HISTONE DEACETYLASE IN HUMAN CANCER

Histone Deacetylase in Human Cancer

Histone Deacetylase in Human Cancer

Introduction

Histone deacetylase inhibitors (HDI) are emerging as possibly useful components of the anticancer armamentarium and as helpful devices to dissect mechanistic pathways. HDIs that globally inhibit histone deacetylases (HDAC) have radiosensitizing effects, but the relative assistance of exact HDAC classes continues unclear. Newly characterized HDIs are now available that preferentially inhibit specific HDAC categories, encompassing SK7041 (inhibits class I HDACs) and splitomicin (inhibits class III HDACs). We investigated in human cancerous diseaseous disease cells the relation radiosensitizations that outcome from impeding exact HDAC classes. We discovered that trichostatin A (TSA; inhibitor of both class I and II HDACs) was the most productive radiosensitizer, followed by the class I inhibitor SK7041, while splitomicin (inhibitor of class III) had smallest effect. Interestingly, radiosensitization by TSA in cell lines expressing p53 was more pronounced than in isogenic lines needing p53. Radiosensitization of units expressing p53 by TSA was decreased by pifithrin-alpha, a small-molecule inhibitor of p53. In contrast, the radiosensitization by TSA of cells expressing low grades of p53 was enhanced by transfection of wild-type p53-expressing vector or pretreatment with leptomycin B, an inhibitor of nuclear export that expanded intracellular levels of p53. These effects on radiosensitization were respectively muted or not seen in cells treated with SK7041 or splitomicin.

Active Compound Retinoic Acid

Retinoids are derivatives of retinol (Vitamin A), which is derived from dietary intake of ß-carotene. The biologically active compound retinoic acid (RA2) has profound effects on vertebrate development and homeostasis, and inhibits the growth of, and/or differentiates, a large number of tumor cell lines in vitro, including human prostate carcinoma cells. Retinoids have achieved some promise as chemopreventive agents in aerodigestive cancer chemoprevention, both in the reversal of preneoplastic lesions and in the prevention of second primary cancers, and have potential activity in the chemoprevention or treatment of prostate cancer. The chemopreventive activity of retinoids is achieved by their effects on a number of malignant properties, which for prostate cancer include inhibition of proliferation, induction of differentiation and apoptosis, and inhibition of cell motility and invasion with concomitant inhibition of vimentin expression and protease production. Despite their anti-proliferative effects on prostate tumor cell lines in culture, however, the use of retinoids clinically in prostate cancer therapy has been limited by toxicity and the frequent and unpredictable resistance of prostate tumors to retinoid actions.

Retinoic Acid Effects

The effects of RA are mediated by three types of retinoic acid receptors (RARs) a, ß and ?, which are members of a large superfamily of nuclear receptors, and form heterodimers with another member of the superfamily, the retinoid X receptor (RXR). After binding of RA, RXR/RAR heterodimers regulate transcription by binding to RA response elements (RAREs), which are usually located in the promoter region of target genes. One of these RAR-target genes is RARß itself, establishing a positive-feedback loop. Loss of RARß is common in prostate malignancies. The co-repressor complex, which docks at RAR in the RXR/RAR heterodimer in the absence of ligand, ...