Daily Archives

One Article


´╗┐Induction of apoptosis was also measured by Annexin V staining

Posted by Andre Olson on

´╗┐Induction of apoptosis was also measured by Annexin V staining. induced apoptosis in B-ALL cell lines and while it was far less effective against other B-cell derived malignancies. Conclusions Here we show that HDAC inhibitors are a potential therapeutic option for B-ALL, and that a more specific inhibitor of HDAC1 and HDAC2 could be therapeutically useful for patients with B-ALL. Introduction There is growing evidence that epigenetics, or heritable non-DNA sequence based gene expression alterations, and the chromatin modification proteins involved, are crucial players in cancer formation and survival (1). These chromatin modifying enzymes E6130 are of E6130 particular interest in leukemias, where they have been linked to gene expression alterations leading to leukemogenesis (2). As many leukemias are dependent on oncogenic fusion proteins that consist of transcriptional regulators (3, 4), epigenetic therapies could prove useful as treatment options. Therefore, the idea of targeting these chromatin modifying enzymes with small molecule inhibitors as a putative anti-leukemia option is growing. Histone deacetylases (HDACs) are one such family of chromatin modifying enzymes whose aberrant activity has been linked to hematological malignancy (4). HDACs regulate gene expression by removing acetyl groups from lysine residues of numerous proteins including histones. In humans, there are 11 classical HDAC isoforms, grouped into four classes. The classical HDACs (excluding Sirtuins) are in class I (HDACs 1-3, 8), II (IIa C HDACs 4, 5, 7, 9; IIb C 6, 10) and IV (HDAC11). HDACs 1-3 are enzymatically active members of E6130 transcriptional corepressor complexes, responsible for chromosomal compaction and gene repression through removing acetyl groups from lysine residues on histones. Interestingly, HDAC6 is mainly a cytoplasmic protein, with functions independent of E6130 histone deacetylation (5). Histone deacetylase inhibitors (HDACi) define a promising class of cancer drugs whose mechanism of action is not completely understood, though they are widely touted as an epigenetic therapy (6). Of the many possible ways HDACi influence cell survival, there are data amassing that HDACs regulate genome stability and repair (7C9). HDACi may induce apoptosis by preventing chromatin compaction, facilitating an accumulation of DNA breaks that would be irreparable. While several other mechanisms have been studied, a definitive route to apoptosis induction is still lacking. There are more Rabbit Polyclonal to VAV1 (phospho-Tyr174) than a dozen HDACi presently being studied as chemical probes and therapeutic agents, which may be subdivided into families based on chemical structure and biochemical spectrum of activity (10). The hydroxamic acid family is the most prevalent, with SAHA (Vorinostat, Zolinza; Merck) being the most clinically successful as of yet. SAHA is known to inhibit the class I HDACs as well as HDAC6 at low nM concentrations (11) and is clinically approved for use in treating cutaneous T cell lymphomas (CTCL). The cyclic peptide family is most well known for the depsipeptide HDACi romidepsin (FK228, Istodax; Celgene) which is also clinically approved for CTCL. Romidepsin is a potent, class I selective HDACi which exhibits on modest activity against HDAC6 at high concentrations may have a greater specificity for the class I enzymes, but also seems effective against HDAC6 (12, 13). The benzamide family of HDACi also exhibits class I selectivity, with inhibition of HDAC1, 2 and 3 apparent at pharmacologically-achievable doses. Several benzamides are presently progressing through clinical trials (14). Only recently have selective inhibitors of HDAC6 been developed, such as tubacin, which demonstrate low potency for nuclear, class I deacetlyases and exhibit toxicity when combined with proteasome inhibitors in preclinical models of multiple myeloma (15, 16). In addition, ongoing research is being performed to determine which transcriptional repressor complexes associate with various inhibitors to help establish a mechanistic understanding of biological effects observed broadly in cancer, inflammatory and neurodegenerative models (17). We are interested in extending HDACi epigenetic.