Vitamins as Possible Cancer Biomarkers: Significance and Limitations

Abstract

The Western-style diet, which is common in developed countries and spreading into developing countries, is unbalanced in many respects. For instance, micronutrients (vitamins A, B complex, C, D, E, and K plus iron, zinc, selenium, and iodine) are generally depleted in Western food (causing what is known as 'hidden hunger'), whereas some others (such as phosphorus) are added beyond the daily allowance. This imbalance in micronutrients can induce cellular damage that can increase the risk of cancer. Interestingly, there is a large body of evidence suggesting a strong correlation between vitamin intake as well as vitamin blood concentrations with the occurrence of certain types of cancer. The direction of association between the concentration of a given vitamin and cancer risk is tumor specific. The present review summarized the literature regarding vitamins and cancer risk to assess whether these could be used as diagnostic or prognostic markers, thus confirming their potential as biomarkers. Despite many studies that highlight the importance of monitoring vitamin blood or tissue concentrations in cancer patients and demonstrate the link between vitamin intake and cancer risk, there is still an urgent need for more data to assess the effectiveness of vitamins as biomarkers in the context of cancer. Therefore, this review aims to provide a solid basis to support further studies on this promising topic.

Keywords: cancer biomarker; cancer risk; vitamin A; vitamin B complex; vitamin C; vitamin D; vitamin E; vitamin K.

Figure 1

Overview of the impact of vitamins A, B complex, and D on the cellular biochemistry. The main effect of vitamin A, B complex, and D on cellular biochemistry is mostly due to the alteration of the transcriptional landscape of the cell, with relevant repercussions on the cell cycle. Vitamin A is involved in the replication and transcription processes but can also modulate the overall cellular expression by binding the transcription factor p300. Additionally, vitamin A modifies the genetic expression at the epigenetic level by modulating the histone acetyltransferase pCAF. Vitamin A is also involved in the glycosylation of proteins, in modulating important aspects of the cell cycle and cell-to-cell adhesion, and in the stability of the biological membranes. Vitamin B₅ plays a relevant role in the metabolism of the cell, since it is incorporated in CoA that is involved in the Krebs cycle (TCA cycle) in the mitochondrial matrix. Additionally, vitamin B₉ is converted to THF, which is then transformed into DHF by the enzyme TS simultaneously with the conversion of dU monophosphate into the methylated deoxythymidine monophosphate (T^me). In depletion of vitamin B₉, the reaction is shifted toward the reagents with the consequent accumulation of dU instead of T^me in the DNA. Since dU is more susceptible to physicochemical insults than the canonical nucleotides, it can generate DNA strand breaks, the accumulation of which increase the mutation rate of the cell, fostering oncogenesis. Vitamin B₉ is also involved in the biosynthesis, mediated by 5-MTHF and MAT of methylated cytosine (C^me), which is essential to the methylation of the DNA and the epigenetic modulation of the cellular expression. Deficiency in vitamin B₉ is therefore associated with depletion of C^me and generalized hypomethylation. Vitamin D is bound by VDR that facilitates the translocation of the vitamin into the nucleus. The complex VDR/D binds to specific recognition sequences called VDREs within the promoters of several genes, including those involved in the regulation of the cell cycle (such as p21) and the epigenetic modulation (such as p300). CBP—CREB-binding protein; CoA—coenzyme A; CREB—cAMP response element-binding protein; DHF—dihydrofolate; DMT—DNA methyltransferase; DNA pol—DNA polymerase; dU—deoxyuridine; MAT—methionine adenosyl transferase; 5-MTHF—5-methyltetrahydrofolate; pCAF—p300/CBP-associated factor; RNA pol—RNA polymerase; TCA—tricarboxylic acid; THF—tetrahydrofolate; TS—thymidylate synthase; VDR—vitamin D recognition protein; VDRE—vitamin D response element.

Figure 2

Overview of the impact of vitamins C, E, and K on the cellular biochemistry. Vitamins C and E as well as most minerals affect the cellular biochemistry mainly by altering the oxidative status of the cells. Vitamin C is converted rapidly to Asc⁻ and AFR. The Krebs cycle produces high energy molecules such as NADH, FADH₂, ATP, or succinate. The Krebs cycle is linked to the respiration process that occurs mainly on the inner membranes of mitochondria, where several multiprotein complexes (I-IV) extract electrons from the high-energy molecules to pump protons (H⁺) into the intermembrane compartment of the mitochondria (third compartment of the figure). Protons are then pumped back into the cytoplasm producing ATP. In particular, complex I (NADH-ubiquinone oxidoreductase) oxidizes NADH to NAD⁺, and complex II (succinate-CoQ reductase) oxidizes succinate to fumarate, yielding FADH₂. The acquired electrons are transferred to ubiquinone (also known as CoQ), which translocates them to complex III, which modulates the transfer of the electrons from CoQ to CytC, which then transfers them to complex IV (cytochrome c oxidase). Complex IV converts O₂ to H₂O in presence of H⁺. Under physiological conditions, the enzyme Cyb5R3 transfers one electron (e⁻) from NADH to AFR, producing Asc⁻ and NAD⁺. An excess of Asc⁻, however, inhibits Cyb5R3 and the Cyb5R3-associated membrane pump VDAC1 transfers AFR into the intermembrane compartment, which then transfers an electron directly to CytC, blocking the respiratory process. Incapable of reaching complex IV, the electrons in the transfer chain proceed back to complex I, producing a burst of ROS (dotted red arrow). Furthermore, AFR is converted into DHA that is then reduced to Asc⁻, producing NAD⁺. The newly produced Asc⁻ then further inhibits Cyb5R3 and the excess NAD⁺ can shift the balance of the reactions taking place in the Krebs cycle (red arrow). However, vitamins C and E act as scavengers neutralizing ROS. Vitamins C, E, and K can modulate the expression of several genes. ROS can directly damage the DNA chain, fostering oncogenesis, but can also influence the epigenetic control of genetic expression by inducing hypomethylation via 8-oxo-dG. AFR—ascorbyl free radical; Asc⁻—ascorbate; CoQ—coenzyme Q; Cyb5R3—NADH-cytochrome b5 oxidoreductase 3; CytC—cytochrome c; DHA—dehydroascorbate; e⁻—electron; FADH₂—flavin adenine dinucleotide (reduced form); NADH—nicotinamide adenine dinucleotide (reduced form); 8-oxo-dG—8-oxo-deoxy-guanosine; ROS—reactive oxygen species; VDAC1—voltage-dependent anion-selective channel 1.

Figure 3

Overview of vitamin C chemistry. Due to its acidic properties, the majority of ascorbic acid is transformed into ascorbate by losing a proton in the C3-position under physiological conditions. Negative charge can be translocated among the molecule, stabilizing the ascorbate anion (the area of electron delocalization additionally marked in red color). The reducing agent ascorbate can be oxidized (e.g., by cellular NAD⁺ or metal ions in the plasma) resulting in the reactive intermediate AFR after losing one proton and one electron (the area of electron delocalization additionally marked in red color). AFR is further oxidized to the more stable DHA by losing another electron. The figure shows all the valence electrons of the oxygen atoms as small circles labeled with e⁻. Most important electrons for the presented reactions are highlighted in red color, while the unpaired electron of the free radical is marked black. Atomic radii of the elements are drawn in size ratio. For simplicity, data of the covalent radii for single bonds were used (H = 32 pm, C = 75 pm, O = 63 pm). AA—ascorbic acid; AFR—ascorbyl free radical; Asc⁻—ascorbate; C—carbon; DHA—dehydroascorbate; e⁻—electron, H—hydrogen; NAD⁺—nicotinamide adenine dinucleotide (oxidized form); O—oxygen.