Exploring the link between nutrients, metabolism and genetic sensitivity in the etiology of cancer is an important focus from a scientific and public health point of view. Since the etiology of cancer is multifactorial, it is necessary to study whether nutritional therapy, especially vitamins and trace elements, have a positive (preventive) or negative (higher risk) impact.
On the other hand, the evidence points to the fact that calorie restriction can reduce the occurrence of cancer, as in the study of Tannenbaum, which reports that in rodents, calorie restriction is positive in relation to the process of carcinogenesis. Therefore, the connection between is emphasized overweight , sedentary lifestyle and increased risk of cancer, especially colorectal, endometrial and breast cancer, which is explained by the ratio of hyperinsulinemia, elevated growth factors, estrogen and endogenous androgens.
Cancer is characterized by a progressive accumulation of mutations in the genome of the cell, where homeostatic mechanisms that determine the balance between proliferation and cell death are affected. Chemical oxidation is defined as the loss of electrons, while reduction is the gain of electrons. Therefore, it is understood that substrate oxidation is always associated with electron receptor reduction. The oxide reduction potential is therefore the redox potential that measures the flow of electrons involved in oxidation processes.
In aerobic beings, multiple chemical reactions with oxygen represent the most efficient mechanism of energy production, since they can generate intermediates or oxygen-reactive substances that accept electrons, form free radicals, unstable and reactive compounds with one or more unpaired orbital electrons. The isoform of oxidonitric synthase during the chronic inflammatory process can induce carcinogenesis, participating in the angiogenesis of tumor progression. The response of the host to this activity leads to the activation of the immune system, and with it the anti-inflammatory cytokines, tumor necrosis factor alpha and oxidant molecules. The human antioxidant system depends on some key nutrients: water- and fat-soluble vitamins, as well as trace elements. Oxidative DNA lesions are a crucial process in carcinogenesis, because they generate damage to nitrogenous bases, highly mutagenic modifications, which produce genetic instability at the sites of cell replication.
Diet and cancer: a complex relationship
The relationship between nutritional status, progression and cancer prognosis is based on the fact that both in clinical practice and in several studies it has been observed that well-nourished patients have a better prognosis and quality of life, emphasizing that malnutrition can negatively affect morbidity and mortality in cancer patients. in response to treatment, due to the toxicity that various antineoplastic treatments can cause, among the effects: nausea, vomiting, diarrhea, mucositis, xerophthalmia.
On the other hand, tumor products also act on the central and peripheral nervous system , causing psychogenic effects such as anorexia, depression and anxiety, tumor cachexia, metabolic changes, thinness, weakness, decreased protein synthesis, loss of functionality. Among the mechanical effects of tumors, obstruction and malabsorption are considered important, which can cause a lack of macro and microelements, and thus significant weight loss, regardless of sufficient intake.
Another important aspect to consider is the fact that specific antioxidants such as flavonoids, folate and vitamin D. may reduce the risk of developing cancer.
Hence the importance of the nutritionist, who must perform screening to measure risk and nutritional assessment to diagnose nutritional status, as well as food history to study the patient’s eating habits.
Research with vitamin C.
Wright and co-workers studied the genetic variants and their impact on the risk of gastric cancer, based on the strong biological evidence that ascorbic acid has in the stomach. The study found ascorbic acid in high concentrations in the juices and gastric mucosa in patients with chronic gastritis, while in patients with cancer the concentration was low. That describes that ascorbic acid neutralizes reactive oxygen and inhibits the formation of N-nitroso compounds. stomach, showing that ascorbic acid can inhibit cell proliferation and apoptosis in gastric cells;
It even seems that ascorbic acid can directly affect the growth of Helicobacter pylori. They conclude that common variants of the SLC23A2 gene directly regulate the active transport of ascorbic acid, which may have a positive effect on the risk of gastric cancer.
On the other hand, Legut et al. Presented results in which deficient levels of vitamin C and anacardiac acid significantly increased the cytotoxicity of the antineoplastic drug in melanoma compared with ammonium sulfate liposomes. Vitamin C and anacardiac acid protect normal cells from damage caused by antineoplastic drugs. The combined formulation of vitamin C, anacardiac acid and mitoxantrone shows favorable results in terms of cytotoxicity and cytoprotection.
Cherdintsev et al. Report that a nitrotriazole derivative called Sanazole, which is usually used in high doses to improve the effectiveness of radiotherapy, causes peripheral neuropathy in some patients, which is classified as neurotoxic. In view of this, they conducted an in vivo study in mice, in which they noticed that the use of ascorbic acid glucoside before the use of sanazole in cancer patients manages to protect the body from neurotoxic effects.
The glutathione system is especially important for defending cells from reactive oxygen species (ROS). Reduced glutathione (GSH) reacts directly with radicals in a non-enzymatic reaction and is an electron donor in the reduction of glutathione peroxidase (GPk) catalyzed peroxides. medicine.
Mikirova et al., Meanwhile, point out that ascorbic acid has therapeutic potential when given intravenously (IV), because plasma ascorbate levels may mediate inflammation, which could increase healing in cancer patients, suggesting that this intravenous form is safe. and can be adjunctive therapy for clinical cancer care.
Study performed using 15 g IVC
The study was performed using 15 g of IVC ascorbic acid in a specific way in patients with different types of cancer, observing favorable results. for their part – point out that ascorbic acid has therapeutic potential when given intravenously (IV), because plasma ascorbate levels may mediate inflammation, which could increase discharge in cancer patients. that this intravenous form is safe and can serve as an adjunct therapy for clinical cancer care. The study was performed using 15 g of IVC ascorbic acid in a specific way in patients with different types of cancer, observing favorable results. which could increase discharge in cancer patients.
They suggest that this intravenous form is safe and can serve as adjunctive therapy to clinical cancer care. The study was performed using 15 g of IVC ascorbic acid in a specific way in patients with different types of cancer, observing favorable results. which could increase release in cancer patients They suggest that this intravenous form is safe and may serve as adjunctive therapy to clinical cancer care. The study was performed using 15 g of IVC ascorbic acid in a specific way in patients with different types of cancer, observing favorable results.
Mehdi et al. Presented important results showing that there is a significant increase in levels of advanced protein oxidation products (AOPP), malondialdehyde (MDA) and adenosine deaminase (ADA) in patients with multiple myeloma before treatment, compared to healthy subjects.
In contrast, total antioxidant capacity (TAC), glutathione, ascorbic acid (vitamin C), α-tocopherol (vitamin E), and antioxidant enzymes were significantly reduced. Therefore, biochemical changes caused by this type of cancer are evident.
Research with vitamin zinc
Christudoss et al., In their research, suggest that aspirin, vitamin C, and zinc may be administered separately to obtain a chemoprotective effect against preoplastic colon and carcinogenic colon progression in dimethylhydrazine (DMH) -induced rats. Therefore, the inhibitory effect is associated with maintaining colon tissue essential from zinc and zinc enzyme levels as close to normal as possible.
Because the effect of high doses of vitamin C as a cancer treatment is controversial, several studies have shown that vitamin C at a concentration of 0.25 to 1.0 mM in plasma, induced by dose and time, can inhibit cell proliferation in acute myeloid leukemia. . Treatment of cells with high doses of vitamin C results in an immediate increase in the content of intracellular glutathione S-transferase and its activity, followed by cysteine consumption.
These results indicate a new role of vitamin C in high concentrations as a modulator of sulfur-containing intracellular components, such as glutathione and cysteine. On the other hand, a clinical study reports a significant reduction in L ascorbic acid alternating with supplements in the treatment of patients with acute myeloid leukemia or myeloid dysplasia syndrome.
During the supplementation phase, patients received intravenous vitamin C daily prior to therapy, observing the in vitro behavior and sensitivity of leukemia cells to vitamin C, indicating that cancer cells are sensitive to vitamin C.
They conclude that although they accurately postulate specific mechanisms, vitamin C is difficult, however, they relate to the identification of genes or proteins that are specifically regulated by vitamin C in certain cellular phenotypes and this could improve the efficacy of cancer therapies.
In vivo study of Kontek et al.
In vivo study of Kontek et al. shows that vitamin C can cause a weak effect on DNA damaged by hydrogen peroxide and a positive effect on DNA damaged in HT29 cells (reduction of approximately 30%). They note that DNA damage was effectively repaired within 120 minutes after incubation in test cells that had one of the highest types of oxidative damage.
For their part, Paiva et al investigated the effects of vitamins C and E on tumors in xenographic mice with the sarcoma model (S180) in vivo. The result of the experimental study suggests that doses of 100 mg / kg of vitamin C and 400 mg / kg of vitamin E create a significant inhibition in tumor behavior. The encapsulation of anticancer drugs in the structure of liposomes protects the drug during its circulation and increases the accumulation of the drug in cancerous tissue, as well as its antitumor activity, while reducing the toxicity of the drug. Dominic’s study. and co-workers, propose a new drug loading method based on the pH gradient of vitamin C / ion.
The formulations are characterized in terms of parameters such as optimal external pH, time and drug-lipid ratio to achieve in vitro stability. In the specific case of epirubicin (EPI), its coencapsulation increases anticancer activity through possible synergistic effects reported by different groups of drugs with vitamin C without encapsulation. The method has another advantage which consists in enabling faster release by destabilization of liposomes at the tumor site, thanks to the very good solubility of EPI in vitamin C salts, as is observed in cryogenic transmission. This affects the drug release process and increases the anticancer activity of the liposome formulation. The antitumor activity of the encapsulated drug was confirmed (it inhibited tumor growth by over 40%, while it was shown that the drug that was not encapsulated did not have anticancer activity).
Fat-soluble vitamin E., called tocopherol: alpha, beta, gamma and delta. Considered the main antioxidant found in the body’s lipid membranes, it protects polyunsaturated fatty acids from cell membranes from their oxidation by blocking free radicals. In addition to preserving carotenoids and selenium in a reduced state, favoring their antioxidant properties.
Its deficiency is characterized by hemolytic anemia, neuronal degeneration and reduction of serum creatinine with excessive losses in urine. Prolonged deficiency of this micronutrient causes musculoskeletal injuries and liver disorders. On the other hand, vitamin E poisoning causes nausea, headache, fatigue, hypoglycemia.
As for its effect on cancer, vitamin E plays an important role in reducing the neurotoxic effects of ciplastin. Vitamin E supplementation with 400 mg / day reduces the frequency and severity of neurotoxicity, and evidence suggests that vitamin E is assigned an important role, along with vitamin C, carotenoids, and folate, in the prevention of pancreatic cancer. While in the study of alpha tocopherol, beta carotene from the Study Group for Cancer Prevention, it was noted that no reduction in the incidence of lung cancer was found among male smokers after 8 years of dietary supplementation with alpha tocopherol or beta carotene. In fact, these tests shed light on the possibility that these supplements may do more harm than good. They also identified an association between vitamin A supplements and breast cancer risk, reporting a statistically significant incidence. Regarding complex B, they reviewed several studies, but did not find a link that supports complex B supplementation with both niacin and breast cancer.
Vitamin A-Retinol or carotenes, carotenoids
Vitamin A -Retinol or carotenes, carotenoids, are a fat-soluble vitamin with a recognized antioxidant effect in vitro. Carotenoids are absorbed in the small intestine and depend on the adequate absorption of fats, bile salts and pancreatic stereos. Its absorption is close to 80%, and then it is transported through the lymphatic system as a part of lipoprotein chylomicrons in the liver.
Its deficiency (serum concentrations <0.35 mmol / l) is characterized by: night blindness, xerophthalmia, Bitot’s spots, among others. Intoxication includes irritability, headache, anorexia, diplopia, alopecia, joint pain, liver disorders, bleeding. Among the antioxidant functions are: regulation of epithelial cell differentiation, inhibition of cell proliferation, increased immune capacity, inhibition of mutagenesis caused by physical carcinogens, reduction of nuclear damage caused by chemical and biological carcinogens. The strongest evidence regarding beta-carotene supplementation and lung cancer currently relates to the fact that high doses of beta-carotene can cause lung cancer in tobacco smokers.
There are two forms of vitamin D in the body: D2, ergo calciferol and D3 hole calciferol. Vitamin D2 present in vegetables and vitamin formulations, D3 is synthesized in the body by exposing the skin to ultraviolet rays. Due to its characteristics, it is considered a hormone, with different functions from other vitamins, in addition to the fact that the body synthesizes it thanks to the sun’s action. Its activation to calcitriol begins in the liver and ends in the kidneys. Involved in bone growth, bone mineralization, and cell differentiation (cells of the immune and hematopoietic systems), it also acts as a medium to link a family of nuclear receptors such as steroids in general. It is a unique and specific nuclear receptor with direct transcriptional activity related to the response elements to vitamin D.
Because of these global effects and the immune system, including cell differentiation and proliferation, vitamin D is credited with a role in carcinogenesis and genetic polymorphism. Vitamin D deficiency has an epidemic prevalence in India ranging between 70% – 100% of the population, as cultural and religious practices do not allow adequate sun exposure as well as dairy consumption, and as a result people suffer from subclinical vitamin D deficiency, which favors high prevalence of osteoporosis, cardiovascular disease, diabetes, and cancer.
Due to the fact that mRNA receptors for vitamin D are detected in the human esophagus, they are assigned a regulatory role in the cell cycle, contributing to inhibition and differentiation in apoptosis of normal and transformed cells, where 25 (OH) 2D3, which is the active form of vitamin D3, contributes by protecting cells from turning into carcinogens. Significant evidence supports the anticancer role of vitamin D3 against breast, prostate, skin, and colon cancers, both in vivo and in vitro experimental models, and the most recent are those supporting Vit D3 metabolites to inhibit the growth and differentiation of esophageal cancer cells in vitro.
However, the evidence does not clearly show a link between vitamin D3 and the risk of esophageal cancer. In a study by Gui-Ling Huang et al., There is evidence of an association between high serum vitamin D3 concentrations and beta-carotene with a low risk of esophageal cancer. On the other hand, in the Pankaj G study, they point out in their hypothesis that the use of chemotherapy in colon cancer can cause changes in diet, such as the removal or reduction of dairy products as part of chemotherapy management due to induced diarrhea.
In addition, it has been observed that patients treated with this treatment do not absorb vitamin D due to subclinical mucositis, which is why these patients may need large amounts of vitamin D over long periods of time to achieve an appropriate serum level of 25 (OH) D. found that an oral formulation of 8,000 IU of vitamin D daily for 8 weeks was a safe regimen to correct vitamin D deficiency in cancer patients.
The response to such supplementation leads to the return of suboptimal to optimal levels in patients with prostate and lung cancer (with initial levels of 20-32 ng / ml), as well as in patients with colon and pancreatic cancer whose baseline levels are usually lowest (below 20 ng / ml). The impact of improvement in patient serum levels of 25 (OH) D, survival and quality of life should be investigated.
Another finding by Pankaj and co-workers is the association of obese cancer patients with vitamin D deficiency, compared with normal-weight cancer patients. Some of the proposed mechanisms explain the association between obesity and hypovitaminosis D, which, in addition to involving a lack of sun exposure due to physical inactivity, also refers to the sequestration of vitamin D in subcutaneous adipose tissue. Recently, such studies have suggested determining whether restoring and maintaining adequate levels of vitamin D may affect tumor control and survival.
Folic acid is soluble in water and its sources are fruits, dark green vegetables and seeds. People are not able to synthesize this vitamin, so it must come from dietary sources. Its bioavailability is higher as folic acid than as folate, because it is not conjugated and therefore more stable. Multiple mechanisms suggest that it has a preventive role in carcinogenesis, including molecular mechanisms such as DNA synthesis, repair, and methylation.
Marinos et al., Point out that even a study by nurses (NHS) showed that a diet high in folate reduces the risk of colon cancer or adenomas, but not when folate comes from a supplement.
It has been suggested that folic acid supplementation may be associated with increased adenoma recurrence and may be detrimental to those patients with a history of colon cancer. Therefore, it is recommended that multivitamins containing folic acid do not exceed 400 μg. It is necessary to emphasize that folic acid has nutritional properties and chemical structures similar to folate and folacin; it is a coenzyme that participates in the synthesis of nucleic bases, purines and pyrimidines to form nucleic acids, along with vitamin B, and in protein metabolism. Folate is important in DNA synthesis, so it somehow plays a role in carcinogenesis. This role is considered important, as the folic acid pathway is a natural antifolate drug such as methotrexate.
Therefore, in the treatment of cancer, they are harmful for both cancer cells and normal cells, which is why they cause the well-known side effects of these drugs. Folic acid deficiency results in megaloblastic anemia, leukopenia, anorexia, diarrhea, glossitis, weight loss, dermatological disorders.
Folate is thought to help prevent cancer by participating in the synthesis, repair and function of DNA. Folate deficiency can result in DNA damage which can lead to cancer. In contrast, other studies suggest that excess folate may promote tumor activation. Folic acid is involved in the metabolism of amino acids and is necessary for the methylation of nucleic acid. It is important to consider that one of the drugs that interferes with folate metabolism is methotrexate, which is known to be used to treat cancer. Its direct interaction is that it inhibits the production of the active form, tetrahydrofolate. In addition, methotrexate may have a toxic effect such as inflammation of the digestive tract, which in turn would affect oral intake.
Folic acid, in turn, can help reverse the toxic effects of methotrexate. However, it is known that small doses of methotrexate can reduce folate stores causing deficiency. In contrast, diets high in folic acid, as well as its supplements, can help reduce the side effects of methotrexate without reducing its effectiveness. Compared to the doses indicated as a supplement, they found that there was an increased risk when doses of folic acid greater than 400 μg / day were added.
Calcium, an important macroelement in the processes of blood coagulation, neuromuscular excitability, nerve transmission and muscle contraction. It also plays an important role in bone and tooth mineralization, enzyme activation and hormonal secretion. Responsible for the transport of vitamin B12 in the gastrointestinal tract and necessary for the maintenance and function of membrane cells. Hypocalcemia is associated with the secretion of calcitonin by tumor C cells of the thyroid gland, sometimes the thymus and parathyroid glands, by reducing the concentration of calcium and phosphate in the plasma and by inhibiting bone absorption. Hypercalcemia is associated with parathyroid tumors.
The most common trace element after iron. The composition of metalloenzymes with great antioxidant power, with a relevant role in cell growth and replication, in full maturation, fertility and reproduction, also in phagocytic, immune and humoral functions, as well as in taste and appetite.
On the other hand, zinc deficiency can alter protein synthesis by reducing serum levels of transport proteins such as albumin, pre-albumin, transferrin, affecting the availability of micronutrients. Deficiency can be caused by low consumption or large intestinal losses (diarrhea, drainage, etc.)
With cisplastin and diuretic therapy, it also occurs during chemotherapy with agents that promote mucositis.
Even low Zn levels correlate with higher mortality in cancer patients receiving high doses of antineoplastic drugs in chemotherapy, as occurs with bone marrow transplantation.
Chistudoss and co-workers report that zinc deficiency or excess appears to be involved in the development or progression of some types of cancer. In their experimental model, it is suggested that plasma zinc deficiency in tissue reserves and zinc-dependent enzyme activity are associated with the development of pre-neoplastic lesions, because such biochemical parameters decrease in proportion to the progression of colon cancer. as happens with bone marrow transplants,
Selenium, a trace element that acts through selenium proteins, some of which are enzymes such as glutathione peroxidase. Its functions include the promotion of body growth, prevention of pancreatic disorders, liver necrosis, degenerative diseases of the white muscle and the appearance of Keshan’s disease (juvenile cardiomyopathy).
It is important for neutrophilic and polymorphonuclear cytotoxicity. An important biological role is its recognized antioxidant power, which is secondary to selenoenzymes (glutathione peroxidase, selenoprotein P, thioredoxin peroxidase, immunomodulatory iodothyronine deiodinase: optimization of cellular and humoral immune response by improving the phenomenon of lymphocyte proliferation and phagocytosis.
During the state of hypercatabolism, a deficit in the nutritional status of selenium is created. Reactant in the acute phase. In critical illness (characterized by an inflammatory condition with oxidative stress), serum selenium levels fall early, with an inverse relationship between these events and mortality.
Manzanares suggests a selenium supplement of 450 ug / day for 14 consecutive days. For their part, Heiland and colleagues suggest a selenium intake of 100 μg / day in critical patients, while in large burns it should be 375 μg / day. They state that the dose of selenium is associated with a reduction in mortality in critically ill patients from 500 to 1000 mg / day.
Scientific opinion regarding the relationship between selenium and cancer risk is very mixed. It was initially seen as a possible carcinogenic system during the 1940s, and then as a possible protective agent between the 1960s and 2000s. More recently, controlled studies have found no effect on cancer risk, but suggest low dermatological dose and endocrine toxicity; in animals they indicate both carcinogenic and preventive effects.
Epidemiologically, the evidence reports that there are no cancer-related preventive effects in increasing selenium doses in healthy individuals, but if the risk of causing disorders and diseases of another nature, the form of organic or inorganic presentation may be dramatically different from these biological effects. Selenium deficiency is associated with cancer risk; it is even considered mineral chemotherapy.
336 patients (black and white race) with Se supplementation and placebo group were examined. After supplementation with Se, a direct association between Se and GSH in the blood was observed, resulting in a higher in whites than in blacks with p <0.01. (44). Se can be effective in preventing lung cancer, especially in people with low Se levels, however it should not be used as a general strategy. It reduces the level of toxicity in chemotherapy and radiotherapy in the same way.
Because cancer treatment and the type of cancer diagnosed affect the patient’s nutritional status, the nutritionist plays a key role in its progression and treatment. Antineoplastic treatments can produce micronutrient deficiencies, hence the importance of nutritional therapy, especially the studied micronutrients, in order to reduce the toxicity of such treatments in a timely manner and thus improve tolerance to them and the quality of the patient’s oncological life.