Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine

@article{Stresemann2008ModesOA,
  title={Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine},
  author={Carlo Stresemann and Frank Lyko},
  journal={International Journal of Cancer},
  year={2008},
  volume={123}
}
The cytosine analogues 5‐azacytosine (azacytidine) and 2′‐deoxy‐5‐azacytidine (decitabine) are the currently most advanced drugs for epigenetic cancer therapies. These compounds function as DNA methyltransferase inhibitors and have shown substantial potency in reactivating epigenetically silenced tumor suppressor genes in vitro. However, it has been difficult to define the mode of action of these drugs in patients and it appears that clinical responses are influenced both by epigenetic… 
DNA methyltransferase inhibitors and their emerging role in epigenetic therapy of cancer.
TLDR
This review summarizes the current data and knowledge about azacytidine, decitabine and zebularine, and their role in present and possible future epigenetic cancer therapy and the molecular modes of action of these agents with consideration of their different toxicities and demethylation profiles.
Epigenetic Regulator, Re-emerging Antimetabolites with Novel Mechanism of Action (Azacitidine and Decitabine): Clinical Pharmacology and Therapeutic Results
TLDR
AZA became the first agent shown to prolong overall survival for higher-risk MDS and to provide longer leukemia-free survival than other treatment, and Oral AZA is also under clinical development.
Comprehensive comparison between azacytidine and decitabine treatment in an acute myeloid leukemia cell line
TLDR
It is found that while AzaC and AzadC share many effects on the cellular level, including decreased global DNA methylation, increased formation of DNA double strand breaks, transcriptional downregulation of important oncogenes and similar changes on the proteome level, Aza c failed in contrast to Azadc to induce apoptosis in MOLM-13.
Delivery of 5-Azacytidine to Human Cancer Cells by Elaidic Acid Esterification Increases Therapeutic Drug Efficacy
TLDR
CP-4200, an elaidic acid derivative of azacytidine, has strong epigenetic modulatory potency in human cancer cell lines, as evidenced by efficient depletion of DNA methyltransferase protein, genome-wide DNA demethylation, and robust reactivation of epigenetically silenced tumor suppressor genes.
Pharmacodynamic Responses to DNA Methyltransferase Inhibition
The DNA methyltransferase inhibitors, 5-azacytidine and decitabine, were initially developed at high dose for clinical use as classical cytotoxic agents and only later reidentified as epigenetically
Why methylation is not a marker predictive of response to hypomethylating agents
TLDR
In the future, methylation analysis concentrating not only on promoters, but also on gene bodies and intergenic regions, may identify key genes in patients with the highest probability of response to azanucleotides and allow a patient-tailored approach.
The Contrasting Delayed Effects of Transient Exposure of Colorectal Cancer Cells to Decitabine or Azacitidine
TLDR
Decitabine has much stronger anti-clonogenic activity than azacitidine and, despite significant immediate toxicity, has negligible long-term effects, according to a head-to-head comparison.
Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis
TLDR
A loss-of-function shRNA screen identifies the histone acetyl transferase and transcriptional co-activator, CREB binding protein (CBP), as a major regulator of AZA sensitivity and finds that the effect of CBP/p300 inhibition is mediated by globally down regulating protein synthesis.
Mechanisms of Action of Hypomethylating Agents: Endogenous Retroelements at the Epicenter
TLDR
Recent data in cancer cell lines demonstrate that reactivation of endogenous retroelements (EREs) and induction of a cell-intrinsic antiviral response triggered by RNA neotranscripts may underlie the antitumor activity of HMAs.
Azacitidine: activity and efficacy as an epigenetic treatment of myelodysplastic syndromes
  • V. Santini
  • Medicine, Biology
    Expert review of hematology
  • 2009
TLDR
Azacitidine was the first agent demonstrated to delay acute myeloblastic leukemia transformation and to prolong survival for patients with higher risk MDS, and it was approved in 2004 by the US FDA for treatment of all MDS risk categories.
...
...

References

SHOWING 1-10 OF 68 REFERENCES
DNA methyltransferase inhibitors and the development of epigenetic cancer therapies.
TLDR
Assays for genome-wide and tumor-specific DNA methylation also need to be further developed to establish the pharmacodynamic parameters of DNA methyltransferase inhibitors in patients and to provide rational approaches to maximizing the therapeutic efficacy of these compounds.
Functional diversity of DNA methyltransferase inhibitors in human cancer cell lines.
TLDR
A comparative analysis of the six most widely known DNA methyltransferase inhibitors indicated that RG108 is the only drug capable of direct enzyme inhibition, showing a substantial diversity in the molecular activities of DNA methyl transferase inhibitors.
Hydroxycarbamide in combination with azacitidine or decitabine is antagonistic on DNA methylation inhibition
TLDR
Surprisingly, HC blocked the ability of both azacitidine and decitabine to inhibit DNA methylation and this antagonistic effect was attributable to the arrest of the cell cycle induced by HC.
Delivery of 5-aza-2'-deoxycytidine to cells using oligodeoxynucleotides.
TLDR
This is the first demonstration of the use of short oligonucleotides to provide effective delivery and cellular uptake of a nucleotide drug and protection from enzymatic degradation, which may pave the way for more stable and potent inhibitors of DNA methylation.
Comparison of biological effects of non-nucleoside DNA methylation inhibitors versus 5-aza-2′-deoxycytidine
TLDR
This study examined three non-nucleoside demethylating agents, (−)-epigallocatechin-3-gallate, hydralazine, and procainamide, and compared their effects and potencies with 5-Aza-CdR, the most potent DNA methylation inhibitor.
Oral decitabine reactivates expression of the methylated γ‐globin gene in Papio anubis
TLDR
The results demonstrate that oral administration of these drugs at doses 17–34 times optimal subcutaneous doses of decitabine reactivates fetal hemoglobin, demethylates the ϵ‐ and γ‐globin gene promoters, and increases histone acetylation of these promoters in baboons (Papio anubis).
Oral decitabine reactivates expression of the methylated gamma-globin gene in Papio anubis.
TLDR
The results demonstrate that oral administration of these drugs at doses 17-34 times optimal subcutaneous doses of decitabine reactivates fetal hemoglobin, demethylates the epsilon- and gamma-globin gene promoters, and increases histone acetylation of these promoters in baboons (Papio anubis).
Characterization of DNA demethylation effects induced by 5-Aza-2'-deoxycytidine in patients with myelodysplastic syndrome.
TLDR
The results are the first to show a genome-wide demethylating activity of decitabine in tumor material, and uncovers novel targets of dec itabine-mediated demethylation that are important for the refinement of treatment schedules with dem methylating drugs.
Reactivation of Epigenetically Silenced Genes by DNA Methyltransferase Inhibitors: Basic Concepts and Clinical Applications
TLDR
This review surveys the available literature on systematic, genome-wide approaches aimed at the identification of epigenetically silenced loci and suggests rational design of epigenetic inhibitors might provide the foundation for a broader use of these drugs in the treatment of cancer.
5-Aza-Deoxycytidine Induces Selective Degradation of DNA Methyltransferase 1 by a Proteasomal Pathway That Requires the KEN Box, Bromo-Adjacent Homology Domain, and Nuclear Localization Signal
TLDR
Results demonstrate a unique mechanism for the selective degradation of DNMT1, the maintenance DNA methyltransferase, by well-known DNA-hypomethylating agents and indicate that covalent bond formation between the enzyme and 5-aza-CdR-incorporated DNA is not essential for enzyme degradation.
...
...