Premium
Testing Novel Depsipeptides for Histone Deacetylases Inhibitor Activity
Author(s) -
Mitchell Caitlyn,
Carle Sigrid,
Enos Stephen,
Miller Justin,
Zang Xiaoyu,
Vallabhaneni Deepak,
Peraro Leila
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.897.31
Subject(s) - depsipeptide , histone , acetylation , chemistry , histone deacetylase 5 , histone deacetylase , biochemistry , biology , microbiology and biotechnology , cancer research , gene
Gene expression is partly controlled by posttranscriptional modifications to histones. These modifications either loosen the binding between histones and DNA, allowing for transcription, or tighten the binding, which prevents transcription. Histone acetyltransferases (HATs) are responsible for histone acetylation, while histone deacetylases (HDACs) remove acetyl groups and are involved in gene silencing. HDAC activity is often upregulated in cancer cells, leading to the repression of several genes that normally prevent tumor formation. Due to the role of HDACs in cancer development and progression, HDAC inhibitors (HDACi) are promising treatments for several cancers. Furthermore, unlike many traditional chemotherapeutics, HDACi appear to have limited effect on normal cell growth and function. Cyclic, cysteine‐containing, depsipeptides are a promising class of HDACi. These HDACi require three major characteristics: a Lewis basic group that associates with the Zn 2+ ion at the heart of the active site, a cyclic region that binds to the nonpolar amino acid residues at the rim of the active site channel, and a linker of four to seven atoms that connects the nonpolar region to the Lewis basic group, presumably mimicking the structure of lysine. We tested four analogs with altered cyclic regions. An MTT assay was used to measure cytotoxicity induced by each depsipetide on the histoiocytic lymphoma cell line, U937. Depsipeptides that were cytotoxic were investigated for their ability to induce apoptosis using a CaspACE TM Assay. Most effective novel depsipeptides were those with smaller, nonpolar cyclic regions.