Histone-Deacetylase Inhibitors for the Treatment of Cancer

Abstract

Histone deacetylase inhibitors (HDACi) are a promising new class of chemotherapeutic drug currently in early phase clinical trials. A large number of structurally diverse HDACi have been purified or synthesised that mostly inhibit the activity of all eleven class I and II HDACs. While these agents demonstrate many features required for anti-cancer activity such as low toxicity against normal cells and an ability to inhibit tumor cell growth and survival at nanomolar concentrations, their mechanisms of action are largely unknown. Initially, a model was proposed whereby HDACi-mediated transactivation of a specific gene or set of genes was responsible for the inhibition of cell cycle progression or induction of apoptosis. Given that HDACs can regulate the activity of a number of nonhistone proteins and that histone acetylation is important for events such as DNA replication and mitosis that do not directly involve gene transcription, it appears that the initial mechanistic model for HDACi may have been too simple. Herein, we provide an update on the transcription-dependent and -independent events that may be important for the anti-tumor activities of HDACi and discuss the use of these compounds in combination with other chemotherapeutic drugs.

MS-275 synergistically enhances the growth inhibitory effects of RAMBA VN/66-1 in hormone-insensitive PC-3 prostate cancer cells and tumours

“…Previously, studies have reported that HDACIs generally induce a G1 phase arrest at lower concentrations and a G2/M phase arrest at higher concentrations Lindemann et al, 2004). We confirmed that the cells were indeed not arrested in G1 by looking at cyclin D1 mRNA levels by RT -PCR, a marker for G1 phase arrest.…”

“…Since PCa is one of the leading causes of deaths worldwide, there is an urgent need to identify effective agents against this disease. Retinoids, rexinoids, retinoid-related molecules (RRMs) and histone deacetylase inhibitors (HDACIs) have shown promising biological activities as single agents in several preclinical studies of both haematological and solid malignancies (Altucci and Gronemeyer, 2001;Lindemann et al, 2004;Bolden et al, 2006;Njar et al, 2006a). Because of the heterogeneous nature of PCa, we hypothesise that agents/ combination of agents affecting various pathways involved in PCa growth and survival may be advantageous.…”

Prospects: Histone deacetylase inhibitors

“…Unlike the alterations in HDACs associated with neoplasms, structural alterations in HATs, including translocations, amplifications, deletions and point mutations have been found in various human cancers-both hematological and epithelial [Lehrmann et al, 2002;Rosato and Grant, 2003;Lindemann et al, 2004;Marks et al, 2004;Drummond et al, 2005]. For example, the HATs, CBP and p300, are altered in some tumors by mutation or translocation.…”

“…SAHA, LAQ824, LBH589A, and PXD-101 are hydroxamate HDAC inhibitors that have moved forward in clinical trials [Lindemann et al, 2004;Marks et al, 2004;Rosato and Grant, 2004;Piekarz et al, 2004b;Drummond et al, 2005;]. An oral preparation of SAHA is phase I and phase II clinical trials [Kelly et al, In Press].…”

Sulforaphane potentiates oxaliplatin-induced cell growth inhibition in colorectal cancer cells via induction of different modes of cell death

“…HDACi, as a new class of chemotherapeutic agents, show significant pro mise against a variety of cancers in clinical trials [9]. Most available HDACi inhibit all class I and II HDACs, thereby increasing acetylation of histone and nonhistone protein targets [10]. In vivo, histone acetylation depends on the balance between histone acetyltransferase (HAT) and histone deacetylase (HDAC), which has been proposed to play an important role in transcriptional regulation by altering chromatin structure [11].…”