Histone deacetylase inhibitors: novel anticancer agents

Abstract

Previous studies have established that the regulation of gene expression is dependent upon the nucleosomal integrity of nuclear DNA. To a large extent, this integrity is dictated by the acetylation status of the core histone particles. The acetylation of histones is, in turn, controlled by the combined activity of specific acetylases and deacetylases. Moreover, disruption of histone acetylases and deacetylases has been linked to a wide variety of human cancers. For this reason, the recent availability of potent and specific histone deacetylase inhibitors has provoked a great deal of interest amongst cancer biologists, oncologists and pharmacologists. Within the past 2- 3 years, several novel histone deacetylase inhibitors have been reported, many of which have already been tested in vivo in mouse models of cancer. In this review we focus on the rationale behind the use of histone deacetylase inhibitors as anticancer agents. Moreover, we review some of the recent findings pertaining to the use of these compounds as anticancer agents.

Rapid Induction of Histone Hyperacetylation and Cellular Differentiation in Human Breast Tumor Cell Lines following Degradation of Histone Deacetylase-1

“…Hyperacetylation of Histone H4 -Antibodies that recognize acetylated forms of histone H4 have been used as a probe for agents that cause histone hyperacetylation (19). In Western blot experiments, we compared the ability of quinidine to cause hyperacetylation of H4 in MCF-7 cells with that of TSA, an established HDAC inhibitor, known to inhibit proliferation in MCF-7 cells (20).…”

Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen

“…HDAC inhibitors can prevent proliferation and induce differentiation of numerous transformed cell types, including neuroblastoma, erythroleukemia, acute myelogenous leukemia, and carcinomas of the skin, breast, prostate, bladder, lung, colon, and cervix (62)(63)(64)(65)(66)(67). Given the extensive clinical experience with VPA, it may provide a relatively safe, well tested alternative to the use of TSA and trapoxin in the therapy of malignant diseases.…”

Histone deacetylase inhibitors: A novel target of anticancer therapy (Review)

“…TSA has also been shown to effectively inhibit squamous carcinoma cell proliferation and keratinocyte growth ex vivo. TSA-mediated arrest was found to be irreversible (53). Therefore, it is possible to envision a topical application of TSA in skin cancer, limiting some of the toxic side effects.…”