Esophageal Squamous Cell Carcinoma (ESCC) Prevention

Role of Vitamin E in prevention of human esophageal squamous cell carcinoma (ESCC)

Kanwal Mazhar, Guiju Sun¹

Abbreviations: ESCC, esophageal squamous cell carcinoma; Vit E, Vitamin E; RONS, reactive oxygen and nitrogen species;

Abstract

Vitamin E (Vit E) has enormous potential for cancer growth inhibition and cancer prevention. It has been studied widely for its anti-oxidant, anti-inflammatory and anti-cancerous activity. The objective of this review is to provide a summary of the research so far in regards to Vit E and the prevention of human esophageal squamous cell cancer (ESCC). ESCC is among the most malignant types of cancer and its incidence rate is increasing due to high consumption of alcohol and smoking. Therefore, finding new strategies to prevent and lessen the risk of ESCC and comprehensive understanding of carcinogenesis is essential. Our data suggest that the combination of tocopherols like γ-tocopherol-rich mixture of tocopherols (γ-TmT) would be more effective to use in the future for the prevention of cancers. This review will provide the brief guideline in understanding of Vit E in the prevention of ESCC.

Key Words; Vitamin E, Esophageal squamous cell cancer, anti-oxidant, cancer prevention

1. Introduction

Cancers of the upper aerodigestive tract, including those which arise in the oral cavity and pharynx, esophagus, and larynx, are significantly causing high morbidity and mortality throughout the world. More than 482,000 esophageal cancers had been estimated to occur globally in 2008, with incidence rates substantially higher in men than in women (1).

Vit E is a lipid-soluble vitamin and exerts its effect through its antioxidative properties (2). A dietary antioxidant is a substance in foods that significantly decreases the adverse effects of reactive species, such as reactive oxygen and nitrogen species (RONS), on normal physiological function in humans (3). Antioxidants have the potential to neutralize the harmful effects of DNA-damaging free radicals such as RONS; nitric oxide (NO) and other unstable oxidants produced by smoking (4). These antioxidants have a protective role in ESCC and other unspecified esophageal cancer (5, 6). Nutritional deficiencies play a main role in the development of ESCC especially in developing countries (7), however, facts from survey studies indicate the significant effect of dietary components on esophageal cancer.

2. Esophageal squamous cell cancer

2.1. Prevalence

Esophageal cancer is the 8^th most common cancer in the world and the 6^th most common cause of cancer-related death throughout the world (8, 9). Esophageal cancer is divided into two categories: squamous cell cancer and adenocarcinoma. While squamous cell cancer had been the most common type of esophageal cancer. Prevalence of esophageal cancer is higher in less-developed regions (10). The incidence of esophageal adenocarcinoma, which historically accounted for less than 10% of all esophageal cancer cases, has increased dramatically in Western populations over the last decades (11), while the ESCC has remained stable (12).

2.2. Etiology

In all occurring esophageal cancers, the etiology of ESCC has been studied mostly due to its frequent prevalence. There are many risk factors in the development of ESCC like smoking, alcohol drinking; exert their carcinogenic effects in large part through oxidative mechanisms, consumption of hot liquids (13-17), consumption of red meat, pork and processed meat, and eggs (18). The consumption of spicy foods, excessive amounts of chili, hot foods and beverages, and leftover food were positively associated with esophageal cancer risk (19).

2.3. Nutrition and Esophageal squamous cell cancer relationship

A number of observational studies exist on particular nutrients and their potential roles in prevention of ESCC. A previous study, in Linxian, China, has been found low nutrient intakes in selenium (Se), zinc, riboflavin, and calcium in both spring and autumn respectively. With the onset of autumn, vitamin A, C, E and protein consumption decreased largely due to seasonal variations in the availability and consumption of eggs, leafy and root vegetables. In Linxian, foods are deficient in several minerals and vitamins, including those linked with esophageal cancer (20). Such studies provide evidence as to which specific nutrients have a protective effect against cancer. The consumption of olive oil, raw and cooked vegetables, citrus fruits and other non citrus fruits lessened the risk of ESCC (21, 22). Intake of salads and a light break-fast (compared to no breakfast) were also protective (23).

In a study of patients with esophageal cancer in India, green leafy vegetables and fruits were protective against esophageal cancer (24). Similalry, in Linzhou, China, fruits and vegetables consumption showed a protective effect in numerous case-control and cohort studies. Consumption of beans, vegetables and vinegar all showed a beneficial effect (25). In a nationwide population based case-control study in Sweden, with 165 cases of ESCC compared to 815 control subjects, those with a high intake of vitamin C, β-carotene, and alpha-tocopherol (α-T) showed a 40-50% decreased risk of ESCC as compared to those with low intake (26). Lyophilized black raspberries have been found to decrease the onset and development stages of ESCC in rats (27). The finding of vitamins was based on the fact that the addition of these substances in the diet resulted in the severe disappearance of constellations of symptoms. Adequate vitamin availability to cells and tissues affect the initiation, progression and outcome of cancers (28). Vit E supplementation has inhibited carcinogenesis, especially in a moderately selenium-supplemented group (29).

3. Vitamin E

3.1. Chemical Structure and Availability

Vit E refers to a group of compounds; tocopherols and tocotrienols present in forms such as α-, β-, γ- and δ-tocopherols (α-, β-, γ – and δ-T) and α-, β-, γ- and δ-tocotrienols (α-, β-, γ- and δ-TT). Tocopherols and tocotrienols have same pattern of methyl groups on the chromanol ring (for α-, β-, γ- and δ-form) but tocotrienols have unsaturated 16-carbon side chain with double bonds at the 3’,7’, and 11’positions (Figure 1) (30).

Fig. 1.Chemical structure of tocopherols and tocotrienols

Humans and animals do not synthesize Vit E therefore we obtain it from dietary sources. Vit E most abundantly found in leafy green (spinach, broccoli) vegetables, seed oils such as wheat germ, sunflower, soybean and safflower oils including some breakfast cereals and yeast beer and in animal foods such as egg yolk (31,32). α-T and γ-T are the major tocopherols present in the human diet. D-α-tocopherol; a naturally occurring form of α-T, has the highest biological activity (33) whereas, γ-T is estimated to be the several times more consumed than α-T (34). As α-T generally recognized as “Vit E” therefore the majority of studies have focused on α-T due to its high blood levels and its role in fetal assimilation (35).

3.2. Vitamin E as an Antioxidant

Vit E is the powerful biological antioxidant, which protects the cell membrane integrity and function by decreasing RONS production and protects unsaturated fatty acids residues in cell membranes (36). Vit E inhibits the RONS production in the vascular wall and also up-regulates endothelial nitric oxide synthase (eNOS) activity which leads to an increase in NO production (37). These reactive species contribute to inflammation and cause oxidative damage to DNA, proteins and membrane lipids (38). Both oxidative stress and aberrant arachidonic acid metabolism are believed to contribute to carcinogenesis in the esophagus (Figure 2) (39).

Fig.2. Effects of ROS on DNA damage leading to carcinogenesis

As Vit E is a potent antioxidant with anti-inflammatory properties, several studies recommend α-tocopherol for its significant effects with regard to cardiovascular disease (40, 41). Some in vitro studies have also shown the superiority of α-T as an antioxidant over other tocopherols. Others, however, have found that anti-inflammatory and anti-nitrative properties of γ-T make it more effective than α-T in the prevention of cancer, as well as neurodegenerative and cardiovascular diseases (42-44). Some studies suggest that mixtures of tocopherols are superior to a single tocopherol at inhibiting inflammation. In one previous study, supplementation of γ-T and α-T in combination was more significant than γ-T or α-T individually in decreasing the levels of C-reactive protein, tumor necrosis factor-α (TNF- α) and nitrotyrosine (45).

4. Vitamin E and Esophageal squamous cell cancer

The relationship between Vit E and cancer and its role in cancer growth inhibition and prevention has been studied widely. These are a few most commonly recognized cancer preventive mechanism of Vit E; down-regulation of NADPH oxidase (46); quenching of ROS and RNS; induction of apoptosis or cell cycle inhibition; control of tumor growth through the initiation of demarcation; and removal of tumor cells by improved efficacy of antitumor actions by the immune system (47-49). Supplementation with Vit E, Se and β-carotene significantly decreased the risk of esophageal and gastric cardiac cancer (50-52). In one cohort study association of α-T with decrease in risk of ESCC has been found (53). The quenching of RONS by γ-T and δ-T and their inhibitory activities against cyclo-oxygenase 2 (COX-2), make γ-T and δ-T stronger anti-inflammatory and anticarcinogenic agents than α-T. Vit E and selenium supplementation inhibited NMBzA-induced esophageal carcinogenesis in rats on low Vit E/Se diet, and supplementation during the early stage was more effective than during the late stage of carcinogenesis. (54).

As a vital enzyme in Arachdonic acid (AA) metabolism, COX-2 overexpression was related to cell proliferation in esophageal dysplasia and ESCC (55,56). Similarly, 5-lipoxygenase (5-LOX) overexpression also promoted tumorignenesis, and 5-lipoxygenase (5-LOX) pathway inhibitors showed a chemopreventive effect in animal models of esophageal cancer (57). Prostaglandin E2 (PGE2) stimulates cell proliferation in a variety of carcinoma cell types in vitro and enhances angiogenesis in vivo (58). COX-2 inhibitors have been reported to suppress cell proliferation by blocking PGE2 production. It is suggested that tumor growth may be supported by PGE2 through inducing angiogenesis, which is necessary to supply oxygen and nutrients to tumors. Vit E/Se supplementation decreased cell proliferation, angiogenesis, 8-hydroxy-2’-deoxyguanosine, biosynthesis of PGE2, leukotriene B4 (LTB4), expression of COX-2 and 5-LOX in the esophagus. Vit E intervention has been shown to increase the plasma activity of several antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and total anti-oxidative capacity (T-AOC) whereas it is able to decrease the levels of Isoprostane 8-epi Prostaglandin F_2α (8-epi-PGF_2α), which is a product of oxidative stress that causes potent smooth muscle contraction (59).

A recent study suggests that γ-tocopherol-rich mixture of tocopherols (γ-TmT) is probably the most promising agent to use. γ-TmT; containing 13%α-tocopherol, 1.5% β-tocopherol, 57% γ-tocopherol and 24% δ-tocopherol, inhibited carcinogenesis in a number of animal models (61-64). In one animal study on treatment of severe combined immunodeficient (SCID) mice with dietary γ-TmT suppressess the formation and growth of LNCaP xenograft tumors in a dose-dependent manner (65). It has been shown that γ-T or the combination of γ- and δ-T were more effective than α-T for inhibiting the growth of several types of cancer cells in culture (66-70). In addition, one recent study demonstrated that δ- and γ-T were more active than α-T for inhibiting lung tumorigenesis (71).

γ -TmT, a by-product in the refining of soybean oil, contains γ-T, δ-T and β-T in ratios approximate to those in dietary vegetable oils. Because it is readily available and inexpensive, γ-TmT and similar tocopherol preparations have a high potential for practical application and deserve further investigation in animal models and human trials. However, it is important to state that there are several controversial effects of Vit E on cancer. Studies of individual foods and their mechanism of action in carcinogenesis at the cellular level are limited.