What is the mechanism of Decitabine?

Decitabine, also known by its chemical name 5-aza-2’-deoxycytidine, is a hypomethylating agent commonly used in the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The primary mechanism by which Decitabine exerts its therapeutic effects is through the inhibition of DNA methyltransferase (DNMT) enzymes, leading to hypomethylation of DNA and subsequent changes in gene expression.

DNA methylation is a crucial epigenetic modification where a methyl group is added to the cytosine base in DNA, typically at CpG dinucleotides. This process is catalyzed by DNMTs and is essential for regulating gene expression, maintaining genomic stability, and ensuring proper cellular differentiation. In many cancers, including MDS and AML, abnormal hypermethylation of tumor suppressor genes occurs, leading to their silencing and contributing to uncontrolled cell proliferation and malignancy.

Decitabine is a nucleoside analog of cytidine, differing from natural cytidine by the substitution of a nitrogen atom for the carbon atom at the 5-position of the pyrimidine ring. Upon entering the cell, Decitabine undergoes phosphorylation by cellular kinases, eventually forming Decitabine triphosphate, which is then incorporated into newly synthesized DNA during the S-phase of the cell cycle in place of the natural cytidine nucleotide.

Once incorporated into the DNA, Decitabine acts as a mechanism-based inhibitor of DNMTs. The enzyme DNMT attempts to methylate the cytosine residue in the DNA, but the presence of the nitrogen atom at the 5-position prevents the completion of this methylation process. This results in the formation of a covalent bond between the DNMT enzyme and the Decitabine-substituted DNA, effectively trapping the enzyme and leading to its degradation. Consequently, the overall levels of active DNMTs in the cell are reduced.

The reduction in DNMT activity leads to a decrease in DNA methylation, particularly at CpG islands located in the promoter regions of genes. The hypomethylation of DNA can reactivate previously silenced tumor suppressor genes, leading to the restoration of their normal function, such as inducing cell cycle arrest, promoting apoptosis, and inhibiting cell proliferation. Additionally, Decitabine-induced hypomethylation can affect other regulatory elements in the genome, leading to broader changes in gene expression that contribute to its anti-cancer effects.

Moreover, Decitabine can induce DNA damage and activate DNA damage response pathways. The incorporation of Decitabine into DNA can cause the formation of DNA-DNMT adducts, which are recognized as DNA lesions by the cell. This activation of the DNA damage response can lead to cell cycle arrest and apoptosis in rapidly dividing cells, such as cancer cells, thereby contributing to the therapeutic effects of Decitabine.

In summary, Decitabine's mechanism of action primarily involves the inhibition of DNMT enzymes, resulting in DNA hypomethylation and consequent reactivation of tumor suppressor genes. These epigenetic modifications lead to changes in gene expression, inhibition of cell proliferation, induction of apoptosis, and activation of DNA damage response pathways, ultimately exerting its anti-cancer effects in the treatment of MDS and AML.