Natural Products Impacting DNA Methyltransferases and Histone Deacetylases

Introduction

• Epigenetics: Involves heritable changes in gene expression without altering DNA sequence.
• Epigenetic Modifications: Include DNA methylation, chromatin remodeling, histone modifications, and non-coding RNAs.
• Cancer and Epigenetics: Dysregulation in epigenetic processes is linked to cancer and other diseases.

Focus of the Review

• Emphasis on natural products inhibiting DNA methyltransferases (DNMTs) and histone deacetylases (HDACs).
• Aim to find lead structures for anticancer drugs targeting epigenetic modifications.
• Challenge: Most natural products lack isoform selectivity, critical for therapeutic potential.

DNA Methyltransferase Inhibitors

• Function: DNMTs transfer methyl groups to DNA, leading to gene repression.
• DNMT Types: DNMT1 (maintenance), DNMT3a, and DNMT3b (de novo methylation).
• Cancer Connection: Aberrant DNMT activity contributes to cancer pathogenesis.
• Challenges: Existing DNMT inhibitors (e.g., azacytidine) are limited by toxicity and stability.

Notable Natural DNMT Inhibitors

1. (–)-Epigallocatechin-3-gallate (EGCG)

   • Found in green tea, inhibits DNMT activity, reactivates silenced genes.
   • Binds non-covalently to DNMT1's catalytic site.

2. Curcumin

   • Derived from turmeric, known for its anti-inflammatory properties.
   • Reported to inhibit growth of cancer cells and induce cell cycle arrest.

3. Quercetin

   • A flavonoid found in fruits and vegetables.
   • Induces apoptosis, inhibits DNMT, especially DNMT1 and DNMT3a.

4. Kazinol Q

   • Isolated from Broussonetia kazinoki, inhibits DNMT1.

5. Resveratrol

   • Found in grapes and berries, inhibits DNMT activity, especially DNMT3b.

6. Nanaomycin A

   • Antibiotic from Streptomyces rosa, selectively inhibits DNMT3b.

Histone Deacetylase Inhibitors

• Function: HDACs remove acetyl groups from histone proteins, affecting chromatin structure and gene expression.
• HDAC Classes: Grouped into four classes based on structure and function.

Types of HDAC Inhibitors

1. Zinc-Binding Inhibitors

   • Trichostatin A: Derived from bacteria, potent HDAC inhibitor.
   • Psammaplin A: Marine sponge-derived, inhibits class I HDACs.

2. Non Zinc-Binding Inhibitors

   • Curcumin: Also acts as an HDAC inhibitor.
   • Sulforaphane: Found in cruciferous vegetables, inhibits HDAC activity, increasing histone acetylation.

Molecular Modeling and Docking

• Used to predict interactions between inhibitors and their targets, aiding in drug design.
• Key Techniques: Molecular docking studies help in identifying potential binding sites and interaction dynamics.

Epigenetic Drug Development

• Challenges: Lack of isoform specificity in natural products limits clinical development.
• Potential Solutions: Combination therapies and chemical modifications might enhance specificity and reduce side effects.
• Current Status: HDAC inhibitors approved for some cancers, numerous others in clinical trials.

Conclusion

• Natural products offer a promising source for discovering new DNMT and HDAC inhibitors.
• Further research and development could lead to more effective cancer therapies with fewer side effects.