Introduction

In order to maintain the compact nature of DNA, chromatin is tightly wrapped around nuclear histones in distinct units called nucleosomes. The enzyme family called histone deacetylases (HDAC) maintains the histone proteins in a state of deacetylation so that DNA can bind tightly. A natural balance exists between histone acetylases (HAC) and HDAC. Synthetic inhibitors of histone deacetylases result in hyperacetylation of histones and the unraveling of the chromatin tightly wrapped in the nucleosome and allow transcription factors to bind and initiate gene expression. Developed for the treatment of cancer, inhibitors of HDAC increase the expression of a variety of genes, which are silenced in malignant cells. As such, the anti-tumor effects of HDAC inhibitors increase the expression of genes driving cell cycle, tumor suppression, differentiation and apoptosis (Marks et al. 2000, 2001; Richon et al., 1998, 2000, 2001). Suberoylanilide hydroxamic acid (SAHA) belongs to the class of hydroxamic acid-containing hybrid polar molecules that inhibit HDAC. SAHA suppresses the proliferation of cancer cells in vitro and reduces the growth of experimental tumors in vivo (Butler et al. 2000; Marks et al. 2001; Richon et al. 2001). SAHA, trichostatin A and butyrate are well-studied inhibitors of nuclear HDAC. However, SAHA also binds to S3 protein in the cytosol, a component of the ribosome (Webb et al. 1999). There are ongoing clinical trials of SAHA (Marks et al. 2001), and patients with cancer have been injected with increasing doses of SAHA (300-600 mg/m2) intravenously (O'Connor et al. 2001). Although solid tumors are treated in clinical trails with HDAC inhibitors, leukemias and multiple myeloma are often cancers that are first studied for treatment with HDAC inhibitors.

3.1.1 HDAC Inhibitors as Anti-tumor Agents

A large number of studies have revealed that inhibitors of HDAC reduce the proliferation of transformed cells in vitro as well as the growth of experimental tumors in vivo. The HDAC inhibitor depsipeptide has been administered to three patients with cutaneous T-cell lymphoma associated with clinical responses (Pierart et al. 1988). SAHA has also advanced to clinical studies in patients with prostatic cancer and lymphoma. The physical property of SAHA to inhibit HDAC is its binding of the hydroxamic acid moiety to the zinc-containing pocket of HDAC (Finnin et al. 1999). This results in increased acetylated histones. SAHA inhibits HDAC 1 and 3 and there is hyperacetylation of histones 3 and 4 (Richon et al. 1998). As a consequence of hyperacetylation, SAHA and other inhibitors of HDAC increase the expression of approximately 1%-2% of genes (Marks et al. 2000). Increased gene expression for the cell cycle kinase inhibitor p21 (Richon et al. 2000), as well as other mechanisms of tumor cell apoptosis, account for the anti-tumor properties of SAHA (Said et al. 2001; Vrana et al. 1999). In vitro, micromolar concentrations of SAHA result in selective apoptotic cell death, terminal differentiation and growth arrest for tumor cells, without toxicity on normal cells. In mice, growth of transplanted human prostatic cancer cells was suppressed by 97% by daily administration of SAHA at 50 mg/kg per day (Butler et al. 2000).

3.1.2 HDAC Inhibition and Expression of Latent Viral Genes

In addition to suppressing tumor growth, inhibitors of HDAC may affect other regulatory pathways. Trichostatin, and other inhibitors of HDAC, for example, increases viral expression, particularly latent viral genes. However, the most commonly used HDAC inhibitor, butyrate, is not associated with increased expression of Herpes viruses. Some studies in vitro suggest that HDAC inhibitors can be used to express genes in vectors used for gene therapy. However, the greatest interest in the therapeutic use of HDAC inhibitors for increased expression of viral genes is that of HIV-1 (Demonte et al. 2004; Hsia and Shi 2002; Van Lint et al. 1996). Since the onset of highly active anti-retroviral therapy for HIV-1, suppression of HIV-1 infection has resulted in a remarkable prolongation of life and a return, in part, of CD4+ T cells.

Despite the near absence of HIV-1 mRNA in the serum and even the inability to detect HIV-1 in peripheral blood mononuclear cells (PBMCs) and even tonsillar tissue, withdrawal of anti-retroviral therapy precipitates a near immediate return of viral mRNA into the circulation. It has become clear that latent virus exists in a cellular compartment not accessible to therapy. Forcing the expression of HIV-1 incorporated into genomic DNA in sequestered cells serves as a reservoir of the infection. In order to "force" expression of HIV-1, which results in the death of the infected cell, cytokines such as IL-2 have been given to patients while on anti-retroviral therapy. The use of cytokines to "force" expression and to increase HIV-1 expression depends upon signal transduction following cell surface cytokine receptor activation. This mechanism is thought to be useful in "purging" HIV-1-infected cells to express latent virus from the host. But this approach has failed. One explanation for the failure of cytokine therapy to purge HIV-1 infection is that the reservoir of latently infected cells may not express the receptor for the particular cytokine. For example, it is unlikely that epithelial cells express receptors for IL-2. The advantage of HDAC inhibitors for purging HIV-1 is twofold: these inhibitors are small molecules and may have access to cellular compartments not accessible to cytokines. Second, HDAC inhibitors enter cells via a cell surface receptor-independent mechanism. HDAC inhibition may be a useful in HIV-1 treatment since the agents can be administered in cycles with anti-retroviral agents given immediately after the purge to prevent infection of new cells.

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