Recent Advances on the Role of B Vitamins in Cancer Prevention and Progression

Abstract

Water-soluble B vitamins, mainly obtained through dietary intake of fruits, vegetables, grains, and dairy products, act as co-factors in various biochemical processes, including DNA synthesis, repair, methylation, and energy metabolism. These vitamins include B1 (Thiamine), B2 (Riboflavin), B3 (Niacin), B5 (Pantothenic Acid), B6 (Pyridoxine), B7 (Biotin), B9 (Folate), and B12 (Cobalamin). Recent studies have shown that besides their fundamental physiological roles, B vitamins influence oncogenic metabolic pathways, including glycolysis (Warburg effect), mitochondrial function, and nucleotide biosynthesis. Although deficiencies in these vitamins are associated with several complications, emerging evidence suggests that excessive intake of specific B vitamins may also contribute to cancer progression and interfere with therapy due to impaired metabolic and genetic functions. This review discusses the tumor-suppressive and tumor-progressive roles of B vitamins in cancer. It also explores the recent evidence on a comprehensive understanding of the relationship between B vitamin metabolism and cancer progression and underscores the need for further research to determine the optimal balance of B vitamin intake for cancer prevention and therapy.

Keywords: B vitamins; Warberg effect; antioxidants; cancer; metabolism; nutrients.

Figure 1

The role of thiamine in Warburg effect and its impact on cancer cell metabolism. Unlike normal cells, cancer cells heavily depend on glycolysis for energy production, even during aerobic conditions, and produce lactic acid instead of relying on oxidative phosphorylation. Glucose is taken up by the cell via GLUT transporters and converted through glycolysis into pyruvate. Instead of entering the TCA cycle within the mitochondria, pyruvate is converted to lactate in the cytoplasm by lactate dehydrogenase A (LDHA). Lactate is transported by monocarboxylate Transporters (MCT) and causes cancer cell proliferation. Further, the pyruvate dehydrogenase complex is inhibited by pyruvate dehydrogenase kinase (PDK), limiting pyruvate’s conversion to acetyl-CoA and reducing the flow into the TCA cycle. Thymine pyrophosphate (TPP) plays a critical role in restoring PDH activity and counteracting the inhibitory effects of PDK. This pathway also integrates alternative pathways, such as the pentose-phosphate pathway, hexosamine biosynthesis, and lipid synthesis, further supporting cancer cell growth and survival. The activity of the TCA cycle is generally reduced, which limits energy production from mitochondria. This metabolic adaptation provides rapid energy and intermediates needed for biosynthesis. As a result, cancer cells can grow and divide rapidly, even in challenging conditions like low oxygen levels.

Figure 2

Role of thiamine in cancer progression and therapy. Thiamine (Vitamin B1) plays a crucial role in cellular metabolism by converting into thiamine pyrophosphate (TPP), a co-factor for enzymes like pyruvate dehydrogenase (PDH), transketolase (TK), and alpha-keto dehydrogenase (α-KDH). These enzymes regulate glycolysis, the pentose phosphate pathway, and the Krebs cycle, essential for ATP and NADPH production, DNA/RNA synthesis, and oxidative stress reduction. In cancer cells, thiamine influences the Warburg effect, where cancer cells rely on glycolysis even in oxygen-rich environments, often due to pyruvate dehydrogenase kinase (PDK) overexpression, which inhibits oxidative phosphorylation. Thiamine supplementation counters this by restoring PDH activity, reducing glycolytic dependence, and promoting oxidative metabolism. Cancer cells modulate thiamine uptake via transporters like SLC19A2, SLC19A3, and SLC44A4. Therapeutically, supplementation with thiamine and its derivatives (such as benfotiamine and oxythiamine) could inhibit tumor growth, reduce oxidative stress, prevent NF-κB-mediated inflammatory signaling, reduce glycolytic activity, and promote oxidative phosphorylation.

Figure 3

Significance of riboflavin in cancer growth and therapy. Riboflavin functions as a precursor for flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), essential coenzymes in redox reactions, the TCA cycle, and reactive oxygen species (ROS) regulation. Riboflavin supports neural health, vitamin metabolism, and glutathione maintenance. Its deficiency, termed ariboflavinosis, can increase oxidative stress and promote cancer risk by impairing folate metabolism and DNA synthesis. In cancer therapy, riboflavin regulates ROS to inhibit tumor growth, promotes apoptosis, and reduces inflammation, enhancing the efficacy of cisplatin and gemcitabine. Photosensitive properties of riboflavin increase its anti-cancer potential. Elevated riboflavin intake correlates with reduced risks for colorectal, lung, and cervical cancers, while high serum riboflavin levels may increase risks for pancreatic and colorectal cancers.

Figure 4

Role of niacin and its cofactors in cancer growth and therapy. The biosynthesis and metabolism of NAD+ (nicotinamide adenine dinucleotide) occur through three main pathways: the de novo pathway (from tryptophan to quinolinic acid and eventually NAD+), the Preiss-Handler pathway (from niacin to NAD+ via intermediates like NAMN and NAAD), and the salvage pathway (from nicotinamide riboside or nicotinamide to NAD+ via NMN). Enzymatic reactions, such as those catalyzed by nicotinamide riboside kinase and nicotinate phosphoribosyltransferase, play critical roles in these conversions. NAD+ serves as a cofactor for key enzymes like sirtuins (SIRTs), Poly (ADP-ribose) polymerases (PARPs), and CD38, which are involved in genomic stability, DNA repair, cell proliferation, and immune suppression, which eventually lead to cancer growth. NAMPT inhibitors, when combined with niacin, effectively block NAD salvage pathways crucial for tumor growth. High dietary niacin intake could correlate with improved survival and lower mortality in cancer patients, supporting its potential as a chemopreventive agent.

Figure 5

Pantothenic acid in cancer: Pantothenic acid is a precursor to Coenzyme A (CoA) and is vital for numerous metabolic processes, including the citric acid cycle, fatty acid metabolism, and hormone production. Increased pantothenic acid levels correlate with enhanced glycolytic activity and cancer cell migration, particularly in breast and gastric cancer cells, and its association with c-MYC and SLC5A6 expression promotes breast cancer growth. Pantothenic acid supplementation could enhance immune responses by increasing antigen presentation, shifting tumor metabolism from glycolysis to oxidative phosphorylation, and preventing tumor growth. High intake has been linked to oral squamous cell carcinoma risk, and pantothenate supplementation has been shown to treat multidrug-resistant cancers and reduce metastasis.

Figure 6

The role of vitamins B6, B9, and B12 mediated one-carbon metabolism in cancer. Folate (vitamin B9) is converted to dihydrofolate and then to tetrahydrofolate (THF), which undergoes further modifications to form derivatives like N⁵, N¹⁰-methylene THF, and N⁵-methyl THF. These derivatives are essential for methylation processes, and nucleotide synthesis requires cancer cell growth. The pathway highlights the involvement of pyridoxine (vitamin B6) in converting homocysteine to cysteine via the trans-sulfuration pathway and cobalamin (vitamin B12) in the re-methylation of homocysteine to methionine, which subsequently forms S-adenosylmethionine (SAM), a key methyl donor in several biochemical and epigenetic methylations. Anti-carcinogenic agents, such as methotrexate and pralatrexate, inhibit steps in folate metabolism, while 5-fluorouracil blocks nucleotide synthesis. This pathway underscores the interdependence of folate, pyridoxine, and cobalamin in one-carbon metabolism in essential biological functions like methylation, DNA synthesis, and cellular regulation.