Histone Deacetylase Inhibitors in Cancer Treatment: A Review of the Clinical Toxicity and the Modulation of Gene Expression in Cancer Cells

Section for Hematology, The University of Bergen and Haukeland University Hospital, Bergen, Norway.
Current pharmaceutical biotechnology (Impact Factor: 2.51). 12/2007; 8(6):388-400. DOI: 10.2174/138920107783018417
Source: PubMed


Characterization of epigenetic events in carcinogenesis has led to the discovery of a new class of oncogenes and thereby a new class of therapeutic targets. Among the new therapeutic approaches are modulation of protein lysine acetylation through inhibition of histone deacetylases (HDACs). HDACs deacetylate histones as well as transcription factors and can modulate gene expression through both these mechanisms in normal and malignant cells. Furthermore, acetylation is an important posttranslational modulation of several proteins involved in the regulation of cell proliferation, differentiation and apoptosis in normal as well as cancer cells. Even though several HDAC inhibitors have been characterized in vitro, only a limited number of these agents are in clinical trials. Various HDAC inhibitors differ in their toxicity profile when comparing the side effects described in the available clinical studies of HDAC inhibition in the treatment of cancer. These drugs may also affect normal hematopoiesis; hematologic toxicity is common to many drugs but stimulation of hematopoiesis seems to occur for others. HDAC inhibitors usually affect <10% of the genes in cancer cells. Divergent effects of HDAC inhibition on the global gene expression profiles have been described when testing various cancer cells, and this is further complicated by altered HDAC expression induced by HDAC inhibitors. However, increased p21 expression seems to be a common characteristic for most studies, suggesting an important role of this molecule during HDAC inhibitory treatment. Even though the initial studies are encouraging, additional in vitro and in vivo pharmacological characterization is definitely needed.

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    • "There is also increasing evidence that aberrant DNA methylation is an important hallmark of CRC. The link between DNA methylation and CRC was first observed in 1983 when it was suggested that cancer cells occurred because of hypomethylation of their genomes [102]. Genomic instability and loss of imprinting genes like IGF2 (insulin-like growth factor 2) may be both initiated by DNA hypomethylation [103, 104]. "
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    ABSTRACT: Genetics and epigenetics coregulate the cancer initiation and progression. Epigenetic mechanisms include DNA methylation, histone modification, chromatin remodeling, and noncoding RNAs. Aberrant epigenetic modifications play a fundamental role in the formation of gastrointestinal cancers. Advances in epigenetics offer a better understanding of the carcinogenesis and provide new insights into the discovery of biomarkers for diagnosis, and prognosis prediction of human cancers. This review aims to overview the epigenetic aberrance and the clinical applications as biomarkers in gastrointestinal cancers mainly gastric cancer and colorectal cancer.
    03/2014; 2014:464015. DOI:10.1155/2014/464015
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    • "Acute myeloid leukemia (AML) is an aggressive bone marrow malignancy and several studies have demonstrated that different types of bone marrow stromal cells support leukemogenesis, including the maintenance of leukemic stem/progenitor cells in osteoblast-containing endosteal niches and in endothelium-containing vascular niches in the bone marrow [1] [2]. Studies of antileukemic drugs mainly focus on the pharmacological effects on the AML cell populations whereas pharmacological effects on the AML-supporting stromal cells are not so well characterized, especially not in studies of the low-toxicity disease-stabilizing therapeutic alternatives [3] [4] [5] [6]. Several clinical studies have described an AML-stabilizing effect of valproic acid (VPA) in combination with all-trans retinoic acid (ATRA) and eventually cytotoxic drugs (e.g., Ara-C) [6] [7] [8] [9] [10] [11] [12] [13] [14]. "
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    ABSTRACT: The combined use of the histone deacetylase inhibitor valproic acid (VPA), the retinoic acid receptor- α agonist all-trans retinoic acid (ATRA), and the deoxyribonucleic acid polymerase- α inhibitor cytarabine (Ara-C) is now considered for disease-stabilizing treatment of acute myeloid leukemia (AML). Leukemogenesis and leukemia cell chemoresistance seem to be supported by neighbouring stromal cells in the bone marrow, and we have therefore investigated the effects of these drugs on primary human endothelial cells and the osteoblastic Cal72 cell line. The results show that VPA and Ara-C have antiproliferative effects, and the antiproliferative/cytotoxic effect of Ara-C was seen at low concentrations corresponding to serum levels found during low-dose in vivo treatment. Furthermore, in functional assays of endothelial migration and tube formation VPA elicited an antiangiogenic effect, whereas ATRA elicited a proangiogenic effect. Finally, VPA and ATRA altered the endothelial cell release of angiogenic mediators; ATRA increased levels of CXCL8, PDGF-AA, and VEGF-D, while VPA decreased VEGF-D and PDGF-AA/BB levels and both drugs reduced MMP-2 levels. Several of these mediators can enhance AML cell proliferation and/or are involved in AML-induced bone marrow angiogenesis, and direct pharmacological effects on stromal cells may thus indirectly contribute to the overall antileukemic activity of this triple drug combination.
    01/2014; 2014(7):143479. DOI:10.1155/2014/143479
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    • "Several previous studies have indicated that histone deacetylase (HDAC) inhibitors can induce disease control in AML [6,7]. Valproic acid is the HDAC inhibitor used in most of these studies, but butyric acid and depsipeptide seem to have similar effects [7]. "
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    ABSTRACT: A large proportion of patients with acute myeloid leukemia (AML) are not fit for intensive and potentially curative therapy due to advanced age or comorbidity. Previous studies have demonstrated that a subset of these patients can benefit from disease-stabilizing therapy based on all-trans retinoic acid (ATRA) and valproic acid. Even though complete hematological remission is only achieved for exceptional patients, a relatively large subset of patients respond to this treatment with stabilization of normal peripheral blood cell counts. In this clinical study we investigated the efficiency and safety of combining (i) continuous administration of valproic acid with (ii) intermittent oral ATRA treatment (21.5 mg/m2 twice daily) for 14 days and low-dose cytarabine (10 mg/m2 daily) for 10 days administered subcutaneously. If cytarabine could not control hyperleukocytosis it was replaced by hydroxyurea or 6-mercaptopurin to keep the peripheral blood blast count below 50 x 109/L. The study included 36 AML patients (median age 77 years, range 48 to 90 years) unfit for conventional intensive chemotherapy; 11 patients responded to the treatment according to the myelodysplastic syndrome (MDS) response criteria and two of these responders achieved complete hematological remission. The most common response to treatment was increased and stabilized platelet counts. The responder patients had a median survival of 171 days (range 102 to > 574 days) and they could spend most of this time outside hospital, whereas the nonresponders had a median survival of 33 days (range 8 to 149 days). The valproic acid serum levels did not differ between responder and nonresponder patients and the treatment was associated with a decrease in the level of circulating regulatory T cells. Treatment with continuous valproic acid and intermittent ATRA plus low-dose cytarabine has a low frequency of side effects and complete hematological remission is seen for a small minority of patients. However, disease stabilization is seen for a subset of AML patients unfit for conventional intensive chemotherapy.
    08/2013; 5(1):13. DOI:10.1186/1868-7083-5-13
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