Histone Deacetylase Inhibitors in Cancer Treatment: A Review of the Clinical Toxicity and the Modulation of Gene Expression in Cancer Cells

Abstract

Characterization of epigenetic events in carcinogenesis has led to the discovery of a new class of oncogenes and thereby a new class of therapeutic targets. Among the new therapeutic approaches are modulation of protein lysine acetylation through inhibition of histone deacetylases (HDACs). HDACs deacetylate histones as well as transcription factors and can modulate gene expression through both these mechanisms in normal and malignant cells. Furthermore, acetylation is an important posttranslational modulation of several proteins involved in the regulation of cell proliferation, differentiation and apoptosis in normal as well as cancer cells. Even though several HDAC inhibitors have been characterized in vitro, only a limited number of these agents are in clinical trials. Various HDAC inhibitors differ in their toxicity profile when comparing the side effects described in the available clinical studies of HDAC inhibition in the treatment of cancer. These drugs may also affect normal hematopoiesis; hematologic toxicity is common to many drugs but stimulation of hematopoiesis seems to occur for others. HDAC inhibitors usually affect <10% of the genes in cancer cells. Divergent effects of HDAC inhibition on the global gene expression profiles have been described when testing various cancer cells, and this is further complicated by altered HDAC expression induced by HDAC inhibitors. However, increased p21 expression seems to be a common characteristic for most studies, suggesting an important role of this molecule during HDAC inhibitory treatment. Even though the initial studies are encouraging, additional in vitro and in vivo pharmacological characterization is definitely needed.

RETRACTED: Wnt-5a signaling restores tamoxifen sensitivity in estrogen receptor-negative breast cancer cells

“…However, these inhibitors have a clear disadvantage in that they will, in principle, inhibit methyl-transferases in all types of cells. Although HDAC and DNMT inhibitors have recently been approved for treatment of patients with myelodysplastic syndromes and are currently in clinical trials for various types of cancer, concerns remain about their toxicity, nonspecificity, and side effects (16)(17)(18).…”

Genetic dissection of histone deacetylase requirement in tumor cells

“…Although current panHDACi are relatively well tolerated, they have been associated with numerous side effects such as cardiac arrhythmia, bone marrow depression, clotting disorders, diarrhea, fatigue, and electrolyte disturbances in phase I and II studies (48). It is expected that compounds that specifically inhibit the subset of enzymatic isoforms required to obtain a desired clinical outcome will substantially broaden the therapeutic window of HDACi (49).…”

Epigenetic Treatments for Cognitive Impairments

“…However, there are also several potential issues concerning the use of HDAC inhibitors for cognitive disorders. First and foremost, the systemic use of these drugs can produce considerable side effects (Bruserud et al, 2007). This may be due to the fact that most available HDAC inhibitors are not isoform-selective, but bind with roughly equal affinity to distinct HDAC proteins in the same family (Kilgore et al, 2010).…”