Largazole as a Novel and Selective Anti-Breast Cancer Agent
Abstract
Histone deacetylases (HDACs) and histone acetylases (HATs) are key players in regulating transcription and histone homeostasis(8). Transcription of tumor suppressor proteins is frequently silenced in tumor cells due the hyper- or aberrant activity of HDACs. Accordingly inhibiting histone deacetylation may re-activate inappropriately silenced genes and may be able to reverse malignant changes(2). Inhibitors of histone deacetylase enzymes (HDACi) have recently attracted substantial attention as potential anti-cancer drugs. The selective degradation of many regulatory proteins in eukaryotic cells is mediated by the ubiquitin system(5). Proteins targeted for degradation are usually covalently ligated to a polyubiquitin chain and subsequently eliminated by the 26S proteasome. Ubiquitination of proteins is carried out by a multi-enzyme complex consisting of E1 (ubiquitin activating enzyme), E2 (ubiquitin conjugating enzyme) and E3 (ubiquitin ligase) (5). The final product of this reaction is formation of a polyubiquitinated protein with attachment of an ubiquitination through an isopeptide bond to an epsilon-amino group of certain Lys residues in the interior of the substrate. There is only one ubiquitin E1 enzyme, more than fifty ubiquitin E2 and perhaps thousands of E3 enzymes in human genome. E3 often controls the specificity and timing of substrate ubiquitination (5). Both HDAC inhibitors and ubiquitin-proteasome inhibitors have found applications in treating specific type of human tumors. However, either type of inhibitor alone does not appear to exhibit a broad spectrum of inhibition in treating a variety of human cancers. These observations have prompted investigations using a combination of both types of inhibitors in anti-tumor studies. It was found that bortezomib killed multiple myeloma cells more efficiently when combined with histone deacetylase inhibitors(11).
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2012
- Accession Number
- ADA573822
Entities
People
- Andrew Phillips
Organizations
- Yale University