Demethylating agents are chemical substances that can inhibit

methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...

, resulting in the expression of the previously hypermethylated silenced

genes In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

(see Methylation#Cancer for more detail).

Cytidine Cytidine (symbol C or Cyd) is a nucleoside molecule that is formed when cytosine is attached to a ribose ring (also known as a ribofuranose) via a β-N1- glycosidic bond. Cytidine is a component of RNA. It is a white water-soluble solid. which ...

analogs such as 5-azacytidine (azacitidine) and 5-azadeoxycytidine (

decitabine Decitabine, sold under the brand name Dacogen among others, acts as a nucleic acid synthesis inhibitor. It is a medication for the treatment of myelodysplastic syndromes, a class of conditions where certain blood cells are dysfunctional, and for ...

) are the most commonly used demethylating agents. They work by inhibiting

DNA methyltransferase In biochemistry, the DNA methyltransferase (DNA MTase, DNMT) family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl m ...

s. Both compounds have been approved in the treatment of

myelodysplastic syndrome A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...

(MDS) by

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) in United States.

Azacitidine Azacitidine, sold under the brand name Vidaza among others, is used for the treatment of myelodysplastic syndrome, myeloid leukemia, and juvenile myelomonocytic leukemia. It is a chemical analog of cytidine, a nucleoside in DNA and RNA. Azacit ...

and

are marketed as Vidaza and Dacogen respectively. Azacitidine is the first drug to be approved by FDA for treating MDS and has been given

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

status.

Procaine Procaine is a local anesthetic drug of the amino ester group. It is most commonly used in dental procedures to numb the area around a tooth and is also used to reduce the pain of intramuscular injection of penicillin. Owing to the ubiquity ...

is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells. There are many other demethylating agents that can be used to inhibit the growth of other diseases.

Mechanism of Action

There is very little known about the mechanism of action of these drugs. However, it was shown in 2015 that a possible mechanism of action of these drugs in colorectal cancer-initiating cells is through activating

dsRNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...

expression which leads to the activation of the

MDA5 MDA5 (melanoma differentiation-associated protein 5) is a RIG-I-like receptor dsRNA helicase enzyme that is encoded by the ''IFIH1'' gene in humans. MDA5 is part of the RIG-I-like receptor (RLR) family, which also includes RIG-I and LGP2, and ...

/ MAVS RNA recognition pathway inducing some sort of viral mimicry inside the cell.

Clinical Applications

The silencing of genes created by abnormal DNA methylation is a major contributor to the formation of cancerous tumors. Variations in DNA methylation of normal cells compared to malignant cells shows a prominent mechanism in how cancerous cells proliferate. Those variations are particularly prevalent in cell cycle regulation, DNA repair, and natural tumor suppression mechanisms. A leading therapeutic strategy in treating solid tumors stems from the use of demethylating agents to suppress DNA methylation in cancerous growths. Azacitidine and decitabine are both frequently used demethylating agents while decitabine is significantly more potent in its demethylating abilities. Both of these drugs are inhibitors of DNA Methyltransferases (DNMT) which are enzymes that are responsible for methylating DNA. In the 1970’s, these drugs have shown promising results in hematological cancers in organisms such as mice. The FDA initially rejected the use of azacitidine clinically due to negative side effects caused by elevated toxicity levels. However, in later clinical trials performed on patients with MDS, myelodysplastic syndromes, azacitidine provided effective and exhibited consistent results which led to FDA approval in 2004. The commercial name of azacitidine became Vidaza. Decitabine, with the commercial name Dacogen, followed with FDA approval in 2006. As more research is completed in the field of genetic mutations, specifically involving DNA Methylation, these drugs can be utilized to their maximum efficiency to clinically treat cancerous tumors. As of 2017, there were no approved demethylating agents for the treatment of solid tumors which can be a focus of research in the future. Treatment utilizing demethylating agents can have further clinical use by targeting cancer stem cells and triggering apoptosis. Demethylating agents and their relevance in clinical studies as therapy to treat lymphocytic leukemia can be seen in. Procaine can also be used as therapeutic development to inhibit the growth of cancer cells in humans. There is a new world of possibilities of using demethylating agents to treat different diseases such as leukemia and cancer as therapeutic treatment.

References

Biochemistry {{biochemistry-stub