Proper nutrition and diet play a vital role in preventing many diseases, including colorectal cancer. In the fight against this disease, nutritional guidelines emphasize eating less saturated fat and obtaining more nutrients from food rather than supplements. While dietary fat from red and processed meats may contribute to colorectal cancer, antioxidants are being studied for their role in bolstering the body's defenses against free radicals.
The Role of Dietary Fat and Bile Acids
Dietary fat, especially from red and processed meats, may contribute to colorectal cancer development. High fat consumption increases the production of bile acids in the digestive tract. While bile acids aid in breaking down fats, a large amount of bile acids in the colon may be converted to secondary bile acids, potentially promoting tumor growth, especially in the cells lining the colon.
Understanding Free Radicals and Antioxidants
Free radicals are by-products of oxygen use by every cell in our body. These substances damage the body's cells through oxidation, a process similar to how metal rusts and butter turns rancid. Oxidation has also been shown to contribute to heart disease, cataracts, aging, and infections. The body's cells have a natural defense strategy against free radicals and can repair the damage they cause. Antioxidants, such as selenium and beta-carotene, may help reinforce this protection. However, clinical trials have not shown that these agents reduce cancer development.
Antioxidants are often touted as must-haves for optimal health, particularly when it comes to fighting diseases like cancer. The compounds, which are present in foods and available as supplements, can play a key role in fighting free radicals. But they aren’t a cure-all, and some sources of antioxidants are more beneficial than others.
How Antioxidants Work
Free radicals are unstable atoms that can damage cellular DNA in the body, which is thought to play a role in the development of cancer. Our bodies produce free radicals when we breathe or exercise, and we’re exposed to even more via environmental toxins like cigarette smoke, air pollution, or the sun’s UV rays. They roam around the body and contribute to the onset of inflammation and related chronic conditions. Antioxidants work by tracking down free radicals and neutralizing their harmful effects. That may help keep more of the body’s cells healthy-and less susceptible to becoming cancerous.
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Sources of Antioxidants: Food vs. Supplements
Studies suggest that antioxidants are best consumed through foods rather than supplements. Examples of antioxidants include carotene, beta-carotene, lutein, and vitamins C and E. Foods rich in antioxidants include fruits, vegetables, and certain types of tea. Brightly colored fruits and vegetables, like tomatoes, carrots, spinach, broccoli, sweet potatoes, strawberries, and citrus fruits, are top sources. Whole grains, nuts, seeds, and wheat germ serve up antioxidants too. Your best bet is to go for a wide variety, since different foods have different antioxidants.
While there seems to be some potential benefit in consuming foods with folic acid as part of a regular healthy diet, studies do not show any anti-cancer benefit from taking folic acid supplements. In fact, some studies suggest that taking folic acid supplements may slightly increase the risk of cancer.
The Downside of Supplements
If antioxidants from food are good, it’s easy to assume that high-dose antioxidant supplements are even better. But there’s no evidence that antioxidant supplements can prevent cancer or other diseases. In fact, very high doses of certain antioxidants may actually increase the risk of some cancers. Another thing to consider: Supplements contain isolated forms of single antioxidants, but that’s not the case with food. Foods that contain antioxidants may also contain beneficial plant chemicals (phytonutrients), vitamins, minerals, and fiber. And all of these compounds may work together to exert their potential disease-fighting effects.
Taking antioxidant supplements during cancer treatment doesn’t seem to have beneficial effects, and research has shown that, in some cases, it could actually lead to worse outcomes.
Other Important Nutrients
Folic Acid
Some studies suggest that folic acid may play a role in the fight against cancer, while others show an increased risk for some types. More studies are needed. It's already known to be essential in forming new cells and tissues as well as keeping red blood cells healthy. The most common sources of folic acid are citrus fruits and dark green leafy vegetables, especially spinach.
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Calcium and Vitamin D
Recent studies have suggested that calcium and vitamin D may not only strengthen bones but may also help fight off colon cancer. Good sources of calcium include: milk, cheese, yogurt, salmon, sardines, and dark-green leafy vegetables such as kale, mustard, and collard greens. Sources of vitamin D include salmon, sardines, fortified cow's milk, egg yolks, and chicken livers -- and don't forget the sun. The sun is an excellent source of vitamin D.
Fiber
Fiber has been thought to be a powerful weapon against cancer. Though there is conflicting research as to whether or not fiber has protective effects against colorectal cancer, there is evidence that fiber intake improves overall health. Good sources of fiber include: whole-grain cereals and breads, prunes, berries, kidney beans and other legumes, fresh fruits and vegetables, and brown rice. Although it’s best to get the fiber you need from food, fiber supplements offer another source. Examples include psyllium and methylcellulose. Anytime you increase your fiber intake, do it slowly to help prevent gas and cramping.
Systematic Review of Vitamins and Antioxidants
A comprehensive literature review was conducted by searching electronic databases to identify studies examining the prospected impacts of dietary vitamins and antioxidants on the prevention of CRC. Following the PRISMA guidelines, the search was conducted using the academic databases PubMed, Medline, Google Scholar, ScienceDirect, and Springer with relevant keywords focused on the studies analyzing the anticipated effects of dietary vitamins and antioxidants on the prevention of CRC. Studies published over a 10-year period (2014-2024) that met the inclusion criteria for this review paper were included.
Findings on Vitamins
According to the outcomes of this review, there is a complex link between vitamins and CRC. While some vitamins such as B2, B6, and D seemed helpful, others such as A and E had mixed results. Vitamin C deficiency was even linked to worse outcomes in cancer patients. Overall, the studies suggest focusing on a balanced diet rich in various vitamins rather than relying solely on individual supplements to prevent CRC.
Findings on Antioxidants
The results of the review suggest that the relationship between antioxidant intake and CRC is more intricate than previously thought. Data from this review indicates that taking specific antioxidant supplements such as selenium and vitamin E does not seem to offer the same protection. This suggests that a balanced diet with a variety of antioxidants is more helpful than focusing on single supplements. While a direct association was not observed, future studies could investigate how different types and combinations of antioxidants might influence CRC development.
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Endogenous and Exogenous Antioxidants: A Deeper Dive
Antioxidants are found inside our body (endogenous) or they can be introduced from the outside into the human body (exogenous).
Endogenous Antioxidants
Catalase (CAT), an enzyme located in the peroxisomes, converts hydrogen peroxide into water and molecular oxygen using iron or manganese as cofactors. Although the role of catalase in tumor is contradictory, some authors reported an increase of catalase levels in colorectal cancer. Cytosolic SOD uses zinc and copper as cofactor, while mitochondrial SOD uses manganese. Many studies showed changes of SOD activity related to gradual progression of CRC; in particular SOD levels proportionally increased with the increase of grade of differentiation of CRC.
Glutathione is a tripeptide of gamma-glutamyl-cysteinyl-glycine, the major cellular thiol protein and is found in all cell compartments. Under physiological conditions, reduced GSH is the predominant form, with a concentration up to 100-times higher than the GSSG form. Under oxidative stress, GSH is converted by GSH-dependent peroxidases, such as glutathione peroxidase (GPx) and glutathione-s-transferase (GST), into GSSG. Glutathione reductase (GR) restores cellular GSH by converting GSSG to GSH at the expense of NADPH. The metabolism of GSH removes and detoxifies the cells by carcinogens, so altering the pathway has an effect on cell survival.
GSH and associated enzymes are controlled by a transcription factor, nuclear factor-2 related erythroid factor-2 (Nrf2). Under physiological conditions, Nrf2 binds Kelch-Like ECH Associated Protein 1 (KEAP1), via a Cullin3 adapter protein, leading to the ubiquitination and degradation of Nrf2. Under oxidative stress, the altered conformation of KEAP1 disrupts its association with Nrf2, with subsequent stabilization of Nrf2. Free Nrf2 translocated to the nucleus where it activated antioxidant response genes responsible for the synthesis and metabolism of GSH, antioxidant proteins such as GPX, drug-metabolism enzymes. Furthermore, GST, which binds both GSH and drugs, is involved in cancer multidrug resistance. GSH-GST-drug conjugated is associated with multiple resistance-associated protein transporters (MRP1), which release drugs out of the cells.
Another example of non-enzymatic exogenous antioxidants is unconjugated bilirubin, the end product of the Heme catabolic pathway. Heme, the precursor of hemoglobin, produced by the action of the alanine synthase, is converted into biliverdin by heme oxygenase enzymes. Biliverdin is then converted to unconjugated bilirubin by biliverdin reductase. Although increased levels of bilirubin have always been known as a sign of liver disorders, most recently bilirubin, along with uric acid, is considered the most potent endogenous antioxidant due to its continuous recovery in the bilirubin/biliverdin redox cycle. Recent data strongly indicate that mean bilirubin levels may be protective against diseases associated with increased oxidative stress, such as CRC. Uric acid is a product of purine metabolism. Other endogenous antioxidants with non-enzymatic activity, such as carotenoids, flavonoids and vitamins will be discussed in the exogenous antioxidants section.
Exogenous Antioxidants
The main natural exogenous antioxidants are contained in fruit and vegetables and are introduced with food in the diet. The role of carotenoids, vitamins and flavonoids in the prevention of CRC will be described below. Carotenoids (carotene, lycopene, lutein, zeaxanthin) are soluble lipids; they exist as alpha and beta isoforms and are responsible for the yellow, red and orange color of fruits and vegetables. They eliminate singlet oxygen (1O2) and peroxyl radicals (ROO). The conjugated double bonds make these compounds able to accept electrons from ROS and thus neutralize free radicals. Once digested, beta-carotene, is transformed into retinol (also known as vitamin A). Retinol inhibited tumor cell invasion and their ability to migrate through the extracellular matrix.
Vitamin C, known as ascorbic acid, is a water-soluble vitamin found in fresh vegetables and fruit. It reacts directly with superoxide ion O2 and singlet oxygen through dehydrogenation, and plays an effective role in cancer treatment and prevention. Current research is focused on identifying the mechanisms by which vitamin C is able to influence the progression of CRC. A recent study on CRC patients showed that ascorbate levels are lower in the colon tumor core than in the peripheral regions. After intravenous infusion of ascorbate, its levels increased in all tumor regions, suggesting an increase in plasma availability. Additionally, increased ascorbate levels modulated HIF activation.
Fat soluble Vitamin E, also known as tocopherol, exists in the, β, γ and δ forms, and is contained in food such as vegetable oil in soy, nuts and corn. It has antioxidant activity on the cell membrane; in particular, it protects cells from lipid peroxidation by stabilizing cell membranes and playing a protective role against ROS-mediated carcinogenesis.
Flavonoids have a skeleton of 15-carbon, containing two benzene rings linked by a connecting chain of 3-carbon atoms (C6-C3-C6 compounds). Flavonoids are able to chelate redox-active metals, such as copper and iron, inhibiting lipid peroxidation by scavenging peroxyl radicals (.ROO). They have a dual effect on ROS homeostasis, in physiological conditions they are antioxidants preventing carcinogenesis, but in oncological disease they are pro-oxidants favoring the activation of the apoptotic pathway. Antioxidant activity can be direct or indirect. The direct antioxidant activity of flavonoids is due to the presence of phenolic hydroxyl groups that stabilize free radicals by expelling and chelating metal ions.
Some authors have studied the antioxidant effect of epigallocatechin-3-gallate (EGCG), contained in green tea (Camelia sinensis). It modulates antioxidant enzymes, such as SOD and CAT, inhibiting tumor evolution. Additionally, colon cancer cells are known to have excessive iron content, which leads to cancer progression. Hydroxytyrosol, a phenolic compound abundant in olive oil, enhances cellular antioxidant defenses, protecting cells from oxidative stress. The flavonol quercetin, abundant in onions, apples, tomatoes, broccoli and citrus fruits, has been shown to have a chemopreventive effect against cancer. There are many mechanisms underlying the chemopreventive effect of quercetin: for example, quercetin inhibits hepatocarcinogenesis by up-regulating the enzymatic and not-enzymatic antioxidant defense system. Furthermore, the catechins and procyanidins of Cocoa protected Caco-2 cells.
Other compounds such as sesamol, curcumin, resveratrol, have a dose-dependent paradoxical effect. Sesamol, a phenolic compound contained in sesame seeds, had a pro-oxidant effect on human colorectal carcinoma HTC116 cells at high concentrations (0.5-10 mM); induction of mitochondrial apoptosis was due to the intracellular O2− generation. Curcumin, the main biologically active compound of Curcuma longa, has an anti-radical effect thanks to the CH2 group of the beta-diketone fraction. Its antioxidant activity makes it a promising candidate for colon diseases prevention and combination therapy. Finally, resveratrol, a polyphenol contained in grapes and red wine, inhibits the formation of superoxide anion and hydrogen peroxide in the body. Furthermore, it reduces lipid peroxidation, decreasing inflammation of the intestinal mucous and preventing the development of colon neoplasia.
The Importance of Overall Nutrition
If you are facing cancer, it’s important to focus on good nutrition overall. It’s never a bad idea to focus on getting antioxidants from fruits and vegetables, including when you have cancer. Eating a variety of foods helps supply your body with the nutrients it needs to feel better and keep up your strength during treatment. You may need to eat more of certain foods to keep up your weight. Your cancer care team can help you set nutrition goals that are right for you.
Cautions and Considerations
Supplements haven’t been shown to protect against cancer, and they have the potential to interact with other medications you might be taking or have a negative impact on cancer treatment outcomes. If you’re thinking about taking any kind of supplement, it’s always important to check with your doctor first.
Until more is known about the effects of antioxidant supplements in cancer patients, these supplements should be used with caution.
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