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Digging deep into “dirty” drugs – modulation of the methylation machinery
Open accessAbstract
DNA methylation and histone modification are epigenetic mechanisms that result in altered gene expression and cellular phenotype. The exact role of methylation in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) remains unclear. However, aberrations (e.g. loss-/gain-of-function or up-/down-regulation) in components of epigenetic transcriptional regulation in general, and of the methylation machinery in particular, have been implicated in the pathogenesis of these diseases. In addition, many of these components have been identified as therapeutic targets for patients with MDS/AML, and are also being assessed as potential biomarkers of response or resistance to hypomethylating agents (HMAs). The HMAs 5-azacitidine (AZA) and 2'-deoxy-5-azacitidine (decitabine, DAC) inhibit DNA methylation and have shown significant clinical benefits in patients with myeloid malignancies. Despite being viewed as mechanistically similar drugs, AZA and DAC have differing mechanisms of action. DAC is incorporated 100% into DNA, whereas AZA is incorporated into RNA (80-90%) as well as DNA (10-20%). As such, both drugs inhibit DNA methyltransferases (DNMTs; dependently or independently of DNA replication) resulting in the re-expression of tumor-suppressor genes; however, AZA also has an impact on mRNA and protein metabolism via its inhibition of ribonucleotide reductase, resulting in apoptosis. Herein, we first give an overview of transcriptional regulation, including DNA methylation, post-translational histone-tail modifications, the role of micro-RNA and long-range epigenetic gene silencing. We place special emphasis on epigenetic transcriptional regulation and discuss the implication of various components in the pathogenesis of MDS/AML, their potential as therapeutic targets, and their therapeutic modulation by HMAs and other substances (if known). The main focus of this review is laid on dissecting the rapidly evolving knowledge of AZA and DAC with a special focus on their differing mechanisms of action, and the effect of HMAs on transcriptional regulation.
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“The prolonged time to initial response, which typically occurs around 3 months from treatment onset 125 , is consistent with the primary effects of low dose treatment being mediated via DNA demethylation and epigenetic reprogramming as opposed to direct cytotoxicity 126-128 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [126]
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“DAC is currently used as a clinical treatment for myelodysplastic syndrome and acute myeloid leukemia [32].”
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“In addition, low dose HMAs also trigger type 1 interferon production and RNase L–mediated cell death by reactivating endogenous retroviruses [89–93].”
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Re-Sensitizing Tumor Cells to Cancer Drugs with Epigenetic Regulators
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“Novel therapies aimed to treat cancer by using histone methylation drugs show positive results (Harb-de la Rosa et al., 2015; Pleyer and Greil, 2015; Castilho et al., 2017; Choi et al., 2017; Curry et al., 2018).”
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“The nucleoside analogs 5-azacytidine (ZCyt, Azacytidine), 5-aza-2 ′ - deoxycytidines (ZdCyd), and 5-fluoro-2 ′ -deoxycytidine (FdC, Decitabine) can be incorporated into RNA and DNA, thereby interfering with DNA, RNA, and protein biosynthesis [148].”
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Effect of small molecule signaling in PepFect14 transfection
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“In academic research a preferred term is off-target drugs, nevertheless a definition proposed by Pleyer et al [32] for dirty drugs summarizes the concept as a drug that targets either “several structurally related proteins, a cellular complex composed of several proteins and/or molecules that govern several downstream…”
BackgroundImpact of individual factors on DNA methylation of drug metabolism genes: A systematic review
Bian, J., Zhao, J., Zhao, Y., Hao, X., He, S., Li, Y., & Huang, L. (2023) · Environmental and Molecular Mutagenesis · doi:10.1002/em.22567 · Cited by 5
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“When DAC is incorporated into DNA, it prevents DNA from becoming methylated and inhibits DNA methyltransferases [4].”
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Nikolopoulos, T., Bochalis, E., Chatzilygeroudi, T., Chondrou, V., Dereki, I., Athanasopoulou, K., Zafeiropoulos, J., Bourikas, K., Patrinos, G. P., Symeonidis, A. S., et al. (2025) · Molecular Medicine · doi:10.1186/s10020-025-01123-7 · Cited by 3
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“Nevertheless, further analyses using ChIP-seq data, promoter motif enrichment, or histone modification signatures are needed to validate the significance of HDAC4 in melanoma prognosis.”
Novel insights into DNA methylation-based epigenetic regulation of breast tumor angiogenesis
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Perera, E., Navarro-Guillén, C., Román-Padilla, J., Huesa-Cerdán, R., Hidalgo-Pérez, J. A., Martos-Sitcha, J. A., Martı́nez-Rodrı́guez, G., Alpízar-Pedraza, D., Fernandes, J. M. O., & Rodriguez‐Casariego, J. A. (2025) · Epigenetics · doi:10.1080/15592294.2025.2566515 · Cited by 2
“DAC is known to be passively incorporated into the DNA and to irreversibly bind DNMT1, thereby blocking maintenance methylation in proliferating cells, but also known to be incorporated into the DNA by active mechanisms [72].”
Wu, F., Danzeng, Q., Wu, R., Shen, Y., & Shi, G. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1835325 · Cited by 1
“Targeting these upstream pathways can reduce DNMT1 abundance or activity, thereby promoting DNA demethylation.”
InfluentialCacabelos, R., Naidoo, V., Tellado, I., Corzo, L., Cacabelos, N., Cacabelos, P., Martínez-Iglesias, O. A., & Segre, R. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-18722-3.00029-3 · Cited by 1
Myelodysplastic Disorders, Monosomy 7
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“Predictors of positive responses to DMTIs is include (1) doubling of PLT count, (2) mutated TET2, (3) mutated EZH2, (4) Phosphoinositide-phospholipase C beta hypomethylation, and (5) low serum level of micro-RNA-21 [96, 104, 105].”
BackgroundMethodEpigenetic modification and regulation of HBV cccDNA
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RetractedInhibitors of Epigenetic Modulators as Therapeutic Alternatives for Cardiovascular Diseases
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Vural, S., Palmisano, A., Reinhold, W. C., Pommier, Y., Teicher, B. A., & Krushkal, J. (2021) · Figshare · doi:10.6084/m9.figshare.14176021
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Metadata
- Authors
- Pleyer, L., & Greil, R.
- Affiliations
- Paracelsus Medical University (AT)
- Corresponding author
- Pleyer, Lisa
- Venue
- Drug Metabolism Reviews
- Publisher
- Informa UK Limited
- Published
- 2015-01-08
- Volume
- 47
- Issue
- 2
- Pages
- 252-279
- ISSN
- 0360-2532 (ISSN-L)
- 1097-9883
- PMC
- PMC4733942
- OpenAlex
- W1992220938
- Cited by
- 84
- References
- 366
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 5 · 2023: 4 · 2022: 5 · 2021: 13 · 2020: 7 · 2019: 11 · 2018: 9 · 2017: 8 · 2016: 7 · 2015: 3
- FWCI
- 0.87
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Drug Metabolism Reviews (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- DNA methylation, histone modifications, myelodysplastic syndrome, acute myeloid leukemia, hypomethylating agents, azacitidine, decitabine, DNA methyltransferases, ribonucleotide reductase, microRNA, therapeutic target
- MeSH terms
- Decitabine, Animals, Antimetabolites, Antineoplastic, Azacitidine, Clinical Trials as Topic, Humans, Myelodysplastic Syndromes, Transcription, Genetic, Leukemia, Myeloid, Acute, DNA Methylation, Histone Code, Epigenesis, Genetic
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