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Mechanisms of DNA methyltransferase-inhibitor interactions: Procyanidin B2 shows new promise for therapeutic intervention of cancer.

Abstract
DNA methyltransferases (DNMTs) is a key epigenetic enzyme for pharmacological manipulation and is employed in cancer reprogramming. During past few years multiple strategies have been implemented to excavate epigenetic compounds targeting DNMTs. In light of the emerging concept of chemoinformatics, molecular docking and simulation studies have been employed to accelerate the development of DNMT inhibitors. Among the DNMT inhibitors known till date, epigallocathechin-3-gallate (EGCG) was identified to be effective in reducing DNMT activity. However, the broad spectrum of EGCG to other diseases and variable target enzymes offers some limitations. In view of this, 32 EGCG analogues were screened at S-Adnosyl-L-homocysteine (SAH) binding pocket of DNMTs and procyanidin B2-3, 3'-di-O-gallate (procyanidin B2) was obtained as potent inhibitor having medicinally relevant chemical space. Further, in vitro analysis demonstrates the efficiency of procyanidin B2 in attenuating DNMT activity at IC50 of 6.88±0.647 μM and subsequently enhancing the expression of DNMT target genes, E-cadherin, Maspin and BRCA1. Moreover, the toxic property of procyanidin B2 towards triple negative breast cancer cells to normal cells offers platform for pre-clinical trial and an insight to the treatment of cancer.
AuthorsArunima Shilpi, Sabnam Parbin, Dipta Sengupta, Swayamsiddha Kar, Moonmoon Deb, Sandip Kumar Rath, Nibedita Pradhan, Madhumita Rakshit, Samir Kumar Patra
JournalChemico-biological interactions (Chem Biol Interact) Vol. 233 Pg. 122-38 (May 25 2015) ISSN: 1872-7786 [Electronic] Ireland
PMID25839702 (Publication Type: Journal Article)
CopyrightCopyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • Biflavonoids
  • Enzyme Inhibitors
  • Proanthocyanidins
  • procyanidin B2
  • Catechin
  • epigallocatechin gallate
  • DNA Modification Methylases
Topics
  • Amino Acid Sequence
  • Animals
  • Biflavonoids (pharmacology)
  • Breast (drug effects, metabolism, pathology)
  • Breast Neoplasms (drug therapy, enzymology, pathology)
  • Catechin (analogs & derivatives, pharmacology)
  • Cell Line, Tumor
  • DNA Methylation (drug effects)
  • DNA Modification Methylases (antagonists & inhibitors, chemistry, metabolism)
  • Enzyme Inhibitors (pharmacology)
  • Female
  • Humans
  • Mice
  • Molecular Docking Simulation
  • Molecular Sequence Data
  • Proanthocyanidins (pharmacology)
  • Sequence Alignment

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