (MBNA) and the effect of Gexia Zhuyu decoction. METHOD: Wistar rats were subcutaneously injected with MBNA (3.5 mg x kg(-1) for twice per week to establish the model. Since the 1st day after the model establishment, they were orally administered with Gexia Zhuyu decoction (16, 8 mg x kg(-1)). At the 10th week, esophageal tissues were collected to observe the pathological changes of esophageal mucosa, detect SFRP1, sFRP4, Axin1, Axin2 and GSK-3ß mRNA levels.by fluorescent quantitation PCR analysis and ß-catenin protein level by Western blotting. RESULT: Being induced by MBNA, rats in the model group showed slight atypical hyperplasia in the histopathological examination. Compared with the normal group, Gexia Zhuyu decoction dose high and low groups showed no significant pathomorphological and histological changes. The model group showed lower gene transcription levels of esophageal tissues sFRP1, sFRP4, Axin1 and Axin2 (P < 0.05 or P < 0.01) and higher ß-catenin protein expression level (P < 0.01) than the normal control group. The Gexia Zhuyu decoction low dose group showed higher gene transcription levels of esophageal tissues sFRP1, sFRP4, Axin1 and Axin2 (P < 0.05 or P < 0.01) and lower ß-catenin protein expression level (P < 0.01) than the normal control group. CONCLUSION: Up-regulated ß-catenin protein level and down-regulated Wnt pathway could enhance Wnt pathway activity of MBNA-induced esophageal precancerous lesions. Gexia Zhuyu decoction could down-regulate the ß-catenin protein level and up-regulate the transcription level of Wnt pathway inhibiting factors, but could not block MBNA-induced esophageal precancerosis lesions.

ß-Escin inhibits NNK-induced lung adenocarcinoma and ALDH1A1 and RhoA/Rock expression in A/J mice and growth of H460 human lung cancer cells.

Lung cancer is the leading cause of cancer-related deaths. ß-Escin, a triterpene saponin isolated from horse chestnut seeds, was tested for inhibition of lung adenoma and adenocarcinoma induced by the tobacco carcinogen 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in female A/J mice; and its possible mode of action was evaluated using the H460 human lung cancer cell line. At 6 weeks of age, 35 mice were fed AIN-76A-modified diet, and one week later, lung tumors were induced with a single intraperitoneal (i.p.) injection of 10 µmol NNK/mouse. Three weeks after the NNK treatment, groups of mice were fed either control or experimental diets containing 500 ppm for 20 weeks (10 control, 5 ß-escin) or 36 weeks (15 control, 5 ß-escin) and evaluated for lung tumor via histopathologic methods. Administration of 500 ppm ß-escin significantly suppressed lung tumor (adenoma + adenocarcinoma) formation by more than 40% (P < 0.0015) at 20 weeks and by 53.3% (P < 0.0001) at 37 weeks. ß-Escin inhibited NNK-induced lung adenocarcinoma formation by 65% (P < 0.001) at 20 weeks and by 53% (P < 0.0001) at 37 weeks. Immunohistochemical analysis revealed that lung tumors from mice exposed to ß-escin showed significantly reduced aldehyde dehydrogenase (ALDH)1A1 and phospho-Akt (p-Akt) expression when compared with those in mice fed control diet. Aldefluor assay for ALDH revealed that among H460 lung cancer cells treated with different concentrations of ß-escin (0-40 µmol/L), the subpopulation of cells with elevated ALDH activity was inhibited significantly. Our findings suggest that ß-escin inhibits tobacco carcinogen-induced lung tumor formation by modulating ALDH1A1-positive cells and RhoA/Rock signaling.

Esophageal cancer: associated factors with special reference to the Kashmir Valley.

Esophageal cancer is one of the most common cancers worldwide. It is a multifactorial disease, and no single agent has been identified so far as the sole cause of the cancer. Many factors like smoking, the consumption of alcohol, fungal-contaminated, spicy and various nitrosamine-containing food stuffs and hot beverages, nutritional deficiency of some vitamins like ß-carotene, vitamin A, C and E and minerals like zinc, selenium and molybdenum, the use of opium, HPV infection and various genetic factors have been found associated with the occurrence of the disease worldwide. Wide geographic differences and substantial changes in the incidence of esophageal cancer occurring over time have been suggested. Among the risk factors in India, betel quid chewing carries a relatively high risk. High incidences in Kashmir have been associated with the consumption of hot salted tea, sun-dried, smoked foods, tobacco in the form of hukka and various genetic factors. The exact cause of esophageal squamous cell carcinoma is unknown. Much work has been carried out on the role of various environmental factors, gene mutations, and polymorphisms worldwide, including Kashmir. Although the Kashmir valley is present on the border of the 'high risk esophageal cancer belt' and esophageal squamous cell carcinoma represents the most commonly occurring malignancy in Kashmir, the amount of information available on various associated factors is still very little as there is a paucity of various epidemiological and molecular studies being carried out in this field.

Diet and nasopharyngeal cancer in a low-risk population.

Asian studies have reported that risk of nasopharyngeal cancer (NPC) is increased in individuals who frequently consume salted fish, which contains high levels of N-nitroso compounds. As part of a collaborative, population-based, case-control study in the U.S., where the annual incidence of the disease is low, we investigated whether dietary intake of preformed nitrosamines or nitrosamine precursors, or of antioxidants including vitamin C and carotenoids, was associated with altered risk of NPC overall, or of specific histologic subtypes of disease. Cases (n = 133) identified at 5 population-based cancer registries and controls (n = 212) identified through random digit dialing completed a telephone interview and self-administered food frequency questionnaire. Dietary exposures were expressed as quartiles of intake, and odds ratios (ORs) calculated using the lowest quartile of intake as the reference category. Risk of non-keratinizing and undifferentiated tumors of the nasopharynx was increased in frequent consumers of preserved meats, which contain high levels of added nitrites. ORs in the 2nd, 3rd and highest quartile were 1.99, 4.35 and 4.59, although 95% confidence intervals did not exclude 1.0. Risk of differentiated squamous cell carcinoma, but not other histologic types, was significantly reduced in individuals with vitamin C intake above the lowest quartile (ORs 0.30, 0.33 and 0.30 in the 2nd, 3rd and highest quartiles, respectively). This association was markedly stronger among non-smokers and former smokers than among current smokers. Finally, individuals who reported consuming supplemental vitamins were at an approximately 50% reduced risk of NPC. Our results indicate that future studies should consider the effects of dietary risk factors on the risk of specific histologic subsets of NPC, and not assume that the disease is etiologically homogeneous.

The inhibitory effect of vitamin E on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced DNA injury and the fixation of the DNA injury in mouse lungs.

In order to estimate the effect of vitamin E on DNA injury and K-ras point mutation at an early stage of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK)-induced lung tumorigenesis in mice, the present study was carried out. Presupplement with vitamin E about 15 times more than control for a week significantly inhibited NNK-induced O6-methylguanine formation in the lungs of mice at 4 and 168 h after the injection. At 30 days after the NNK injection. the activation of K-ras oncogene with a 12th codon GC-->AT transition was detected in 56% of lung samples tested by mutant-allele-specific amplification. Vitamin E supplement reduced the frequency of the mutation to 30%. These results suggest that vitamin E suppresses NNK-induced DNA injury and subsequent fixation of the injury during the initiation and post-initiation phases of the lung tumorigenesis in mice.

Immunotoxic effects of smokeless tobacco on the accessory cell function of rat oral epithelium.

Smokeless tobacco (ST) is known to adversely effect the oral mucosa, but knowledge about the influence on immune defence is limited. Few studies have investigated the effect of ST on the local immune response. In the present study, we have assessed the effect of a crude Swedish moist snuff (SS) extract, alkaloids, and nitrosamines on T-cell mitogenic response to Con A using epithelial cells, including Langerhans cells, of the rat oral mucosa as accessory cells. SS extract at a concentration of 4% reduced the T-cell proliferation by 50% (IC50 = 4%). Pretreatment of either oral epithelial cells or T-cells with SS extract also gave a significant inhibition of T-cell proliferation. This effect was not obtained following preincubation with SS components as alkaloids and different tobacco-specific nitrosamines (TSNA). None of the tested compounds were found to possess any mitogenic properties. This in vitro study showed that SS extract can evoke an immunosuppressive effect on mitogen-driven T-cell proliferation using cells from oral epithelium as accessory cells. This effect was more pronounced when SS extract was employed compared to when the single SS components were used alone.

Dietary control of cancer.

Many laboratory studies and human epidemiological data suggest that most cancer deaths are attributable to lifestyle, including nutritional factors and tobacco and alcohol consumption. Tobacco consumption is causally related to cancer of the lung, mouth, larynx, esophagus, bladder, kidney, and pancreas. Nutrients and non-nutrient dietary components probably account for cancer of the colon, breast, prostate, and stomach. This report is based on literature and our own data pertaining to the role of dietary fat, calories, and fiber in the development of colon and breast cancer. We also discuss the evidence from epidemiological, mechanistic, and preclinical efficacy studies indicating a protective effect of micronutrients, non-nutrients, and certain antioxidants in food against oral and lung cancers. Given the continuing cancer burden and the relatively slow impact of proven cancer treatment strategies in reducing cancer mortality, it is essential to evaluate promising nutrients and non-nutrients in foods as chemopreventive agents in persons at increased risk for cancer. Development of reliable intermediate biomarkers is valuable for clinical chemoprevention intervention trials. The purpose of this report is to provide the reader with plausible approaches to cancer control.

Endogenous formation of nitrosamines and oxidative DNA-damaging agents in tobacco users.

One-third of all cancers worldwide can be attributed to various tobacco habits. Both in tobacco smoke and smokeless tobacco, carcinogenic N-nitroso compounds (NOC) are implicated as DNA-damaging agents in cancers of the aerodigestive tract and the pancreas. The exposure from nitrosamines in certain types of tobacco use such as "toombak" in Sudan could be as high as a few milligrams per day. Using the N-nitrosoproline test, it has been shown that smoking contributes to endogenous nitrosation and likely increases NOC formation in vivo. Smokeless tobacco, most widely used in the form of chewing of betel quid (BQ) with tobacco, was shown to particularly enhance endogenous nitrosation in the oral cavity, a site where chewing habits are causally associated with cancer. Poor oral hygiene was found to contribute to the formation of nitrosamines in the oral cavity. The evidence so far accumulated demonstrates that tobacco habits increase endogenous NOC formation, thus adding to the burden of exposure by preformed carcinogenic NOC in tobacco products. In snuff dippers, the unexpected higher level of HPB released from hemoglobin, an exposure marker for carcinogenic tobacco-specific nitrosamines, has been attributed to the endogenous formation of these carcinogens. Recent studies have demonstrated that besides carcinogenic tobacco-specific nitrosamines, reactive oxygen species derived from BQ ingredients could also play a role in the etiology of oral cancer in chewers. Although the use of chemopreventive agents may block nitrosation reactions in vivo in tobacco users, cessation of tobacco habits is the only safe way for an efficient reduction of cancer risk, in view of the high exposure to other (preformed) tobacco-related carcinogens.

Betel cytotoxicity.

An attempt to summarise the phytochemical composition of the betel quid, formation of N-nitrosation products during chewing, results of carcinogenicity and mutagenicity studies and the relationship between betel chewing and submucous fibrosis have been made from presently available literature. The present review provides a better understanding of the capacity of the quid ingredients in inducing preneoplastic changes for evaluation of the risk involved with its chewing.

Food in the aetiology of cancer.

During recent years much evidence has accumulated indicating that diet and nutrition may be important in the aetiology of human cancer. This paper discusses some of the components of diet that have been implicated as both causative and protective agents. Total calorie intake and overnutrition have been associated with breast and uterine cancers, high fat intake with cancer of the breast and large bowel and nitrates with gastric cancer. High fibre intakes are suggested to protect against colo-rectal cancer, and vitamin A, selenium and vitamin E have been inversely associated with various cancers.

[Etiology of bladder cancer]. / Eziologia del carcinoma vescicale.

Multiple agents have been suggested as urinary bladder carcinogens. Of these, certain aromatic amines and some tryptophan metabolites (Anthranilic acid, 3 hydroxy Anthranilic acid) have been proved to be carcinogenic. Others are suggested but are not conclusively proved as carcinogenic agents. Various animal species have been used as experimental models for the study of induction of cancer of the bladder and substantial progress has been made in the search for etiologic factors and pathogenesis of bladder tumors. A carcinogenic model of cancer bladder induction is proposed. However, knowledge of the tumorigenesis of cancer of the bladder is still limited and fragmentary. It appears, however, that Tryptophan dysmetabolism play a major role in this field and future experimental and epidemiologic studies should take this fact into consideration.

Recent research on the etiology of esophageal cancer in China.

China could be expected to offer good opportunities for the investigation of esophageal cancer since it has both high and low incidence areas. However, it seems impossible to attribute the induction of esophageal cancer to one particular substance--it rather seems to be caused by a variety of factors. To the authors' opinion, esophageal cancer may originate from exposure to N-nitroso compounds or mycotoxins. Lack of certain trace elements or essential vitamins may also play a role. Contrary to France, which also has high incidence areas of esophageal cancer, excessive alcohol consumption is of no importance in China. It is not clear whether genetic factors can be discussed.

Metal interactions in carcinogenesis: enhancement, inhibition.

Metals constitute a fundamentally important part of the total human environment. Since human exposure often involves complex mixtures of metal compounds and, possibly, organic compounds which may be carcinogenic per se, interactions between these compounds may add significantly to human cancer risk. Our present knowledge about these kinds of interactions is very limited. The best investigated area is benzo(a)pyrene (BP)-metal oxide particle interactions in respiratory carcinogenesis in the hamster. Metal oxide particles were also shown to modify the carcinogenic effect of nitrosamines. Several reports describe experiments in which selenium compounds exerted a generally anticarcinogenic and antimutagenic activity. Inorganic arsenic compounds, which are accepted to be carcinogenic in man, have so far been negative in animal experiments except for one recent suggested report. Several authors have, however, suggested that these compounds may act as cocarcinogens due to their inhibition of DNA repair, although animal experiments to demonstrate a cocarcinogenic effect of arsenic compounds have been negative so far, except for one preliminary report. The concentration of zinc in the diet seemed to influence both transplanted tumor growth and the carcinogenicity of several organic compounds, and the possibility of a correlation between dietary zinc and certain cancer forms in man has been suggested. Protection against development of Leydigiomas usually induced by cadmium injection was afforded by simultaneous injection of zinc salts. Nickel carcinogenesis has been reported to be antagonized by manganese, and synergism between Ni and organic carcinogens, e.g. BP, has been demonstrated. There is no firm evidence that lead may be a cocarcinogen, although some limited experimental evidence is available. Oxidizing agents have been demonstrated to increase, and reducing agents to antagonize, the mutagenic effect of chromium compounds in vitro. The content of carcinogenic and other metals in asbestos has been suggested to modify the carcinogenic properties of asbestos. Since much of the information available at present is suggestive, further research on these interactions as well as other possible interactions in metal carcinogenesis is needed. Studies should be made both in well defined in vitro systems and in relevant animal models.

Tobacco use, occupation, coffee, various nutrients, and bladder cancer.

In a Canadian population-based case-control study of 480 males and 152 female case-control pairs, the relative risk for development of bladder cancer for ever used versus never used cigarettes was 3.9 for males and 2.4 for females, with a dose-response relationship in both sexes. A reduced risk was associated with the use of filter cigarettes compared to nonfilter cigarettes. After control for cigarette usage, a significant risk was noted for male pipe smokers. For male ex-smokers the risk after 15 years of no smoking was less than one-half that of current male smokers. Bladder cancer risk was found for workers in the chemical, rubber, photographic, petroleum, medical, and food processing industries among males and for workers occupationally exposed to dust or fumes among both sexes. Bladder cancer risk was elevated for males consuming all types of coffee, regular coffee, and instant coffee and for females consuming instant coffee, but no dose-response relationship was found. Risk was found for males consuming water from nonpublic supples but not for females. No risk was observed in males or females consuming nitrate-containing foods, beverages other than coffee, or fiddlehead greens. Hair dye usage in females and phenacetin usage in males and females carried no risk. Divergent findings by area for aspirin suggested that an overall association was not causal. Reevaluation of the data on artificial sweeteners confirmed a significant bladder cancer risk in males and a dose-response relationship. The cumulated population attributable risk for bladder cancer was 90% for males from cigarette smoking, industrial exposure, and exposure to nonpublic water supplies and 29% for females from cigarette smoking, industrial exposure, and instant coffee consumption.