Identification of kazinol Q, a natural product from Formosan plants, as an inhibitor of DNA methyltransferase.

DNA methylation plays a pivotal role in the epigenetic regulation of the transcription of a number of cancer-related genes, thereby representing an important target for cancer prevention and treatment. In our search for DNA methyltransferase (DNMT) inhibitors from Formosan plants, by screening against a library consisting of 12 structurally distinct natural products, we identified kazinol Q {4-[6-(1,1-dimethyl-allyl)-7-hydroxy-chroman-2-yl]-3,6-bis-(3-methyl-but-2-enyl)-benzene-1,2-diol} as an inhibitor of recombinant DNMT1 with IC50 of 7M. The effect of kazinol Q on DNMT inhibition was validated by its ability to reactivate the expression of a DNA methylation-silenced gene, E-cadherin, in MDA-MB-231 breast cancer cells. Moreover, kazinol Q suppressed the proliferation of MCF-7 breast and LNCaP prostate cancer cells, in part, through apoptosis induction. The role of DNMT1 inhibition in mediating kazinol Q's antiproliferative effect was supported by the protective effect of ectopic expression of DNMT1 on kazinol Q-induced cell death. Molecular modeling analysis suggests that kazinol Q inhibited DNMT activity by competing with cytosine binding, a mechanism similar to that described for (-)-epigallocatechin-3-gallate (EGCG). Relative to EGCG, kazinol Q exhibits several desirable features for drug development, including chemical stability and increased hydrophobicity, and might have therapeutic relevance to cancer treatment. Copyright (c) 2013 John Wiley & Sons, Ltd.