Micronutrients in the Prevention of Cancer: History
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Contributor:
Oladapo F. Fagbohun
,
Caroline R. Gillies
,
Kieran P. J. Murphy
,
H. P. Vasantha Rupasinghe

Cancer is an escalating global issue, with 19.3 million new cases and 9.9 million deaths in 2020. Therefore, effective approaches to prevent cancer are urgently required. Diet plays a significant role in determining cancer risk. Nutrients and food bioactives influence specific signaling pathways in the body. There have been significant advances in cancer prevention research through nutrigenomics or with the effects of dietary components on the genome.

  • antioxidants
  • cancer
  • nutrigenomics
  • vitamins

1. Introduction

Ancient civilizations frequently used minerals as treatments for disease, amulets, and talismans. The discovery of vitamins began in the late 19th century. It was observed that the health of people around the world was similar despite eating different foods; therefore, it was determined that the components of food contributed to heath. A variety of food, such as meat, seafood, grains, fruits, and vegetables, is required to obtain all the necessary micronutrients in the diet (Table 1). There are multiple diseases that are associated with deficiencies of micronutrients in the diets, such as scurvy, rickets, and pellagra [1]. The Vitamin Theory observed that animals fed a synthetic diet containing the known nutrients (macromolecules and salts) would not survive; therefore, other components in food contribute to survival. Casimir Funk coined the word “vital amines”, which was later shortened to “vitamin”. He proposed four vitamins: anti-beriberi, anti-rickets, anti-scurvy, and anti-pellagra. Later, Elmer McCollum and his assistant Marguerite Davis found two vitamins called fat-soluble A and water-soluble B. As vitamin research continued, all the vitamins were discovered, as well as provitamins (such as β-carotene), and their function was determined. It took 50 years to determine the structures and be able to synthesize all vitamins [2][3]. Overall, the continued research of biology, anatomy, physiology, and pharmacology has improved drug treatments and disease therapies.
Table 1. Summary of the nutrigenomic effects of micronutrients on the potential for prevention of cancer.
Micronutrient Food Sources Genes Affected Beneficial Effects Preventable Cancers References
Vitamin A Liver, fish oils, eggs, milk, leafy green vegetables JAK-STAT 1, RARs 2, RXRs 3, JNK 4, Pakt/pERK/Pegfr-genes Antioxidant, apoptosis, immune response Gliomas, lung, prostate, colon, breast [4][5][6][7][8][9]
Vitamin B1 (Thiamine) Pork, fish, legumes, yogurt, sunflower seeds p53/p21 affiliated 2-oxoglutarate thiamine pathway Cell upregulation All types of cancer [10]
Vitamin B2 (Riboflavin) Meat, fish, dairy products, eggs Weakly studied Cell upregulation targeted Breast [11]
Vitamin B3 (Niacin) Liver, meat, fish GPR109A activation. Tumor suppression Cell upregulation and inflammation All types of cancer [12]
Vitamin B5 (Pantothenic acid) Organ meats, chicken, mushrooms, nuts, seeds, milk Sodium-dependent multivitamin transporter (SMVT) pathway, pantothenate/pantetheine pathway Cell upregulation Solid cancer [13]
Vitamin B6 (Pyridoxine) Liver, poultry, fish, chickpeas, dark green leafy vegetables, bananas, oranges Sulfur and selenohomocysteine transsulfuration and transmethylation pathway Cellular metabolism under high oxidation states All types of cancer [14]
Vitamin B7 (Biotin) Liver, fish, eggs, avocados, sweet potato, nuts, and seeds Sodium-dependent multivitamin transporter (SMVT) pathway, pantothenate/pantetheine pathway Cell upregulation Solid cancer [13]
Vitamin B9 (Folate) Liver, seafood, beans, sunflower seeds, dark green leafy vegetables, fruits C4639T, SHMTI C1420T 9 Apoptosis, anti-inflammatory Colon, breast, prostate, pancreatic, cervical [5][6][7][15]
Vitamin B12 (Cobalamin) Meat, fish, eggs, dairy Methionine synthase pathway Apoptosis and cell anti-proliferation All cancer types [16]
Vitamin C Fruits and vegetables Bcl-2 5, 2-oxoglutarate-dependent dioxygenase pathway, ten-eleven translocase (TET) DNA demethylase pathway Antioxidant, apoptosis, immune response, prevent carcinogen formation, p53 upregulation, decreased ATP levels, suppression of antioxidant gene expression of NRFα Solid tumours, malignancies [6][7]
Vitamin D Fish, fortified milk and orange juice VDR Fok1 6, MKP5 7, NF-κB 8
Dysregulation of wnt/β-catenin metastasis		 Apoptosis, anti-inflammatory, cell–cell adherence Colon, prostate, leukemia, skin [5][6][15]
Vitamin E Peanuts, almonds, sunflower seeds and oil, pumpkin Transcriptional factor 3 (sFAT3), NF-kβ pathway, COX2 pathway, 5-lipoxygenase-catalyzed eicosanoids pathways Apoptosis, anti-inflammatory All cancer types [17][18]
Vitamin K green leafy vegetables CYP11A1-driven non-canonical metabolite pathway Apoptosis, anti-inflammatory, cell–cell adherence All carcinomas [19]
Selenium Organ meats, seafood, Brazil nuts p53, Rb 10, DNA methyltransferase pathway, histone deacetylase pathway Antioxidant, apoptosis, immune response, anti-inflammatory Leukemia, prostate, lung, colorectal, bladder, uterine, ovarian [7][9][20][21][22][23]
Zinc Red meat, poultry, milk, beans, nuts Component of many transcription factors and enzymes Antioxidant, p53 4, immune function All cancer types [9][20][24]
Copper Organ meats, shellfish, seeds, nuts Component of many transcription factors and enzymes Antioxidant, apoptosis, immune response, anti-inflammatory All cancer types [9][20][24]
Magnesium Legume dark green leafy vegetables, nuts, seeds Component of many transcription factors and enzymes Antioxidant, apoptosis, immune response, anti-inflammatory All cancer types [9][20][24]
Manganese Shellfish, nuts, soybeans, black pepper, coffee, tea Component of many transcription factors and enzymes Antioxidant, apoptosis, immune response, anti-inflammatory All cancer types [6][7][9][20][21][22][23]
Research on the medicinal uses and health benefits of minerals continued throughout the Middle Ages and continues today in the form of medical geology, which is a new field of study that focuses on the effects of minerals on the body. Malachite, a compound containing copper, was often used to treat wounds. Medical geology is a new field of study that focuses on the effect of minerals on the body [25].

2. Vitamin A and Carotenes

Vitamin A, or retinol, is present in animal products such as liver and eggs [8]. Carotenes, the precursors of vitamin A, are often found in plant-based foods [7][8]. For example, lycopene is a type of carotene that provides red color in tomatoes, and it is particularly important in the prevention of prostate cancer. Vitamin A is effective at reducing the risk of gliomas, lung cancer, colorectal cancer, and breast cancer [7][8]. As an antioxidant, vitamin A prevents DNA damage due to reactive oxygen species (ROS), which contributes to carcinogenesis [6][7][9]. The vitamin A metabolite retinoic acid amide inhibits the Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway, which prevents lung cancer by promoting apoptosis of pre-cancerous cells [7]. A study by Hu [26], using a case–control study to recruit 256 confirmed non-small cell lung cancer (NSCLC) patients, identified the association of vitamin A precursor protein with several types of cancer. The protein known as retinol-binding protein 4 (RBP4) was found to be relatively correlated to the risk of the growth of NSCLC. RBP4 families of protein are secretory molecules that bind and transport retinol from food sources after their release into the bloodstream as well as thyroxine carrier proteins to form retinol-RBP4 ternary complex for specific physiological functions. RBP4 specifically signals pro-oncogenic pathways by stimulating retinoic acid 6, which triggers their downstream activation. Furthermore, RBP4 also mediates the onset of insulin resistance. The association between vitamins and the cadence of lung cancer was studied among 38,207 men and 41,498 women in a cohort study involving 3.98 mg and 7.80 mg retinol, respectively [4]. There was an association between retinol and the risk of lung cancer, especially for men with small cell carcinomas. Therefore, the required and recommended dose needs to be implemented in dietary guidelines if vitamin A is to reduce the risk of several types of cancer.
Other uses of vitamin A involve immune functions with regulatory roles in cellular and humoral immune response [27], with the protection of epithelium integrity as the utmost priority. It also has effects on the RARs genes, which code for aminoacyl-tRNA synthetase; the RXRs genes, which code for retinoid X receptors; and the JNK genes, which code for c-Jun N-terminal kinases [7][9][28]. RARs are nuclear retinoic acid receptors involved in controlling the expression of specific subsets of genes in a ligand-dependent manner by binding specific response elements via a network of interactions with co-regulatory protein complexes directed by C-terminal ligand domain located within them as well as transrepressing other gene pathways alongside their involvement in the activation of translation, cellular differentiation, proliferation, and apoptosis of kinase cascades [29]; JNK, on the other hand, is known as c-Jun NH2-terminal kinase responsible for phosphorylating c-Jun at Ser-63 and Ser-73 and acts specifically since its discovery over 25 years ago as a tumor suppressor [28]. JNK is activated in response to stress and proinflammatory cytokines, such as IL-6 and TNFα, as well as mediating oncogenic transformation. This was discovered after analysis of JNK deficiency in mouse models suggested the correlation between loss-of-function mutations in the mkk-4 gene with aggressive tumor development and metastasis in human cancer [30]. Consequently, modulation of these genes has an impact on the function of these proteins resulting in changes in apoptosis, cell differentiation, and immune response [6][7].

3. Vitamin C

Vitamin C, also known as ascorbic acid, has cancer-preventing properties depending on the dose provided [7][20]. It can be found in many fruits and vegetables, such as citrus fruits, peppers, and broccoli [7]. For many decades, the role of ascorbate as an anticancer agent has been debated. Moreover, the unregulated use of vitamin C as a dietary supplement or pharmacologically applied intravenous infusion by cancer patients, with numerous reports of clinical benefits, has made it difficult to postulate authenticity. However, the lack of understanding of the mechanism of action has hindered the design of appropriate clinical trials. Vitamin C promotes apoptosis of pre-carcinogenic and carcinogenic cells at high doses but promotes cell differentiation of pre-carcinogenic and carcinogenic cells at low doses [7]. Several studies have linked the significant hydrogen peroxide production by the auto-oxidation of supra-physiological concentrations of ascorbate and stimulation of the 2-oxoglutarate-dependent dioxygenase family of enzymes with a co-factor requirement for ascorbate. Additionally, vitamin C acts as an antioxidant by reducing ROS to hydrogen peroxide. At high doses, hydrogen peroxide can accumulate in carcinogenic cells and cause apoptosis [7]. In an in vivo study carried out on laryngeal squamous cell carcinoma human subjects, vitamin C was shown to activate necrotic cell death mechanisms through ROS production as well as the stimulation of protein kinase C (PKC) signaling, thereby increasing cytosolic calcium and the reduction of the risks of malignancies [6][7].
The major precursor of vitamin C (ascorbate) potentially generates hydrogen peroxide, leading to oxidative stress, and thereby targeting cancer cells [31]. Dietary vitamin C, typically in low doses, can also cause apoptosis by acting on the Bcl-2 gene, a gene that codes for a protein that is anti-apoptotic and prevents the formation of N-nitrosamine carcinogenic compounds, causing an increased immune response [6][7]. Overall, high-dose vitamin C supplementation may be effective in preventing solid tumors and malignancies, but dietary vitamin C alone is insufficient in the prevention of cancer [7]. Recent data suggest ascorbate may have a promising role in the regulation of ten-eleven translocase (TET) DNA methylases, a major factor in tumor survival, angiogenesis, stem cell phenotype, and metastasis. Since it is highly soluble in water, it is readily acquired and distributed with constant turnover. More recent studies link the mechanism of action in cancer regulation to increased cell cycle arrest, p53 upregulation, decreased ATP levels, compromised mitochondrial function, suppression of antioxidant gene expression of Nrf-2, or cell death by apoptosis.
Although, the similar structure of dehydroascorbate and glucose means it can be taken up into the cells via GLUT transporters and then reduced by either GSH, NADH, or NADPH-dependent enzymes, thus exhausting the cell of necessary molecules and, hence, upregulation of GLUT1 in KRAS and BRAF mutant cells to account for the antitumor activity of vitamin C in colorectal cancer. Given its lack of toxicity, that it is readily available, and its low cost, vitamin C is a potential cancer-preventive agent. However, a robust clinical trial is needed to ascertain its potency.

4. Vitamin D

Vitamin D can be obtained from fish, dairy, eggs, and mushrooms, or synthesized in the skin from cholesterol in the presence of sunlight [8]. It is important for maintaining the metabolism of minerals, primarily calcium and phosphorus, in the intestine, kidneys, and bones [8][15]. This lipid-soluble vitamin participates in all proliferation, apoptosis, differentiation, metastasis, and angiogenesis [32]. Liu and colleagues [32] showed the relationship between vitamin D and lowering the risk of lung cancer as well as breast cancer and its better prognosis. The study included 813,801 human subjects from different environments in Europe and the nutrigenetic effect of vitamin D was clearly studied by determining the various signaling pathways involved in mutation to K-Ras and epidermal growth factor receptors as well as proteins involved in metastasis and proliferation of cancers such as the dysregulation of Wnt/β-catenin. Since vitamin D is synthesized by the skin and tightly regulated by sunlight exposure, lack of exposure has been discovered to increase the risk of the development of many deadly cancers. However, it is estimated that there is about 30–50% reduction in the risk of breast, colorectal, and prostate cancer by either increasing sunlight exposure or vitamin D intake to about 1000 IU/d [33]. After synthesis, it is hydroxylated in the liver to 25-hydroxyvitamin D (25(OH)D), the major form of vitamin D. Several studies suggested that the relationship between vitamin D and protection against breast cancer [34].
The mechanism by which vitamin D reduces cancer risks has been attributed to the inhibition of cancer-promoting signaling pathways, including mutations in epidermal growth factor receptor (EGFR) and the dysregulation of Wnt/β-catenin, which determines proliferation and metastasis [32][35]. Furthermore, vitamin D exerts its cancer-prevention effects by upregulating the secretion of E-cadherin and catenin, which aids in cell–cell adherence to prevent metastases and repress the expression of cyclooxygenase 2 (COX2), thereby inhibiting prostaglandin synthesis, which can stimulate tumor cell proliferation and angiogenesis. Vitamin D deficiency is associated with an increased risk of oral, breast, ovarian, prostate, and colon cancer [7][15]. Chronic inflammation of tissues provides an environment that promotes cancer cell growth [15]. The vitamin D receptor (VDR) can target genes with roles in inflammation, cell growth, and cell differentiation [7]. There are polymorphisms of the VDR genes that can determine an individual’s susceptibility to a type of cancer. For example, the VDR Fok1 gene polymorphism increases the risk of oral cancer because apoptosis is reduced [7][36].
Vitamin D can reduce inflammation by regulating the inflammatory pathway [15]. This involves downregulating genes that initiate cancer, such as MAP kinase phosphatase 5 (MKP5), nuclear factor kappa B (NF-κB), and leukocytes [6][32]. These nutrigenomic effects make vitamin D effective at reducing the risk of leukemia, colorectal, breast, prostate, and pancreatic cancer [5][6][7]. In a Mendelian randomization study where four single nucleotide polymorphisms (RS2282679, RS10741657, RS12785878, and RS6013897) were associated with vitamin D, there was little evidence for a linear casual association between circulating vitamin D concentration and risk of various types of cancer [37]. Finally, recent studies have proven beyond a reasonable doubt that vitamin D obtained from food (fish, dairy, eggs, and mushrooms) can be metabolized and activated through a CYP11A1-driven non-canonical metabolite pathway, and its dysregulation promises new methods for vitamin D-based cancer therapies [36][38].

5. Vitamin E

Food sources rich in vitamin E (tocopherols) are nuts, plant seeds, and oils. Humans rely on these food sources to obtain vitamin E. Until the 20th century, many selenium and vitamin E cancer preventions (SELECT) and α-tocopherol and β-carotene cancer prevention (ATBC) trial studies focused on α isoform of vitamin E (α-tocopherol) with no meaningful results on its anticancer effects. A paradigm shift to other isoforms of tocopherols gave an insight into the signaling pathway regulated by vitamin E [17]. The mechanism by which vitamin E exerts its anticancer effects includes scavenging reactive nitrogen and oxygen species, anti-angiogenic effects, inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase enzyme, and inhibition of the nuclear transcription factor (NF-kB) signaling pathway [18]. Other forms of vitamin E (β, δ, and ɣ) are important antioxidant vitamins. Similar to vitamin D, tocopherols also inhibit multiple pathways that promote cancer progression, such as COX and 5-lipoxygenase-catalyzed eicosanoids [32].
Of interest, vitamin E regulates and activates transcriptional factor 3 (sFAT3). This evidence strongly suggests that the forms of vitamin E can protect against cancer or act as an adjuvant for improving cancer therapy. The uniqueness of vitamin E is found in its chromanol ring and phytyl side chain. The saturated side chain known as tocotrienols with three double bonds on the side chain of vitamin E makes it capable of scavenging lipid peroxide radicals by donating hydrogen bonds, while the phenol group on the chromanol ring makes it a good antioxidant source by effectively quenching free radicals via one-electron reduction, thereby preventing the propagation of free radical reactions in lipid peroxidation [39]. In essence, little is still known about the anticancer properties of vitamin E and its precursors, which offers research opportunities for scientists to explore in the future [18].

6. Vitamin K

Vitamin K is necessary for blood clotting and the prevention of bleeding. It is found in leafy green vegetables, meats, dairy, and eggs. Limited evidence exists on the association between vitamin K and cancer. However, there is growing evidence that vitamin K is involved in tumorigenesis [3]. Refolo and colleagues postulated that vitamin K2 inhibits cancer cell proliferation in HepG2 and HLF human cell lines through downregulating PI3K/Akt signaling [19]. In the cancer and nutrition Heidelberg cohort study of 24,340 cancer-free patients, there was a significant inverse association between vitamin K2 intake and cancer mortality [40]. The mechanism of action of the signaling pathway of whether vitamin K is either upregulated or downregulated is not yet elucidated. However, the undercarboxylated form of prothrombin, a precursor of vitamin K, is upregulated in lowering the risk of HCC signaling [3][41]. More studies are needed to ascertain the hypothesis that vitamin K-related pathways can be used to diagnose, treat, and prognosticate a number of cancer-related diseases.

7. Vitamin B

There are eight B vitamins, each with specific functions in the body. B vitamins are one of the most important groups of vitamins owing to their direct impact on cell metabolism, brain functions, and energy levels. In general, they are necessary for the production of hormones and neurotransmitters, the breakdown of macronutrients, and immune function [42][43]. The latter functions suggest the current treatment methods that scientists are looking into for the management of cancer patients. The B vitamins can be obtained by consuming a variety of fruits, vegetables, and animal products [42][43] since most mammals cannot synthesize them on their own. Recent data showed that cancer patients are often deficient in vitamin B1, especially those undergoing chemotherapy; therefore, there is a signal of genetic alteration in cancer patients. Thiamine has effects on transcriptional activities of the master metabolic regulator and genome guardian p53, in which the direct target of genome guardian regulates cell cycle dynamics and DNA damage response. One mechanism of action of the correlation between vitamin B and cancer is related to a p53/p21-dependent change in the partitioning of glutamate conversion of 2-oxoglutarate through glutamate oxaloacetate transaminase (GOT2) or the glutamate dehydrogenase (GDH)-linked NAD(P)-dependent metabolism of 2-oxoglutarate in the affiliated thiamine pathway [10]. The study between vitamin B2 and breast cancer in a 2017 metastasis analysis involving 12,268 breast cancer human subjects showed a weak correlation, suggesting a low association with cancer therapy [11]. On the other hand, vitamin B3 is related to GPR109A activation, which functions as a tumor suppressor with effects on lipids and tissue-specific regulation of metabolism and inflammation [12], while vitamin B6 (pyridoxal phosphate) modulates the fate of sulfur and selenohomocysteine between transsulfuration and the transmethylation pathway in cellular metabolism under high oxidation states linked directly to cancer therapy in recent and modern research [12]. Furthermore, deficiencies of vitamin B5 are very rare but linked to inflammation and cancer. Uptake requires sodium-dependent multivitamin transporter (SMVT), the same transporter of vitamin B7 (biotin). More studies are, therefore, required to understand the role of vitamin B7 in cancer therapy. However, analysis of pantothenate shed light on the role of pantetheine in human health [13]. Moreover, elevated B12 has been linked to the development of cancer in two recent studies [16]. This is because vitamin B12 is a co-factor of methionine synthase implicated in methylation reaction as well as the synthesis of purine bases, which are crucial in tumor-initiating cells and cell proliferation. Although, the mechanism is poorly understood and more studies are required [16]. Finally, vitamin B9 is referred to as folate, the natural form present in foods, and folic acid, the synthetic form found in supplements and fortified food [5][6][7][20][38]. Similar to vitamin C, the effect depends on the amount consumed [38]. Low concentrations of folate in the blood are associated with double-stranded breaks in the DNA caused by the insertion of uracil, which can then cause carcinogenesis due to mutation [7]. Low folate is associated with colorectal, pancreas, prostate, or breast cancer [38]. However, high amounts of folate are associated with the formation of pre-cancerous cells as well [7][20][38]. This is because folate is a co-factor for enzymes involved in RNA and nucleotide synthesis by donating a methyl group [20]. When the amount of folate in the body is too high, increased methylation leads to increased carcinogenesis due to polymorphisms of the C4639T and serine hydroxymethyltransferase 1 (SHMT1) C1420T genes [7]. Therefore, it has been found that folic acid supplements are not necessary because North Americans receive enough from foods naturally containing folate and fortified foods (Araghi et al., 2019; Nasir et al., 2020). Overall, folate is effective at reducing the risk of gastric, colorectal, breast, and pancreatic cancer [5][6][7].

This entry is adapted from the peer-reviewed paper 10.3390/ijms24076092

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