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Histone Deacetylase Inhibitors for the Treatment of Myelodysplastic Syndrome and Acute Myeloid Leukemia

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Histone Deacetylase Inhibitors for the Treatment of Myelodysplastic Syndrome and Acute Myeloid Leukemia Leukemia (2011) 25, 226–235 & 2011 Macmillan Publishers Limited All rights reserved 0887-6924/11 www.nature.com/leu REVIEW Histone deacetylase inhibitors for the treatment of myelodysplastic syndrome and acute myeloid leukemia A Quinta´s-Cardama1,3, FPS Santos1,2,3 and G Garcia-Manero1 1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA and 2Hematology Department, Hospital Israelita Albert Einstein, Sa˜o Paulo, Brazil Epigenetic changes have been identified in recent years as drugs whose mechanism of action has been linked to modula- important factors in the pathogenesis of myelodysplastic tion of gene transcription have taken center stage of both syndrome (MDS) and acute myeloid leukemia (AML). Histone clinical and preclinical research in AML and MDS.8 deacetylase inhibitors (HDACIs) regulate the acetylation of histones as well as other non-histone protein targets. Treat- Histone deacetylase inhibitors (HDACIs) represent one class ment with HDACIs results in chromatin remodeling that permits of gene expression modulating drugs, which is currently being re-expression of silenced tumor suppressor genes in cancer developed for therapy of several types of cancer.9 HDACIs were cells, which, in turn, can potentially result in cellular differ- initially developed as putative epigenetic agents, owing to their entiation, inhibition of proliferation and/or apoptosis. Several ability to modify acetylation status of histones and induce gene classes of HDACIs are currently under development for the expression.10 Typically, optimal gene expression occurs when treatment of patients with MDS and AML. Although modest 11 clinical activity has been reported with the use of HDACIs as histones are in a state of maximal acetylation. Therefore, single-agent therapy, marked responses have been observed in HDACIs have the potential to cause re-expression of genes selected subsets of patients. More importantly, HDACIs appear abnormally suppressed in cancer cells, thus potentially reversing to be synergistic in vitro and improve response rates in vivo the malignant phenotype and inducing growth inhibition, cell- when combined with other agents, such as hypomethylating cycle arrest, differentiation and/or apoptosis.9 However, more agents. Furthermore, HDACIs are also being investigated in recent results of laboratory and clinical studies have indicated combination with non-epigenetic therapies. This article synthe- sizes the most recent results reported with HDACIs in clinical that besides modulation of gene expression, HDACIs have a trials conducted in patients with MDS and other myeloid diverse array of mechanisms of action, and the complexity of malignancies. their effects on malignant cells has only begun to be unraveled.9 Leukemia (2011) 25, 226–235; doi:10.1038/leu.2010.276; HDACIs are being actively investigated as potential therapy of published online 30 November 2010 MDS and AML. Herein, we summarize the results of the most Keywords: histone deacetylase inhibitors; myelodysplastic important clinical and preclinical studies with these drugs.12 syndromes; acute myeloid leukemia Histone modifications and transcriptional activity Introduction DNA is wrapped around the nucleosome, an octamer composed of two units of each of the main histones (H2A, H2B, H3 and H4), Myelodysplastic syndromes (MDS) are a group of clonal and forms a ‘beads-on-a-string’ structure, which folds into hematopoietic stem cell disorders characterized by ineffective higher-order chromatin.13 Chromatin structure modifications are hematopoiesis, peripheral blood cytopenias and a propensity to 1 important modulators of the transcriptional activity of specific transform to acute myeloid leukemia (AML). AML is a myeloid genes. Post-transcriptional modifications of histones have an malignancy characterized by increased self-renewal, limited 2 important role in changing the chromatin structure and thus differentiation and deregulated proliferation of myeloid blasts. modulating gene expression.13 Covalent histone modifications Treatment outcomes of both MDS and AML are suboptimal. include acetylation, methylation, phosphorylation, poly(ADP)- Outside the context of stem cell transplantation, MDS remains ribosylation and ubiquitination.13 Certain modifications of an incurable malignancy, and most patients with AML treated specific amino-acid residues in histones lead to a more open with chemotherapeutic regimens relapse and perish to their 3,4 chromatin configuration (euchromatin), which makes it more disease or associated complications. AML and MDS are accessible to the transcription machinery, whereas other typically diagnosed in elderly individuals (median age 65–70 modifications change the chromatin into a more tightly wound years), and an intensive treatment approach can be applied only structure (heterochromatin), which is associated with transcrip- in the minority of patients owing to increased therapy-related 14,15 5–7 tional silencing. It is believed that the combination of mortality and decreased efficacy. Thus, there is a great need specific histone modifications constitutes a ‘histone code’ that for new agents with more benign toxicity profiles and improved determines the state of the chromatin and thus the transcrip- activity for the treatment of MDS and AML. In recent years, tional activity of genomic regions.14 Acetylation is one of the main histone modifications Correspondence: Dr A Quinta´s-Cardama, Department of Leukemia, associated with the regulation of gene expression.15 Histones Unit 428, The University of Texas MD Anderson Cancer Center, 1515 possess N-terminal tails that are rich in lysine. Acetylation of Holcombe Boulevard, Houston, TX 77030, USA. lysine residues opens the chromatin and promotes gene E-mail: [email protected] 3These authors contributed equally to this work. transcription, whereas histone deacetylation promotes chroma- 15 Received 25 March 2010; revised 30 September 2010; accepted 15 tin condensation and represses gene transcription. Histone October 2010; published online 30 November 2010 deacetylation is mediated by histone deacetylases (HDACs).15 HDAC inhibitors for MDS and AML A Quinta´s-Cardama et al 227 HDACs are conventionally divided into families: class I, including the human HDACs 1, 2, 3 and 8; class II, which encompasses the human HDACs 5, 6, 7, 9 and 10; class III includes the NAD-dependent HDACs related to the yeast Sir2 protein (sirtuins); and class IV, defined by the recently identified human HDAC 11.15,16 Class I, II and IV HDACs are zinc (Zn2 þ )- dependent enzymes and are considered the classical HDACs, distinctive from the unrelated sirtuins.17 Available HDACIs only target the classical HDACs, whereas sirtuin inhibitors are currently under development. Besides histones, HDACs also have several other substrates, including transcription factors (for example, p53, signal transducer and activator of transcription 1 and 3), signaling mediators, steroid receptors, chaperone proteins (heat-shock protein 90 (Hsp90)) and DNA repair enzymes (Ku70).18 Thus, a more appropriate name for these enzymes would be ‘lysine deacetylases’.18 Figure 1 Chemical structure of representative compounds from the major classes of HDACIs. Short-chain fatty acids (valproic acid), Histone deacetylase inhibitors hydroxamic derivatives (vorinostat), non-hydroxamate small mole- cule inhibitors (MGCD0103) and cyclic peptides (depsipeptide (romidepsin)). Increased activity of HDACs leading to reduced or abnormal histone acetylation patterns has been described in cancer cells.19,20 It has been shown that malignant cells present with higher level of HDACs than normal tissues, generating factors and other proteins involved in transcription.18 Micro- hypoacetylated histones.20 Aberrant HDAC activity has also array analyses of leukemic cell lines after exposure to HDACIs been described in certain leukemia subtypes that carry chimeric (trichostatin, vorinostat, romidepsin) have revealed modulation proteins resulting from translocations involving transcription of a large number of genes (approximately 10–20% of the factors such as core binding factor (t(8;21)(q22;q22)FAML1-ETO; genome) repressing and inducing the expression of genes in inv(16)FCBFA-MYH11) and retinoic acid receptor alpha equal measure.26,27 One of the more commonly HDACI- (RARA; t(15;17)(q24;q21)FPML-RARA).21–24 These chimeric induced genes is the cyclin-dependent kinase (CDK) inhibitor proteins recruit HDACs to co-repressor complexes and block CDKN1A (p21WAF1/CIP1).28–30 Induction of CDKN1A by vorino- transcription of genes that lead to myeloid differentiation. Use of stat is p53 independent and accompanied by changes in all-trans retinoic acid (ATRA) in patients with PML-RARA- the acetylation pattern of histones in the CDKN1A gene positive acute promyelocytic leukemia relieves the transcrip- promoter.28,30 Increase in the level of p21WAF1/CIP1 is linked to tional blockade and impedes recruitment of HDACs, thus cell-cycle arrest which is observed upon exposure to HDACIs, leading to cellular differentiation.25 but is not essential for HDACI-induced apoptosis.31,32 HDACIs The development of HDACIs started with the discovery that also decrease the expression of cyclin proteins and CDKs several compounds that were known to induce differentiation and lead to hypophosphorylation of retinoblastoma protein, of leukemic cell lines were inhibitors of HDACs and induced contributing to cell-cycle arrest.33 Mitotic arrest and mitotic cell hyperacetylated histones.10 This led to
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