5-6-7-8-tetrahydrofolic-acid and Neoplasms

Cancer is a disease of uncontrolled cell growth and a major cause of death worldwide. Many molecular events characterize tumor initiation and progression. Global gene expression analyses using next-generation sequencing, proteomics and metabolomics show genomic, epigenetic, and metabolite concentration changes in various tumors. Molecular alterations identified include multiple cancer-driving mutations, gene fusions, amplifications, deletions, and post-translational modifications. Data integration from many high-throughput platforms unraveled dysregulation in many metabolic pathways in cancer. Since cancer cells are fast-growing, their metabolic needs are enhanced, hence the requirement for de novo synthesis of essential metabolites. One critical requirement of fast-growing cells and a historically important pathway in cancer is the nucleotide biosynthetic pathway and its enzymes are valuable targets for small molecule inhibition. Purines and pyrimidines are building blocks of DNA synthesis and due to their excessive growth, cancer cells extensively utilize de novo pathways for nucleotide biosynthesis. Methotrexate, one of the early chemotherapeutic agents, targets dihydrofolate reductase of the folate metabolic pathway that is involved in nucleotide biosynthesis. In this review, we discuss the nucleotide biosynthetic pathways in cancer and targeting opportunities.

Topics: Antimetabolites, Antineoplastic; Biosynthetic Pathways; Cell Proliferation; Energy Metabolism; Enzyme Inhibitors; Folic Acid Antagonists; Humans; Methotrexate; Neoplasms; Protein Processing, Post-Translational; Purine Nucleotides; Pyrimidine Nucleotides; S-Adenosylmethionine; Tetrahydrofolate Dehydrogenase; Tetrahydrofolates

Traditional antitumor drugs inhibit the proliferation and metastasis of tumour cells by restraining the replication and expression of DNA. These drugs are usually highly cytotoxic. They kill tumour cells while also cause damage to normal cells at the same time, especially the hematopoietic cells that divide vigorously. Patients are exposed to other serious situations such as a severe infection caused by a decrease in the number of white blood cells. Energy metabolism is an essential process for the survival of all cells, but differs greatly between normal cells and tumour cells in metabolic pathways and metabolic intermediates. Whether this difference could be used as new therapeutic target while reducing damage to normal tissues is the topic of this paper. In this paper, we introduce five major metabolic intermediates in detail, including acetyl-CoA, SAM, FAD, NAD

Topics: Acetyl Coenzyme A; Antineoplastic Agents; Carcinogenesis; Cell Proliferation; Disease Progression; Flavin-Adenine Dinucleotide; Humans; NAD; Neoplasm Invasiveness; Neoplasms; S-Adenosylmethionine; Tetrahydrofolates

Topics: Animals; Antibody Formation; Carcinogens; Choline; Choline Deficiency; Diet; DNA; Folic Acid; Folic Acid Deficiency; Humans; Immunity, Cellular; Lipotropic Agents; Liver; Liver Neoplasms; Methionine; Methylation; Neoplasms; Neoplasms, Experimental; Pharmaceutical Preparations; Risk; Tetrahydrofolates; Vitamin B 12; Vitamin B 12 Deficiency

Folate metabolism can be an effective target for cancer treatment. However, standard cell culture conditions utilize folic acid, a non-physiological folate source for most tissues. We find that the enzyme that couples folate and methionine metabolic cycles, methionine synthase, is required for cancer cell proliferation and tumour growth when 5-methyl tetrahydrofolate (THF), the major folate found in circulation, is the extracellular folate source. In such physiological conditions, methionine synthase incorporates 5-methyl THF into the folate cycle to maintain intracellular levels of the folates needed for nucleotide production. 5-methyl THF can sustain intracellular folate metabolism in the absence of folic acid. Therefore, cells exposed to 5-methyl THF are more resistant to methotrexate, an antifolate drug that specifically blocks folic acid incorporation into the folate cycle. Together, these data argue that the environmental folate source has a profound effect on folate metabolism, determining how both folate cycle enzymes and antifolate drugs impact proliferation.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Folic Acid; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Methotrexate; Neoplasms; Tetrahydrofolates

Topics: Alcohol Dehydrogenase; Animals; Environmental Pollutants; Formaldehyde; Glutathione; Humans; Neoplasms; Tetrahydrofolates

The chemotherapeutic drug methotrexate inhibits the enzyme dihydrofolate reductase

Topics: Ammonia-Lyases; Animals; Cell Line, Tumor; CRISPR-Cas Systems; Female; Folic Acid Antagonists; Glutamate Formimidoyltransferase; Histidine; Humans; Male; Methotrexate; Mice; Mice, Inbred NOD; Mice, SCID; Multifunctional Enzymes; Neoplasms; Nucleotides; Reduced Folate Carrier Protein; Tetrahydrofolate Dehydrogenase; Tetrahydrofolates; Xenograft Model Antitumor Assays

Mammalian folate metabolism is comprised of cytosolic and mitochondrial pathways with nearly identical core reactions, yet the functional advantages of such an organization are not well understood. Using genome-editing and biochemical approaches, we find that ablating folate metabolism in the mitochondria of mammalian cell lines results in folate degradation in the cytosol. Mechanistically, we show that QDPR, an enzyme in tetrahydrobiopterin metabolism, moonlights to repair oxidative damage to tetrahydrofolate (THF). This repair capacity is overwhelmed when cytosolic THF hyperaccumulates in the absence of mitochondrially produced formate, leading to THF degradation. Unexpectedly, we also find that the classic antifolate methotrexate, by inhibiting its well-known target DHFR, causes even more extensive folate degradation in nearly all tested cancer cell lines. These findings shed light on design features of folate metabolism, provide a biochemical basis for clinically observed folate deficiency in QDPR-deficient patients, and reveal a hitherto unknown and unexplored cellular effect of methotrexate.

Topics: Carbon; Cytosol; Formates; HCT116 Cells; HeLa Cells; Humans; MCF-7 Cells; Methotrexate; Mitochondria; Mitochondrial Proteins; Neoplasm Proteins; Neoplasms; Tetrahydrofolate Dehydrogenase; Tetrahydrofolates

A hypothesis is suggested, which emphasizes the role in carcinogenesis of the attack on low molecular nucleophilic substances (LMN) by electrophilic agents - chemical carcinogens, phisical factors, and antitumor alkylating agents. The significance of the degree of nucleophilicity (electronic charge, order of bonds, index of valence) as a locus minoris resistentiae of the LMN in the electrophilic attack on the latter is emphasized as well as the probable role of the hydrogenated pteridines in influencing carcinogenesis by means of ascorbate, tocopherol, SH-containing compounds etc. In support of this hypothesis the preference of electrophilic agents (derivatives of nitrogen mustard and nitrosoureas) for the places with highest degree of nucleophilicity as targets, in experiments in vitro with nucleic bases and pteridines is emphasized.

Topics: Alkylating Agents; Antineoplastic Agents; Carcinogens; Folic Acid; Kinetics; Neoplasms; Nitrosourea Compounds; Quantum Theory; Spectrophotometry, Ultraviolet; Tetrahydrofolates