lung cancer: data for foods & supplements

For the patient, among the fundamental health changes one can make is diet modification. This is also one of the few aspects of health the individual can control. Lung cancer continues to be a significant burden of cancer in the United States, and the world. Furthermore, lung cancer remains the leading cause of cancer death in the United States, for men and women. In the last few years multiple studies showing data have emerged for lung cancer fortunately, which will hopefully light the way forward for nutritional modification to ameliorate one’s risk. Data is significant for certain fruits, vegetables, vitamins (including Vitamin A and Vitamin D), green tea, and curcumin.  

A number of foods, food extracts, and vitamin supplements have been explored in colon cancer, and a large number of these are detailed below. With this burgeoning field, we believe in being data-driven, and special attention is paid to human trials, the methodology of the individual studies, and the external generalizability of a given set of data. 

Diet Types

The following are diets that have been systematically studied in humans with relation to lung cancer risk, and published in the medical literature.  

Study 1

One of the largest studies comparing diet types was in the NIH-AARP (National Institutes of Health-American Association of Retired Persons) Diet and Health study (15). In this effort, 460,770 American participants were involved. Over a median of 10.5 years, 9,272 lung cancer cases were diagnosed among participants.   

The diets were classified by four “diet quality” indices. These included Healthy Eating Index-2010 (HEI-2010), Alternate Healthy Eating Index-2010 (AHEI-2010), alternate Mediterranean Diet score (aMED) and Dietary Approaches to Stop Hypertension (DASH). Key details are as follows: the HEI-2010 index (http://www.cnpp.usda.gov/sites/default/files/healthy_eating_index/CNPPFactSheetNo2.pdf) emphasizes intake of fruits, vegetables, whole grains, dairy, and plant proteins. It calls for moderation of refined grains and sodium chiefly. The Alternate Healthy Eating Index-2010 is similar, but scored differently.   

The alternate Mediterranean Diet score (aMED) is a modified version of the traditional Mediterranean Diet score, for the purpose of accounting for US dietary habits. One point each is given for intake at or above the sex-specific median intake for components considered to be healthy: vegetables (excluding potatoes), fruits, nuts, legumes, grains, fish, and monounsaturated-fat/saturated-fat ratio. One point is given for intake less than the median for those components considered unhealthy (red and processed meat). In addition, one point is given for alcohol intake within a specified range (5-25 g/day). (http://www.medscape.com/viewarticle/789825)  

The DASH diet (http://www.nhlbi.nih.gov/files/docs/public/heart/hbp_low.pdf) encourages greater intake of grains, vegetables, fruits, lowfat dairy products, lean meats, and nuts.   

In the NIH-AARP study (15), patients were divided into quintiles for their scores on each diet. Overall, when comparing the highest vs. lowest quintiles (best vs. worst adherence to the prescribed diets), all the diets conferred a lower risk of lung cancer. Specifically, the hazard ratios (HRs) were similar for all 4 diets for the highest quintiles, ranging from 0.83-0.85. (therefore a 15-17% relative risk reduction) Furthermore, higher consumption of whole grains and fruits was significantly inversely associated with lung cancer risk.  

HRs (95% CIs) for lung cancer were as follows: HEI-2010=0.83 (0.77-0.89), AHEI-2010=0.86 (0.80-0.92), aMED=0.85 (0.79-0.91) and DASH=0.84 (0.78-0.90)  

This is one of the largest prospective studies examining diet type and cancer risk. Although the categories of “beneficial” foods are broad, that may be helpful in affording a greater range of choices. Incorporating whole grains, fruits, and nuts has multiple health benefits. The alternate Mediterranean diet also allows for alcohol in the range specified above. With similar hazard ratios, any of these diets are reasonable for lung cancer risk reduction.  

Study 2

Multiple food types have been linked to anti-inflammatory properties. There are also dietary “inflammatory scores”, such as the “dietary inflammatory index”. These are a tool to attempt to quantify the anti-inflammatory properties of a diet as a whole.  A dietary inflammatory index (DII) was examined in multiple diets in relation to the risk of developing lung cancer. (24)   

The results were compared to those based on the aMED score, an established dietary index that measures adherence to the traditional Mediterranean diet. The alternate Mediterranean Diet score (aMED) is a modified version of the traditional Mediterranean Diet score, for the purpose of accounting for US dietary habits.  

Data was gleaned from a prospective clinical trial of 4,336 heavy smokers, and food questionnaires were completed. This information allowed for calculation of the DII and the aMED score.  

Results showed that with fully adjusted multivariate analysis, only the association with aMED remained statistically significant (p trend = 0.04) for a protective effect from lung cancer. Incidentally the alternate Mediterranean diet does score lower on the dietary inflammatory index scale. The study also found a association of dyspnea and the development of radiological evidence of emphysematous lung changes in a statistically significant manner.  

This study provides further evidence for the benefit of the alternate Mediterranean diet for diminishing the risk of lung cancer. This is a large prospective trial, specifically for heavy smokers.  

Study 3  

A case-control study of diet and lung cancer risk was carried out in Iran. (31) In this effort, 242 lung cancer patients and 484 matched controls were studied. Patients were divided into 3 groups (based on nutritional consumption of items such as fruit), and the middle and upper third consumer groups were compared to the lower third.   

On multivariate analysis, 3 food categories were found to be protective: fruit (Ptrend < 0.0001), vegetable (P = 0.001) and sunflower oil (P = 0.006). Multiple foods were found to be associated with increased risk, including rice, liver, cheese, and beef.  

Although the study population is quite different from a Western one, this adds to the general body of data in a modern case-control human study. 

Lycopene protection from lung injury 

An animal study of ferrets was conducted to assess the effect the lycopene supplementation in reducing tobacco-induced lung injury. (6) Specifically, this effort investigated whether the tobacco carcinogen 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induced lesions in both lungs and livers of ferrets. Lycopene supplementation was given at 2 doses, and another group did not have any lycopene intervention. 

The data from this experiment showed that firstly, the tobacco carcinogen NNK results in higher incidences of lung tumors. For the groups with lycopene supplementation, they were found to have decreased expression of receptors related to nicotine ( α7 nicotinic acetylcholine receptor) as well as intracellular cancer growth-signaling proteins. Importantly, both the number of cancer lesions in the lung and liver were reduced in the lycopene groups, as well as the mortality rate of the ferrets. 

This is solid experimental data that lycopene supplementation could provide potential benefits against tobacco carcinogen-induced lung and liver injury, including the risk of development of cancer.  

Green and Black Tea 

One of the fascinating epidemiological differences is a phenomenon termed the “Japanese Smoking Paradox”. This refers to Japan's relatively high rate of smoking persons, and yet the lung cancer death rate is quite low. Various dietary factors have been surmised as contributors, including the intake of tea.  

A large systematic review across multiple databases including PubMed, the Cochrane Library, and the Wanfang database was conducted and published in the journal Nutrition in 2014. Patients involved in the data analysis spanned from 1966 to 2014, and both cohort studies and case-control studies that evaluated the association of tea and lung cancer were included. Overall 38 lung cancer studies (26 case-control studies and 12 cohort studies) with 59,041 lung cancer cases and 396,664 controls were included. (34) 

Several interesting observations were reported. Firstly, the pooled analysis revealed that tea consumption was significantly associated with decreased risk for lung cancer (RR = 0.78; 95% CI, 0.70-0.87), or a 22% decreased risk. Multiple subgroups were evaluated, including by gender, type of tea, and geography. The relative benefit was numerically higher in Japan and China (RR = 0.74; 95% CI, 0.62-0.88) compared to Western nations (RR = 0.85; 95% CI, 0.75-0.97). Interestingly women were found to have a possibly greater benefit compared with men. 

Additionally green tea was found to confer a 25% reduction in risk of lung cancer (RR, 0.75; 95% CI, 0.62-0.91) compared to 18% for black tea (RR, 0.82; 95% CI, 0.71-0.94). Both types of teas were associated with a decrease in risk in a statistically significant fashion.  

This systematic review provides a large amount of data across geographies, and is suggestive for at least one possible reason for the Japanese Smoking Paradox. However, the strength of the benefit of tea was apparently greater in Japan and China even for those who consumed it. Overall, this is a well-conducted systematic review spanning geographies and several decades. 

Green Tea and Cisplatin Chemotherapy 

There is lab evidence for green tea enhancing the sensitivity of cisplatin chemotherapy and consequent improvement in slowing cancer cell growth. Cisplatin is the main cornerstone of cytotoxic chemotherapy treatment for lung cancer.  

In cell models of non-small cell lung cancer (NSCLC) and also mice, the impact of adding epigallocatechin gallate (EGCG), a predominant polyphenol in green tea, was tested. (2) Firstly, when EGCG was added to NSCLC cells (A549, H460 and H1299 cell lines), including the A549 cell line being a cisplatin-resistant one, lung cancer cell growth was better stopped compared to without EGCG. Importantly this effect was noted for the cisplatin-resistant cell line, and also a mouse xenograft model.  

The biological mechanism by which this occurs may be because there is also published data that EGCG stimulates CTR1 (copper transporter 1), which allows for greater entry and accumulation of cisplatin into cancer cells. This was shown for ovarian cancer cells specifically. 

This lab study tested both in vitro (NSCLC cell lines) and in vivo (mouse xenograft model), and cell growth was inhibited better with EGCG. That there is a plausible biological mechanism for why cisplatin would work better in combination with EGCG is helpful in translating these findings. Therefore there is basis for an external generalizability to lung cancer patients drinking green tea while on cisplatin chemotherapy. 

Amino acids for Muscle Wasting 

A key clinical sign of untreated or advanced cancer is muscle loss, or “muscle wasting”. There is also data for a reduced anabolic response in cancer, more precisely. A study published in the Annals of Oncology in 2015 evaluated whether supplementing with with an essential amino acid mixture may help mitigate this muscle wasting. (19)  

A small study was undertaken in Arkansas comprising 13 patients with advanced non-small cell lung cancer (NSCLC) (stage III and IV) and 11 healthy age-matched subjects. Patients were randomized to either 14 g of free EAA (essential amino acids) with high leucine levels (EAA/leucine) versus a balanced amino acid mixture containing both EAA and non-EAA as present in whey protein. 

Outcomes showed that protein synthesis and net protein anabolism were higher after intake of the EAA/leucine than the balanced amino acid mixture (P < 0.001). This comparison held for both the cancer patient and healthy control groups. In addition, a significant linear relationship was observed between net protein anabolism and the amount of EAA available in the systemic circulation (R2=0.85, P < 0.001). Lastly, the high anabolic potential of dietary EAA in cancer patients is independent of their overall nutritional status, systemic inflammatory response or course of cancer treatment. 

This well-conducted study in human patients with NSCLC provides intriguing data that certain key amino acids are either lacking in cancer patients, or are being consumed with greater affinity by the cancer (instead of healthy tissues). The supplementation of free essential amino acids with high leucine levels importantly was found to be statistically significantly superior to a “balanced” amino acid mixture.  

Vitamin A 

Cigarette smoke exposure has been shown to lead to a reduction in retinoic acid (Vitamin A) in rat lungs, and even the formation of precancerous lesions in the trachea. This was more deeply investigated in rat lungs with different concentrations of cigarette exposure. (10) 

24 rats were divided into 4 groups. Three of these groups were the experimental ones, and exposed to increasing doses of cigarette smoke from 20, 40 or 60 commercial cigarettes/day for 5 days/week. After 6 weeks, the retinoic acid concentrations in the lung tissue as measured via high performance liquid chromatography (HPLC) significantly decreased (P < 0.01) in cigarette smoke exposed groups. In addition, Western Blot analysis revealed that cigarette smoke exposure increased lung protein expression of RAR α (RAR = retinoic acid receptor) in a threshold manner and decreased RAR β and RAR γ expression in a dose-dependent fashion. Further analysis showed that there was a significant increase in protein expression of cJun and cyclin D1 demonstrating a threshold effect similar to that exhibited by RARα. These are proteins (particularly cyclin D1) that are known to be activated or altered in cancer formation.  

This lab study nicely demonstrated that cigarette smoke affected RAR in a dose-dependent manner, and cancer promoting proliferative markers including cyclin D1 were increased with a threshold effect similar to RARa. Therefore there may be an independent signaling pathway for RARa (and Vitamin A deficiency) in lung cancer. A plausible hypothesis is that Vitamin A repletion may help. 

Curcumin (Turmeric) 

Curcumin is another natural spice that has been investigated in multiple cancer types. In general, the concept of augmenting the body's naturally occurring tumor suppressing proteins, by using nontoxic bioactive food components, is an appealing approach cancer chemoprevention. For lung cancer, the effect on curcumin causing DNA damage was examined in a lab effort in a human cancer cell line (NCI-H460 cells). The form of curcumin utilized was demethoxycurcumin (DMC).  (22) 

Analysis revealed via Western blotting that DMC suppressed multiple protein levels associated with DNA damage and repair. These included 14-3-3σ, BRCA1, MGMT, MDC1, and p53. (14-3-3σ = important checkpoint keeper of DNA damage response, MGMT = O6-methylguanine-DNA methyltransferase, MDC1 = mediator of DNA damage checkpoint 1, and p53 functions normally as a tumor suppressor) 

By microscopy, DMC also had the effect of promoting p53 to translocate from the cytosol to the nucleus within the cell.  

This is solid experimental evidence for curcumin (in the form of demethoxycurcmin) inducing DNA damage. The proteins affected by curcumin were those known to have important roles in DNA damage and repair.  

The effect of curcumin on retinoic acid receptor β (RARβ), a tumor suppressor, was studied in lung cancer cell lines and mouse models. (23) DNA hypermethylation of the promoter region of RARβ (which consequently prevents RAR from functioning as it normally would) is a major mechanism for its silencing in tumors. Furthermore, there is data for curcumin to possibly be a DNA methyltransferase inhibitor, and therefore may prevent this “silencing” step. 

In this study, curcumin was tested with lung cancer A549 and H460 cell lines. Curcumin significantly elevated RARβ expression at the mRNA and protein levels. Additionally, curcumin decreased RARβ promoter methylation, supporting the hypothesis of one mechanism of anti-cancer activity by curcumin.  Specifically, this was demonstrated that curcumin downregulated the mRNA levels of DNMT3b (a DNA methyltransferase). 

In a xenograft mouse model of lung cancer, the addition of curcumin strongly suppressed tumor growth, compared to controls. Biological correlative studies showed that RARβ mRNA was increased and DNMT3b mRNA was decreased by curcumin treatment, consistent with the results seen in cell lines. 

This laboratory effort, completed with appropriate control groups and tested in both lung cancer cell lines and mouse models, showed consistent results in terms of curcumin – the sole difference between groups – and regression of lung cancer cells growth (and regression in tumor growth). In addition detailed analysis provided strong data for curcumin to function against lung cancer as a DNA methyltransferase inhibitor; this therefore prevents the “silencing” of tumor suppressor genes that otherwise may prevent cancerous tumor growth. 

Caffeic acid  

Caffeic acid and its derivatives are found naturally in a variety of foods and spices, including sage, thyme, oregano, ginger, cumin, and star anise. A very small amount is available in coffee, at typically much lower concentrations than in the spices listed.   

The cytotoxic and apoptotic properties of caffeate derivatives were measured in a lab study performed a human lung cancer cell line (A549). (36) The cells were treated with 0-100 μM of caffeate derivatives for 0-48 hours, and cell viability was then quantified by the standardized MTT assay.  

Results showed that the caffeate derivatives tested  all significantly decreased cell viability of A549 cells. The 50% inhibitory concentration values ranged from 54.2 to 80.2 μM. Tested types included octyl, phenylpropyl, and decyl caffeates. Apoptosis (a primary programmed cell death process, that when deranged promotes cancer) was observed via propidium iodide staining, for cells treated with octyl and decyl caffeates. Additional biological evidence for the pro-apoptotic effect of caffeic acid included Bcl-2 and caspase levels (key proteins in apoptosis regulation) being altered after treatment.  

This testing of caffeic acid derivatives on human lung cancer cells was a thorough study, measuring cell viability, whether or not apoptosis changes were seen microscopically (changes were seen), and also biological correlatives such as the measurement of changes in key proteins in apoptosis regulation. Therefore this publication supports the anti-lung cancer properties as well as a specific mechanism of action of caffeic acid. Lastly, caffeic acid can be found in multiple common spices including sage, thyme, oregano, ginger, and cumin.