Abstract
Since epigenetic alterations are believed to be involved in the repression of tumor suppressor genes and promotion of tumorigenesis in ovarian cancers, novel compounds endowed with a histone deacetylase (HDAC) inhibitory activity are an attractive therapeutic approach. In this review, we discuss the biologic and therapeutic effects of HDAC inhibitors (HDACIs) in treating ovarian cancer. HDACIs were able to mediate inhibition of cell growth, cell cycle arrest, apoptosis, and expression of genes related to the malignant phenotype in a variety of ovarian cancer cell lines. Furthermore, HDACIs were able to induce the accumulation of acetylated histones in the chromatin of the p21WAF1 gene in human ovarian carcinoma cells. In xenograft models, some of HDACIs have demonstrated antitumor activity with only few side effects. Some clinical trials demonstrate that HDACI drugs provide an important class of new mechanism-based therapeutics for ovarian cancer. In this review, we discuss the biologic and therapeutic effects of HDACIs in treating ovarian cancer, especially focusing on preclinical studies and clinical trials.
Highlights
Ovarian cancer is the most lethal gynecologic malignancy [1]
histone deacetylase (HDAC) catalyze the removal of acetyl groups on the aminoterminal lysine residues of core nucleosomal histones, and this activity is generally associated with transcriptional repression
HDACs induce neutralization of the charge on the histones which allows the phosphate backbone of the DNA to open up and facilitate the transcription of many genes, including tumor suppressor genes silenced in cancer
Summary
Ovarian cancer is the most lethal gynecologic malignancy [1]. Early-stages of ovarian cancer are frequently asymptomatic and difficult to detect and diagnosis usually occurs after the disease advanced. Acetylation of histone proteins neutralizes the positive charge on lysine residues and disrupts nucleosome structure, allowing unfolding of the associated DNA with subsequent access by transcription factors, resulting in changes in gene expression. HDACs catalyze the removal of acetyl groups on the aminoterminal lysine residues of core nucleosomal histones, and this activity is generally associated with transcriptional repression. HDACs induce neutralization of the charge on the histones which allows the phosphate backbone of the DNA to open up and facilitate the transcription of many genes, including tumor suppressor genes silenced in cancer. Some investigators believed that the expression of E-cadherin can promote carcinogenesis from normal ovarian surface epithelial cells unlike the other carcinomas [10], HDACIs markedly increased the expression level of Ecadherin in endometrial and ovarian cancer cells and exhibit antiproliferative activity in these cells [11] (Figure 1)
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