Histone deacetylases as new therapy targets for platinum-resistant epithelial ovarian cancer

Abstract

Introduction: In developed countries, ovarian cancer is the fourth most common cancer in women. Due to the non-specific symptomatology associated with the disease many patients with ovarian cancer are diagnosed late, which leads to significantly poorer prognosis. Apart from surgery and radiotherapy, a substantial number of ovarian cancer patients will undergo chemotherapy and platinum based agents are the mainstream first-line therapy for this disease. Despite the initial efficacy of these therapies, many women relapse; therefore, strategies for second-line therapies are required. Regulation of DNA transcription is crucial for tumour progression, metastasis and chemoresistance which offers potential for novel drug targets.

Methods: We have reviewed the existing literature on the role of histone deacetylases, nuclear enzymes regulating gene transcription.

Results and conclusion: Analysis of available data suggests that a signifant proportion of drug resistance stems from abberant gene expression, therefore HDAC inhibitors are amongst the most promising therapeutic targets for cancer treatment. Together with genetic testing, they may have a potential to serve as base for patient-adapted therapies.

Keywords: Chemotherapy; HDACS; Molecular targeting; Ovarian cancer; Platinum; Platinum resistance.

Fig. 1

Histone acetylation/deacetylation regulates transcription. The balance between the acetylated and deacetylated states of histones is mediated by two different sets of enzymes: histone acetyltransferases (HATs) and histone deacetylases (HDACs). Acetylation of the histone tails is associated with an open chromatin structure and active transcription. Conversely, removing the acetyl groups on the histone tails by HDAC enzyme activity is associated with condensed chromatin structure and transcriptional repression. Adapted from Marks et al. (2001)

Fig. 2

Schematic representation of class I; HDAC1, 2, 3 and 8, class IIa; HDAC4, 5, 7 and 9, class IIb; HDAC6 and 10 and class IV; HDAC11. HDAC enzymes with the structural and the functional domains included the capacity of the structurally diverse HDAC inhibitors to inhibit the activity of each HDAC classes or specific isoform HDACs are shown. Adapted from Bolden et al. (2006)

Fig. 3

Vorinostat inhibits HDAC activity by binding to the pocket of the catalytic site. The hydroxamic acid moiety of vorinostat binds to a zinc atom (pink); this allows the rest of the molecule to lie along the surface of the HDLP protein. Adapted from Marks et al. (2001)