Ricky W. Johnstone

Anticancer activities of histone deacetylase inhibitors

Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin, and have a key role in the epigenetic regulation of gene expression. In addition, the activity of non-histone proteins can be regulated through HDAC-mediated hypo-acetylation. In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies. However, such studies have also indicated that the effects of HDAC inhibitors could be considerably broader and more complicated than originally understood. Here we summarize recent advances in the understanding of the molecular events that underlie the anticancer effects of HDAC inhibitors, and discuss how such information could be used in optimizing the development and application of these agents in the clinic, either as monotherapies or in combination with other anticancer drugs.

Apoptosis: A Link between Cancer Genetics and Chemotherapy

Defects in apoptosis underpin both tumorigenesis and drug resistance, and because of these defects chemotherapy often fails. Understanding the molecular events that contribute to drug-induced apoptosis, and how tumors evade apoptotic death, provides a paradigm to explain the relationship between cancer genetics and treatment sensitivity and should enable a more rational approach to anticancer drug design and therapy.

Histone-deacetylase inhibitors: novel drugs for the treatment of cancer.

The opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs) allow gene expression to be exquisitely regulated through chromatin remodelling. Aberrant transcription due to altered expression or mutation of genes that encode HATs, HDACs or their binding partners, is a key event in the onset and progression of cancer. HDAC inhibitors can reactivate gene expression and inhibit the growth and survival of tumour cells. The remarkable tumour specificity of these compounds, and their potency in vitro and in vivo, underscore the potential of HDAC inhibitors as exciting new agents for the treatment of cancer.

The TRAIL apoptotic pathway in cancer onset, progression and therapy.

Triggering of tumour cell apoptosis is the foundation of many cancer therapies. Death receptors of the tumour necrosis factor (TNF) superfamily have been largely characterized, as have the signals that are generated when these receptors are activated. TNF-related apoptosis-inducing ligand (TRAIL) receptors (TRAILR1 and TRAILR2) are promising targets for cancer therapy. Herein we review what is known about the molecular control of TRAIL-mediated apoptosis, the role of TRAIL in carcinogenesis and the potential therapeutic utility of recombinant TRAIL and agonistic antibodies against TRAILR1 and TRAILR2.

New and emerging HDAC inhibitors for cancer treatment

Epigenetic enzymes are often dysregulated in human tumors through mutation, altered expression, or inappropriate recruitment to certain loci. The identification of these enzymes and their partner proteins has driven the rapid development of small-molecule inhibitors that target the cancer epigenome. Herein, we discuss the influence of aberrantly regulated histone deacetylases (HDACs) in tumorigenesis. We examine HDAC inhibitors (HDACis) targeting class I, II, and IV HDACs that are currently under development for use as anticancer agents following the FDA approval of two HDACis, vorinostat and romidepsin.

Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders.

Epigenetic aberrations, which are recognized as key drivers of several human diseases, are often caused by genetic defects that result in functional deregulation of epigenetic proteins, their altered expression and/or their atypical recruitment to certain gene promoters. Importantly, epigenetic changes are reversible, and epigenetic enzymes and regulatory proteins can be targeted using small molecules. This Review discusses the role of altered expression and/or function of one class of epigenetic regulators--histone deacetylases (HDACs)--and their role in cancer, neurological diseases and immune disorders. We highlight the development of small-molecule HDAC inhibitors and their use in the laboratory, in preclinical models and in the clinic.Epigenetic aberrations, which are recognized as key drivers of several human diseases, are often caused by genetic defects that result in functional deregulation of epigenetic proteins, their altered expression and/or their atypical recruitment to certain gene promoters. Importantly, epigenetic changes are reversible, and epigenetic enzymes and regulatory proteins can be targeted using small molecules. This Review discusses the role of altered expression and/or function of one class of epigenetic regulators — histone deacetylases (HDACs) — and their role in cancer, neurological diseases and immune disorders. We highlight the development of small-molecule HDAC inhibitors and their use in the laboratory, in preclinical models and in the clinic.

Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis

Elevated expression of members of the BCL-2 pro-survival family of proteins can confer resistance to apoptosis in cancer cells. Small molecule obatoclax (GX15-070), which is predicted to occupy a hydrophobic pocket within the BH3 binding groove of BCL-2, antagonizes these members and induces apoptosis, dependent on BAX and BAK. Reconstitution in yeast confirmed that obatoclax acts on the pathway and overcomes BCL-2-, BCL-XL-, BCL-w-, and MCL-1-mediated resistance to BAX or BAK. The compound potently interfered with the direct interaction between MCL-1 and BAK in intact mitochondrial outer membrane and inhibited the association between MCL-1 and BAK in intact cells. MCL-1 has been shown to confer resistance to the BCL-2/BCL-XL/BCL-w-selective antagonist ABT-737 and to the proteasome inhibitor bortezomib. In both cases, this resistance was overcome by obatoclax. These findings support a rational clinical development opportunity for the compound in cancer indications or treatments where MCL-1 contributes to resistance to cell killing.

The histone deacetylase inhibitor and chemotherapeutic agent suberoylanilide hydroxamic acid (SAHA) induces a cell-death pathway characterized by cleavage of Bid and production of reactive oxygen species.

Many chemotherapeutic agents induce mitochondrial-membrane disruption to initiate apoptosis. However, the upstream events leading to drug-induced mitochondrial perturbation have remained poorly defined. We have used a variety of physiological and pharmacological inhibitors of distinct apoptotic pathways to analyze the manner by which suberoylanilide hydroxamic acid (SAHA), a chemotherapeutic agent and histone deacetylase inhibitor, induces cell death. We demonstrate that SAHA initiates cell death by inducing mitochondria-mediated death pathways characterized by cytochrome c release and the production of reactive oxygen species, and does not require the activation of key caspases such as caspase-8 or -3. We provide evidence that mitochondrial disruption is achieved by means of the cleavage of the BH3-only proapoptotic Bcl-2 family member Bid. SAHA-induced Bid cleavage was not blocked by caspase inhibitors or the overexpression of Bcl-2 but did require the transcriptional regulatory activity of SAHA. These data provide evidence of a mechanism of cell death mediated by transcriptional events that result in the cleavage of Bid, disruption of the mitochondrial membrane, and production of reactive oxygen species to induce cell death.

Histone deacetylase inhibitors in cancer therapy: is transcription the primary target?

The study of HDIs in cancer, initially motivated by the study of aberrant transcriptional repression, is rapidly evolving. It is now apparent that the transcriptional effects of HDIs may be but one facet of their action. In specific forms of cancer such as the myeloid leukemias, HDIs may indeed be working as predicted to block histone deacetylases and potentiate acetylation at specific genes. However, the focus on histone acetylation neglects the many other facets of epigenetic regulation of gene expression. True targeting of transcription in leukemia and other tumors might require a combination of agents to modify chromatin, including DNA methyl transferase inhibitors, histone methylase inhibitors, HDIs, and specific stimulators of transcription factor activity.In the more common forms of cancer, HDIs are also promising therapeutic agents, but here their mechanism of action may be quite different. HDIs have pleiotropic effects on cells, with outputs of differentiation, growth arrest, and cell death all possible. It is not clear if transcription is the primary HDI target in these cells, or if other effects, perhaps triggered by aberrant mitosis, play a fundamental role. In patients, these effects may be dependent on the particular genetic lesions of the tumor, the dose and length of exposure of the tumor to drug, and the possibility that HDIs could affect secondary signaling pathways. A combination of basic, clinical, and translational studies will ultimately determine the clinical utility of these agents and their mechanism of action.

Epigenetics in cancer: targeting chromatin modifications.

Posttranslational modifications to histones affect chromatin structure and function resulting in altered gene expression and changes in cell behavior. Aberrant gene expression and altered epigenomic patterns are major features of cancer. Epigenetic changes including histone acetylation, histone methylation, and DNA methylation are now thought to play important roles in the onset and progression of cancer in numerous tumor types. Indeed dysregulated epigenetic modifications, especially in early neoplastic development, may be just as significant as genetic mutations in driving cancer development and growth. The reversal of aberrant epigenetic changes has therefore emerged as a potential strategy for the treatment of cancer. A number of compounds targeting enzymes that regulate histone acetylation, histone methylation, and DNA methylation have been developed as epigenetic therapies, with some demonstrating efficacy in hematological malignancies and solid tumors. This review highlights the roles of epigenetic modifications to histones and DNA in tumorigenesis and emerging epigenetic therapies being developed for the treatment of cancer. [Mol Cancer Ther 2009;8(6):1409–20]