Hypomethylating agent

A hypomethylating agent (or demethylating agent ^[1] ) is a drug that inhibits DNA methylation: the modification of DNA nucleotides by addition of a methyl group. Because DNA methylation affects cellular function through successive generations of cells without changing the underlying DNA sequence, treatment with a hypomethylating agent is considered a type of epigenetic therapy.

Currently available hypomethylating agents block the activity of DNA methyltransferase (DNA methyltransferase inhibitors / DNMT inhibitors). Currently two members of the class, azacitidine and decitabine, are FDA-approved for use in the United States in myelodysplastic syndrome and are being investigated for use in a number of tumors. ^[2]

Clinical use

Two hypomethylating agents are approved for the treatment of myelodysplastic syndrome by the United States FDA ^{[3] [4]}

• decitabine ^{[5] [6]} Also has EU approval for acute myeloid leukemia (AML). ^[7]
• azacitidine ^[8]

Natural Hypomethylating Agents

There are some natural Hypomethylating Agents which play some roles in effect networks of systems biology. ^{[9] [10] [11] [12] [13]}

Compound	Source	Mechanism Type
(-)-Epigallocatechin-3-gallate (EGCG)	Green tea (catechin)	Direct (competitive)
Curcumin	Turmeric	Direct (covalent Cys¹²²⁶ block)
Nanaomycin A	Streptomyces rosa (bacterium)	Direct (selective)
Quercetin	Fruits, vegetables (flavonoid)	Direct
Sulforaphane	Broccoli sprouts (isothiocyanate)	Direct + HDAC synergy
Genistein	Soybean (isoflavone)	Direct (competitive)
Boswellic acids (AKBA)	Boswellia serrata (terpenoid)	Direct + miRNA network
Resveratrol	Grapes, berries (stilbene)	Direct (S-phase trap)
Parthenolide	Tanacetum parthenium (sesquiterpene)	Direct (covalent-like)
Trigonelline	Coffee beans, fenugreek (alkaloid)	Indirect (NAD⁺ precursor, Nrf2/TGFβ networks)

Mechanism of action

DNA methylation is the modification of DNA nucleotides by addition of a methyl group. These methyl groups are associated with changes in the ability of the corresponding DNA to be used. Patterns of DNA methylation are stable during cellular division. Methylation of tumor suppressor genes in some cancers contributes to the growth and survival of the cancer. Hypomethylating agents decrease the amount of cellular DNA methylation, allowing for tumor suppressor gene expression. ^[14]

See also

• DNA methyltransferase

References

1. Garcia-Manero G (November 2008). "Demethylating agents in myeloid malignancies". Curr Opin Oncol. 20 (6): 705–10. doi:10.1097/CCO.0b013e328313699c. PMC   3873866 . PMID   18841054.
2. Hambach L, Ling KW, Pool J, et al. (December 2008). "Hypomethylating drugs convert HA-1 negative solid tumors into targets for stem cell based immunotherapy". Blood. 113 (12): 2715–22. doi: 10.1182/blood-2008-05-158956 . PMID   19096014.
3. "Azacitadine - National Cancer Institute". NCI. September 17, 2014.
4. "Decitabine - National Cancer Institute". NCI. May 19, 2011.
5. Aribi A, Borthakur G, Ravandi F, et al. (February 2007). "Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia". Cancer. 109 (4): 713–7. doi: 10.1002/cncr.22457 . PMID   17219444.
6. De Padua Silva L, de Lima M, Kantarjian H, et al. (January 2009). "Feasibility of allo-SCT after hypomethylating therapy with decitabine for myelodysplastic syndrome". Bone Marrow Transplant. 43 (11): 839–43. doi:10.1038/bmt.2008.400. PMID   19151791.
7. "EC Approves Marketing Authorization Of DACOGEN For Acute Myeloid Leukemia". 2012-09-28. Retrieved 28 September 2012.
8. Garcia-Manero G, Stoltz ML, Ward MR, Kantarjian H, Sharma S (September 2008). "A pilot pharmacokinetic study of oral azacitidine". Leukemia. 22 (9): 1680–4. doi:10.1038/leu.2008.145. PMID   18548103.
9. Besharati, Mohammad Reza, Mohammad Izadi, and Alireza Talebpour. "Some natural hypomethylating agents in food, water and environment are against distribution and risks of COVID-19 pandemic: Results of a big-data research." Avicenna Journal of Phytomedicine 12, no. 3 (2022): 309. https://pmc.ncbi.nlm.nih.gov/articles/PMC9482712/
10. Jafari, Nafiseh; Besharati, Mohammad Reza; Izadi, Mohammad; Talebpour, Alireza (2022). "COVID and nutrition: A machine learning perspective". Informatics in Medicine Unlocked. 28 100857. doi:10.1016/j.imu.2022.100857. ISSN   2352-9148. PMC   8767975 . PMID   35071732.
11. Al-Damook, Nosayba; Sakkal, Molham; Khair, Mostafa; Mousa, Walaa K.; Khoder, Ghalia; Ghemrawi, Rose (2025-11-14). "Targeting Cancer Through Thymoquinone: From Molecular Mechanisms to Clinical Prospects". International Journal of Molecular Sciences. 26 (22): 11029. doi: 10.3390/ijms262211029 . ISSN   1422-0067. PMID   41303508.
12. Akone, Sergi Herve; Ntie-Kang, Fidele; Stuhldreier, Fabian; Ewonkem, Monique Bassomo; Noah, Alexandre Mboene; Mouelle, Simon Eitel Misse; Müller, Rolf (2020-08-13). "Natural Products Impacting DNA Methyltransferases and Histone Deacetylases". Frontiers in Pharmacology. 11 992. doi: 10.3389/fphar.2020.00992 . ISSN   1663-9812. PMC   7438611 . PMID   32903500.
13. Saldívar-González, Fernanda I.; Gómez-García, Alejandro; Chávez-Ponce de León, David E.; Sánchez-Cruz, Norberto; Ruiz-Rios, Javier; Pilón-Jiménez, B. Angélica; Medina-Franco, José L. (2018-10-10). "Inhibitors of DNA Methyltransferases From Natural Sources: A Computational Perspective". Frontiers in Pharmacology. 9 1144. doi: 10.3389/fphar.2018.01144 . ISSN   1663-9812.
14. Herman, J. G.; Baylin, S. B. (2003). "Gene silencing in cancer in association with promoter hypermethylation". New England Journal of Medicine. 349 (21): 2042–54. doi:10.1056/NEJMra023075. PMID   14627790.