DNA methyltransferase-1 inhibitors as epigenetic therapy for cancer

Area of Science:

• Epigenetics
• Cancer Biology
• Pharmacology

Background:

• Aberrant DNA methylation patterns in cancer silence tumor suppressor genes.
• DNA methyltransferases (DNMTs) regulate gene expression through methylation.
• DNMT1 is a key target due to its high expression in the S-phase of the cell cycle.

Purpose of the Study:

• To review current strategies for inhibiting DNA methyltransferases (DNMTs) in cancer.
• To discuss various classes of DNMT inhibitors, including nucleoside analogues and non-nucleoside compounds.
• To highlight challenges and future directions in DNMT inhibition therapy.

Main Methods:

• Comprehensive literature review of nucleoside analogues and non-nucleoside inhibitors of DNMTs.
• Categorization of inhibitors into synthetic and natural compounds.
• Discussion of mechanisms of action, bioavailability, toxicity, and resistance.

Main Results:

• Identified nucleoside analogues (e.g., azacytidine, decitabine) and synthetic non-nucleoside inhibitors (e.g., hydralazine, RG108).
• Highlighted natural compounds (e.g., curcumin, genistein, EGCG, resveratrol) with DNMT inhibitory potential.
• Discussed challenges such as bioavailability, toxicity, and resistance to hypomethylation therapies.

Conclusions:

• DNMT inhibition is a promising strategy for cancer treatment by re-expressing silenced tumor suppressor genes.
• A diverse range of compounds, both synthetic and natural, show potential as DNMT inhibitors.
• Addressing challenges like toxicity and resistance is crucial for developing effective combinatorial therapies.