Folic acid: friend or foe in cancer therapy

Abstract

Folic acid plays a crucial role in diverse biological processes, notably cell maturation and proliferation. Here, we performed a literature review using articles listed in electronic databases, such as PubMed, Scopus, MEDLINE, and Google Scholar. In this review article, we describe contradictory data regarding the role of folic acid in cancer development and progression. While some studies have confirmed its beneficial effects in diminishing the risk of various cancers, others have reported a potential carcinogenic effect. The current narrative review elucidates these conflicting data by highlighting the possible molecular mechanisms explaining each point of view. Further multicenter molecular and genetic studies, in addition to human randomized clinical trials, are necessary to provide a more comprehensive understanding of the relationship between folic acid and cancer.

Introduction

Folate is the natural form of vitamin B9. It is water-soluble and naturally found in plants and vegetables, such as dark leafy greens, citrus fruits, and meat products. Folate is also added to foods and sold as a supplement in the form of folic acid. In fact, this form is better absorbed than the folate form from food sources, 85% vs. 50%, respectively. This essential nutrient is a crucial part of many diverse biological processes. For example, it has an indispensable role in cell maturation and nucleotide synthesis through the methylation of uracil to thymine, which is essential for DNA synthesis and repair.^1,2 Moreover, folate metabolism is fundamental to both normal and cancer cell proliferation. Previous studies have suggested that folic acid has homocysteine lowering effects and is possibly beneficial for the prevention of cardiovascular disease (CVD) and stroke.^3,4 On the contrary, folic acid might also promote the progression of atherosclerosis because of its stimulatory effect on cell proliferation. After it was discovered that insufficient folate levels are linked to birth defects of the spine (spina bifida) and brain (anencephaly),^5–7 folic acid supplementation began being advised for women planning to conceive or those already pregnant as a proactive measure. This can help promote optimal fetal development and support a healthy pregnancy journey. Furthermore, not getting enough folic acid can lead to megaloblastic anemia. ⁸

There are several conflicting studies regarding the relationship between folic acid and cancer risk.^9–12 Some reports have shed light on the protective effect of folic acid. Recent trials have suggested that taking folic acid, particularly during the preconception period and pregnancy, can prevent certain types of cancer, such as acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), by reducing the risk of chromosomal abnormalities. ¹³ In addition, other studies have shown that increased folate intake is significantly associated with a diminished risk of head and neck squamous cell carcinoma. ¹⁴ In a case–control study by Li et al., a remarkable correlation was found between insufficient folate serum levels and an increased risk of cervical intraepithelial neoplasia (CIN) and cervical cancer. ¹⁵ Other data from multiple studies showed that DNA methylation can serve as a biomarker for detecting colorectal cancer (CRC). ¹⁶ Additionally, folic acid supplementation can increase DNA methylation levels in colonic tissues and leukocytes. A literature review reported that the risk of rectal cancer is higher in people who have Kirsten rat sarcoma (K-Ras)-mutated tumors with high folate consumption. ¹⁷ Furthermore, research has indicated that high folate levels in heavy smokers can possibly exacerbate the cancer-causing effects of smoking. ¹⁸

In this review, we delve into the contrasting data surrounding folic acid and its impacts on cancer risk. We describe the molecular mechanisms through which folic acid can induce cancer in certain individuals, while also highlighting the molecular pathways that may protect against cancer.

Folic acid and cancer protection

Folate plays a pivotal role in the prevention and management of various types of cancer. Several studies have demonstrated its influence on cancer risk and progression. Hwang et al. reported that elevated folate levels can impact S-adenosylmethionine (SAM) concentrations, thereby influencing cytochrome P450 2E1 (CYP2E1) expression levels and reducing the risk of oral cancer. ¹⁹ Another study investigated the association between folate intake and reduced risks of esophageal adenocarcinoma and squamous cell carcinoma in high-risk populations. ²⁰ Notably, these cancers are often associated with high alcohol and tobacco consumption, which can impair folate levels and thereby compromise genetic integrity. ²¹ In lung cancer, several studies have suggested that higher folate intake, both from dietary sources and supplements, may have a protective effect. ²² There is also emerging evidence that higher intake of nutrients related to one-carbon metabolism can lower the risk of renal cell cancer. ²³ The intake of folic acid and multivitamin supplements may decrease the risk of leukemia, a common cancer among children under 15 years of age. ²⁴ Maternal supplementation of folic acid has been linked to a reduced risk of ALL. ²⁵ Williams and colleagues demonstrated in their research that folate has the potential to prevent sunlight-induced DNA damage and consequently reduce the risk of skin cancer. ²⁶ Additionally, the photodegradation of folate by solar ultraviolet (UV) radiation may explain the better cancer prognosis observed in summer compared with winter months. ²⁷ Observational studies have similarly indicated that adequate folate intake might reduce the risk of colon cancer ²⁸ and breast cancer (BC), ²⁹ particularly among individuals who consume alcohol. Furthermore, small clinical trials conducted over periods ranging from 3 months to 2 years have shown improvement in CRC biomarkers with folic acid supplementation exceeding 0.4 mg/day. ³⁰ Interestingly, the Nurses’ Health Study found that higher folate intake could mitigate the increased risk of BC observed in women who consume more than one alcoholic drink per day. ³¹ Additionally, various reports have suggested a synergistic interaction between folate intake and reduced colon cancer risk. ³² A case–control study in Uruguay found an inverse relationship between folate intake and the risk of various cancer types. ³³ Similarly, increased folate intake has been associated with a decreased risk of pancreatic cancer in women, although no significant effect was observed in men, possibly because of sex-related differences.^34,35 However, data from another study did not corroborate these associations. ³⁶ Work by Butterworth and colleagues elucidated that inadequate levels of folic acid are related to an increased risk of cervical dysplasia, with folate supplementation leading to regression of the dysplastic lesions. ³⁷ Mullin mentioned that folate had a protective effect against cancer initiation. However, after preneoplastic tumor formation, it may also help against cancer progression. ³⁸ Finally, high folate consumption (≥300 μg per day) has been linked to a decreased risk of ovarian cancer, further underscoring the role of this nutrient in cancer prevention. ³⁹

Protective mechanisms of folic acid in cancer

Folic acid plays a critical role in various biological processes, including DNA synthesis, repair, and methylation, making it essential for cell growth and division. ⁴⁰ Folic acid has been studied for its potential protective effects against certain types of cancer, particularly when it is obtained through dietary sources or supplements. Below, we discuss some mechanisms through which folic acid may offer protection against cancer.

The role of folic acid role in DNA synthesis

Folates are crucial for the synthesis of purines and pyrimidines, which are necessary processes for accurate DNA replication. Adequate folate levels can reduce the likelihood of errors in the genetic code. This is critical for preventing DNA damage and mutations, which are key contributors to cancer development. With folic acid depletion, the conversion of dUMP cannot proceed, leading to its abnormal intracellular accumulation and misincorporation into DNA in place of thymine. ⁴¹ Excessive uracil content can cause point mutations, single- and double-strand DNA breaks, chromosome breaks, and micronuclei formation.^42,43 Folate supplementation, along with vitamin B12, was shown to reverse the potential precursors of bronchial squamous cell carcinoma in the lungs, providing a biological basis for the protective effect of folate in reducing lung cancer risk. ⁴⁴ Folate is also involved in DNA repair mechanisms. Damaged DNA is more likely to accumulate genetic mutations that can lead to uncontrolled cell growth, which is a hallmark of cancer. ⁴⁵

Effects of folic acid on gene expression

Folates act as methyl group donors and are involved in DNA methylation, an essential epigenetic process that influences gene expression. Aberrant DNA methylation patterns, such as hypermethylation of tumor suppressor gene promoters or hypomethylation of oncogene promoters, are commonly observed in cancer cells.^46,47 DNA hypomethylation of oncogenes and hypermethylation of tumor suppressor genes are observed in pancreatic cancer. ⁴⁸ Studies have shown that when patients with colorectal neoplasms are treated with high doses of folic acid, proper DNA methylation patterns can be restored. ⁴⁹ Low folate levels, along with a methionine deficiency, can disrupt DNA methylation patterns, including methylation of a CpG island in the estrogen receptor (ER) gene. This has been suggested to potentially contribute to a higher incidence of ER-negative breast tumors.^50,51 Disrupted methylation is not limited to altered gene expression. Demethylation of centromeres can cause structural and functional aberrations within the chromosome, notably during mitosis, which lead to abnormal chromosome segregation and aneuploidy. ⁵² Several studies have revealed a connection between folic acid deficiency and the incidence of aneuploidies involving chromosomes 17 and 21, which are commonly observed in BC and leukemia.^53,54 Similarly, chromosome 8 ⁵⁵ has been found to exhibit abnormal numbers in prostate cancer, skin cancer, BC, cholesteatoma, and leukemia. Notably, trisomy 8 is a recurrent chromosomal abnormality in AML, making it a recognized cytogenetic marker for AML.^56,57

Antioxidant properties of folic acid

Research has revealed that folic acid acts as a potent scavenger of free radicals and can effectively protect physiological components from oxidative stress. Despite its water-soluble nature, folic acid can also inhibit lipid peroxidation. The ability of folic acid to scavenge and repair thiyl radicals positions it as a potential antioxidant vitamin. ⁵⁸ Sunlight is the major source of skin damage through direct DNA damage from the formation of pyrimidine dimers and other photoproducts. ⁵⁹ Indirect damage can also occur via reactive oxygen species (ROS) and reactive carbonyl species (RCS) generation by photooxidation and photosensitization reactions.^60–62 Chronic DNA damage results in progressive losses of genomic integrity and end-stage skin damage in the form of skin cancer. ⁶³ Most human papilloma virus (HPV) infections clear on their own without causing cervical abnormalities. ⁶⁴ However, the persistence of genital HPV infections can lead to CIN and invasive cervical cancer, influenced by various infectious, behavioral, and lifestyle-related cofactors.^65,66 Lifestyle factors, such as smoking, exercise, and diet, can generate ROS, leading to oxidative stress and damage to biomolecules like lipids, proteins, and DNA. Oxidative stress is linked to several chronic diseases, including various cancers. Antioxidant deficiency can make an individual more susceptible to oxidative stress and thereby increase their cancer risk. Notably, exogenous antioxidant supplementation has been shown to reduce oxidative damage by scavenging ROS and decreasing the oxidation of cellular molecules. ⁶⁷ Thus, dietary patterns can play a preventative role in various cancers, especially those of epithelial origin. ⁶⁸

Role of folic acid in homocysteine regulation

Folate is involved in converting homocysteine into methionine. ⁶⁹ Elevated homocysteine levels are associated with a higher risk of various diseases, including certain cancers.^70,71 In diabetes patients, plasma homocysteine levels can be elevated in insulin-resistant states (lowered by insulin). ⁷² Therefore, adequate folate intake can help reduce homocysteine levels, potentially lowering the risk of pancreatic cancer. ⁷³

Folic acid and collagen synthesis

Folate also participates in the synthesis of collagen, a structural protein in the skin. Healthy skin with proper collagen structure can provide better protection against UV radiation and may reduce the risk of skin cancer. ²⁶ Additionally, cervical tissues benefit from proper collagen structure, making them more resistant to infections and cancerous changes. ⁷⁴

Regulatory effects of folic acid on enzymes

S-adenosyl methionine is a naturally occurring compound that is produced as the body processes folate. One of its functions is regulating the expression and activity of CYP2E1, which converts ethanol into acetaldehyde and is primarily expressed in the liver. Increased folate levels can have an inhibitory effect on CYP2E1 expression. ⁷⁵ Acetaldehyde is recognized as a potentially carcinogenic substance and is considered a contributing factor to oral cancer development. ⁷⁶ Aldehyde dehydrogenase 1 (ALDH1), an enzyme responsible for metabolizing aldehydes like acetaldehyde, is regulated by three known response elements: nuclear factor Y (NF-Y), CCAAT/enhancer-binding protein-β (C/EBPβ), and retinoic acid receptor-α (RARα). Folate interacts with one of these response elements to enhance the expression of the ALDH1A1 and ALDH1L1 genes. This interaction may potentially help reduce cancer risk by lowering acetaldehyde levels and improving DNA stability. ¹⁹

Overall, the relationship between folic acid and cancer is not entirely straightforward. In some cases, high-dose folic acid supplementation may have the opposite effect and potentially promote cancer, as discussed below. This is particularly relevant for individuals with pre-existing cancer or precancerous lesions. Additionally, the protective effects of folic acid may vary depending on the type of cancer. Figure 1 summarizes the currently known molecular mechanisms of the folic acid-mediated protective effects against cancer.

Figure 1.

Molecular mechanisms of the protective effect of folic acid against cancer. These mechanisms include its role in nucleotide synthesis, DNA methylation, homocysteine metabolism, DNA repair, and reduction of oxidative stress. ALDH1, Aldehyde Dehydrogenase 1; CYP2E1, Cytochrome P450 2E1.

Potential carcinogenic effect of folic acid

Despite the aforementioned studies, some reports have discussed an association of elevated folate intake with an increased risk of cancer progression. A literature review indicated that excessive intake of folate can increase the likelihood of precancerous cell growth. ¹⁷ A randomized clinical trial (RCT) indicated a correlation between folic acid supplementation and an increased risk in pre-existing lesions and adenoma multiplicity. ⁷⁷ There has been substantial interest in this topic. The interaction between folic acid and CRC is more complex. Several studies have revealed that individuals older than 50 years of age who take B vitamins, like B9 and B12, have a high risk of cancer, particularly CRC.^78–80 A nested case–control study performed by Van Guelpen et al. over a 4-year follow-up period showed that participants with elevated plasma folate levels had an approximately four-fold higher risk of CRC than those with lower levels. ⁸¹ A large multicenter trial was conducted on a resected colorectal adenoma population who were randomly given either 1 mg of folic acid or a placebo over a 3- to 5-year follow-up period. Follow-up colonoscopy showed no protective impact of folic acid supplementation. ⁷⁷ In fact, additional work found a notable risk in the multiplicity of recurrent adenomas with supplementation, as well as a marginally significant increase in “high-risk” adenomas. ⁸² In controlled studies in a variety of colon cancer animal models, a setting in which neoplastic tumors are already present, intake of folic acid was no more protective. With established foci, additional microscopic foci and macroscopic tumors rapidly arose along with supplementation.^83,84 A potential link between lung cancer and folic acid intake has become a subject of interest. Stanisławska-Sachadyn and colleagues reported that folate levels above the median value (>17.5 nmol/L in the healthy controls) were associated with a high risk of lung cancer among smokers. It was also believed that smoking carcinogenicity was increased with the addition of folic acid intake in the heavy smoker population. Additionally, women with the solute carrier family 19 member 1N (SLC19A1) genotype and folic acid supplementation are at high risk of lung cancer. ⁸⁵ Treatment with folic acid plus vitamin B12 was found to be related to increased cases of cancer and all-cause mortality in patients with ischemic heart disease in Norway, mainly driven by increased lung cancer incidence in participants. ⁸⁶ The connection between folic acid and prostate cancer has also been a research focus. In a study conducted by Rycyna et al., increased blood folate levels were believed to play a role in prostate cancer development. ⁸⁷ The results of a meta-analysis also supported this finding, ⁸⁸ along with those of the Aspirin/Folate Polyp Prevention Study (AFPPS) trial, which followed patients with folic acid supplementation over 10 years. ⁷⁷ Moreover, a study on cardiovascular patients who took folic acid to reduce homocysteine levels showed a high incidence of prostate cancer among men with a mean age of 60 years. ⁸⁸ In a randomized trial, men who received folic acid as a preventative measure for colon polyp recurrence had increased prostate cancer diagnoses. ⁸⁹ Likewise, Zhang et al. reported that routine intake of folate >400 µg/day could enhance the risk of BC. ⁹⁰ A leading study observed a considerable positive association between total folate and supplemental folic acid intake amounts with postmenopausal BC. ⁹¹ A trial was conducted among a population of pregnant women, with those who were randomly given the highest folic acid dose (5 mg/day) having a 70% greater risk of total cancer than the placebo group. ⁹² In the 1940s, clinical investigators gave huge doses of folic acid to individuals with acute leukemia. Subsequently, the proliferation rate of the leukemic clone increased enormously,^93,94 corresponding to what Sidney Farber politely termed ‘‘the acceleration phenomenon’’. ⁸² A cohort study was performed to explore the interrelationship between childhood cancer risk and high-dose folic acid consumption in mothers with epilepsy. The researchers found that prenatal exposure to a high-dose of folic acid could increase the risk of cancer by three-fold in the children of mothers with epilepsy who had filled the prescriptions for anti-seizure medication. However, the children of mothers with epilepsy who filled the prescriptions for anti-seizure medication, but not for high-dose folic acid, did not have an increased risk of cancer. In the folic acid-exposed groups, leukemia was the most common cancer type, followed by lymphoma and central nervous system tumors. ⁹⁵

Molecular mechanisms of potential carcinogenic effects of folic acid

The roles of folate in nucleotide synthesis and as a cofactor in the rate-limiting step of DNA synthesis, ⁹⁶ makes it a probable growth factor for neoplastic cells. ⁸² Aggressively dividing cells, such as those present in solid tumors, have high consumption rates of particular vitamins. As a result, there is overexpression of the receptors responsible for the uptake of those vitamins. ⁹⁷ Additionally, many cancer cells can upregulate the expression of membrane receptors that mediate folate uptake, as well as the expression of certain critical folate-dependent enzymes that are necessary for DNA synthesis.^98,99 There are two folate receptors, folate receptor α (FR-α) and FR-β, which are both expressed in malignant tissues of epithelial and non-epithelial origin. ⁹⁷ Furthermore, they have been detected in ovarian carcinoma (>90%), lung cancer (50%), BC (25%), endometrial cancer, renal cancer (50%), CRC (including Caco-2 cells), and cancers of myeloid hematopoietic cells, the brain (66%), and placental cells. ⁹⁷ FR expression levels in tumors have also been directly associated with the tumor stage. ⁹⁷

CRC

One potential mechanism behind the folic acid-mediated promotion of CRC growth is its ability to provide nucleotide precursors to rapidly replicating neoplastic cells. These precursors can facilitate accelerated cell proliferation and growth. Because nucleotides are the fundamental building blocks of DNA, rapidly dividing cancer cells require a substantial supply of nucleotides for DNA replication. Folic acid can stimulate nucleotide synthesis, giving cancer cells growth and proliferation advantages. ¹⁰⁰ Additionally, folic acid can possibly promote CRC through de novo methylation of promoter CpG islands of tumor suppressor genes. This process can lead to gene inactivation, which contributes to tumor progression. The addition of methyl groups to DNA at CpG islands is an epigenetic modification that can silence gene expression. Tumor suppressor genes act as safeguards against uncontrolled cell growth and proliferation. ¹⁰¹ When these genes are silenced through DNA methylation, cancer cells can grow and multiply without restraint. ⁹ The ability of folic acid to provide methyl groups can enhance the DNA methylation process, ultimately leading to the suppression of tumor suppressor gene expression and increased CRC growth and progression. E-cadherin, a transmembrane glycoprotein and member of the cadherin family of cell adhesion molecules, mediates cell–cell adhesion via calcium-dependent interactions. E-cadherin may function as a tumor suppressor gene in tumor invasion and metastasis. ¹⁰² Pellis et al. concluded that the presence of high folic acid levels (100 ng/mL) are associated with a significant decline in E-cadherin expression levels in colon cancer cells in vitro. ¹⁰³

Lung cancer

Polymorphisms in folate metabolic pathway genes have been demonstrated to alter serum folate levels. The 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme can affect folate distribution for DNA synthesis and methylation. Individuals with the MTHFR 667 C->T genotype have been found to have an increased risk of lung cancer. People with at least one variant allele for MTHRF 667 and serine hydroxymethyltransferase (SHMT) also displayed a higher lung cancer risk compared with wild-type carriers for both genes.^104,105 Another study showed that the SLC19A1 c.80>A genotype was associated with lung cancer risk, while the SLC19A1 c.80AA genotype correlated with a higher risk in women and a lower risk in men, contrary to the GG genotype. ⁸⁵

Prostate cancer

Folate has an essential role in the synthesis of nucleotides that are required for neoplastic cell proliferation. Folate receptor expression levels are also increased in several cancer types. ⁹⁸ PSMA, a type II membrane protein with glutamate carboxypeptidase activity, is overexpressed in prostate cancer when folate hydrolase is active.^106,107 Elevated PSMA expression levels are correlated with higher tumor grade, higher Gleason score, and disease recurrence.^108,109 Folate also has a key role in DNA methylation.^110,111 Changes in methylation patterns involving global DNA hypomethylation ¹¹² and gene-specific hypomethylation ¹¹³ appear to be important molecular events in prostate cancer. One study showed that the MTHFR A1298C genotype is associated with a two-fold higher risk of low-grade prostate cancer. A positive correlation was observed between serum folate levels and prostate cancer incidence with a dose-response relationship among men of predominantly African origin. For the MTHFR A1298C, MTHFR C677T, MTRR A66G, and MTR A2756G polymorphisms, men who had both high folate concentrations and a variant genotype showed a greater likelihood for total prostate cancer incidence compared with men with low folate concentrations and wild-type genotypes. ¹¹⁴

BC

Folic acid can contribute to epigenetic changes in gene-regulatory mechanisms, which may lead to gene silencing and enhanced BC development. ⁹⁷ It can also promote the growth of tumors that express FR-α, which is approximately 25% of BC cases. ⁹¹ A cohort study conducted on triple negative breast cancer (TNBC) patients detected FR-α overexpression, which may confer a growth advantage to epithelial tumors by improving folate uptake. Therefore, these TNBC patients may benefit from targeted anti-FRα therapy. ¹¹⁵ Very high folic acid intake can possibly enhance the growth of an existing breast neoplasm or cancer. ⁸⁰ Because of this, folic acid deprivation with anti-folate chemotherapy, such as 5-fluorouracil, methotrexate, or other drugs that interfere with thymidylate uptake and ultimately DNA synthesis, is considered a sufficient treatment approach for BC patients. ¹¹⁶ Figure 2 summarizes the molecular mechanisms of the potential carcinogenic effects of folic acid.

Figure 2.

Molecular mechanisms of the carcinogenic potential of folic acid. CpG, Cytosine-phosphate-Guanine; E-Cadherin, Epithelial Cadherin; FR-α, folate receptor-alpha; FR-β, folate receptor-beta; MTHFR, methyltetrahydrofolate reductase; SHMT, serine hydroxymethyltransferase; SLC19A1, Solute Carrier Family 19 Member 1.

The impact of folate on cancer risk is influenced by several factors. Timing plays a critical role, as folate appears to be more protective during early developmental stages, such as fetal development or periods of rapid cell division, like pregnancy.^13,24,25 However, its effects may differ during adulthood, particularly among individuals with pre-existing cancer or precancerous lesions. ³⁴ The specific dosage of folate is another key factor to consider. While moderate dietary intake of folate is generally considered beneficial, high-dose folic acid supplementation can yield contrasting effects. Excessive supplementation can lead to unexpected consequences, potentially promoting cancer growth, especially among individuals with specific genetic mutations.^117,118 Furthermore, individual variability is a significant factor. Responses to folate can vary based on genetic factors, including mutations in specific genes that are related to folate metabolism. ¹¹⁹

Mandatory fortification of folic acid

Food fortification is the insertion of essential micronutrients that are lacking in a population’s diet into commonly consumed foods during processing. ¹²⁰ This process was a milestone that can help reduce micronutrient deficiencies in different aspects. ¹²¹ Undoubtedly, these deficiencies can affect an individual’s survival, as well as their mental and physical development, which in turn can influence the economies of countries.^122,123 Indeed, a large portion of the population must be treated to have a significant positive effect on public health. ¹²⁴ Given these issues, mandatory fortification programs have been implemented in many countries to maximize their effects and reduce the high costs associated with prevention programs, such as education campaigns and other intervention methods that require behavioral changes. ¹²⁵

Folic acid is one critical micronutrient that can be delivered by fortification and is considered one of the most significant public health interventions worldwide. ¹²⁶ Folic acid intervention by flour fortification (wheat or maize flour fortification) has been done in over 80 countries. ¹¹⁴ Periconceptional supplementation to reduce a childbearing age woman’s susceptibility to having an infant with a neural tube defect (NTD) ¹²⁷ can also be performed. The association of NTDs and folate has been one of the most successful public health initiatives in the past 50 to 75 years, ¹²⁸ with a recommended folic acid dose of 400 μg per day to prevent NTDs. ¹²⁹ Surveys in the United States have indicated a decline of 19% to 32% in NTD prevalence since the initiation of folic acid fortification in 1998.^130–133 Additionally, Canada, South Africa, Costa Rica, Chile, Argentina, and Brazil have shown declines in NTDs (19% to 55%) since fortification began.^134–143 Some unintended benefits have also been observed with folic acid fortification. These include elevated hemoglobin concentrations and a lower CVD risk, mainly by a reduction of total homocysteine (tHcy), an independent risk factor of CVD. ¹⁴⁴ Enhanced cognitive function is also an observed benefit. ¹⁴⁵ A collective analysis of six RCTs mentioned that a depression score reduction occurred with folic acid supplementation. Even people who are diagnosed with depression or at risk of depression must ensure they have the appropriate amount of folic acid. ¹⁴⁴

There are some concerns regarding folic acid fortification, despite the reduced incidence of NTDs discussed above. ¹²⁷ It can potentially lead to massive consumption levels, which might result in adverse effects. It may be necessary to continue monitoring fortification interventions to quickly identify any emerging concern and investigate it further. ¹⁴⁶ These potential adverse effects include the masking of vitamin B12 deficiency anemia, which can progress to neuropathies. This would delay the diagnosis of the anemia,^147,148 although a recent study has disproved this effect. ¹⁴⁹ In addition, other work revealed that unmetabolized folic acid is present in circulation after consuming over 200 μg of folic acid. ¹⁵⁰ This could be associated with cognitive impairment among seniors. ¹⁵¹

A potential, but controversial, influence of folic acid fortification is cancer development. Many articles have been published that argue how folic acid can affect cancer progression, oscillating between its ability to reduce cancer progression, increase susceptibility to cancer development, or no association at all. American and Canadian ecologic studies have demonstrated a decline in childhood cancer incidence after folic acid fortification was initiated, with an estimated dose below 0.4 mg per day.^152–154 Other papers have indicated a minimized risk of childhood central nervous system tumors ¹⁵⁵ and ALL^25,156,157 according to self-reported folic acid consumption at doses nearly 0.4 mg per day, with no certain consumption of more than 0.8 mg. There was no detected change in the pre-fortification versus post fortification duration for ALL, brain cancers, embryonal cancers, or hepatoblastoma among the 0- to 4-year or 5- to 9-year age groups. ¹⁵³ An approximately 30% decline of Wilms’ tumor risk was observed after the intervention started, as well as a 60% decline in neuroblastoma. ¹⁵² Additional studies are needed in the United States during the post-folic acid grain fortification era, but preliminary analysis has suggested that folic acid grain fortification did not affect the risk of pancreatic cancer. ³⁵

Other evidence has shown that high folic acid intake has increased certain health risks in specific populations, including men with prostate cancer.^158,159 Excessive circulating folate was observed following the fortification approach, which covered 1% to 4% of the United States population.^158,160 Furthermore, dietary supplement users account for more than 10% of the population. This will result in folic acid consumption over the upper tolerable limit.^159,161 Another study perhaps supports the concerns that folic acid fortification has led to an increased risk of lung cancer in cigarette smokers along with high folic acid levels. ⁸⁵

Certain public health crises have emerged, in part by folic grain fortification and overall supplemental use of folic acid.^162–164 A probable cancer-promoting impact of significantly high folate and folic acid intake and blood levels have been suggested in North America. This has also been corroborated by animal studies and clinical trial outcomes.^77,83 Individuals within the nutrition community have conveyed worries that elevated folic acid intake, either from fortification or supplements, may accidentally increase the cancer risk among people in the United States.^80,82 The United States implemented mandatory fortification of cereal grains with folic acid in 1998 during pregnancy. Since then, the BC risk increased with consumption of these highly fortified cereals. ⁹¹

In response to some concerns, mandatory folic acid fortification is not established in Europe. Voluntary folic acid fortification strategies are applied in the United Kingdom, while other regions have no fortification strategy. ¹⁴⁴ One article showed that folic acid fortification is retained in the current version of the Lives Saved Tool (LiST). Although fortification programs are being introduced in most low and middle-income countries, the impacts of these programs have been restricted either by low levels of fortification in industrialized food, low consumption of fortified food, or both. ¹⁶⁵

Folic acid receptors and cancer risk: future prospectives

Many types of human cancer, such as BC, ovarian cancer, endometrial cancer, lung cancer, CRC, and cerebral tumors, have shown increased FR expression levels compared with healthy tissues.^166,167 FR can be a target to improve cancer therapy outcomes. Through nanoformulations, the effectiveness and potency of anti-cancer drugs can be enhanced by targeting FR by using folic acid or other chemically-related agents that have a high affinity for FRs. Monoclonal antibodies against FRs are also used. ¹⁶⁸ FR-α expression has been observed in the choroid plexus. Thus, FR-targeted formulations could be a good approach for improving the passage of anti-cancer agents to the central nervous system. ¹⁶⁹ The present review recommends novel future pharmacogenomic studies involving the alteration of FR expression in different types of cancer to potentially help improve the efficacy of anti-cancer drugs.

Conclusion

The current review describes study results that suggest opposing roles for folic acid in different types of cancer. Further pharmacogenomic studies and promising multicenter clinical trials are necessary to provide a more comprehensive understanding of this conflicting issue. These will provide additional evidence to help determine if folic acid can be used as a prophylactic supplement to reduce the risk of cancer or as an adjuvant to current anti-cancer protocols. If the results suggest that folic acid is carcinogenic, then high intake should be avoided, especially for those with an increased cancer risk.

Data availability statement

The data from the current study are accessible from the corresponding authors upon reasonable request.