Vorinostat Induces Apoptosis and Differentiation in Myeloid Malignancies: Genetic and Molecular Mechanisms

Silva, Gabriela; Cardoso, Bruno; Belo, Hélio; Almeida, António

doi:10.1371/journal.pone.0053766

Cited by 56 publications

(46 citation statements)

References 63 publications

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“…Vorinostat received FDA approval for use in cutaneous T-cell lymphomas in 2006. This drug increased expression of genes previously found to be down regulated in MDS and/or AML (cFOS, COX2, IER3, p15, RAI3) and suppressed expression of genes over-expressed in these malignancies (AXL, c-MYC, Cyclin D1) [214]. One mechanism by which HDAC inhibitors can induce cancer cell apoptosis is by induction of DNA damage and genomic instability through generation of ROS [213].…”

Section: Redox Active Drugs Used For Differentiation/redox Therapymentioning

confidence: 99%

Oxidative stress, redox regulation and diseases of cellular differentiation

Zhang

Townsend

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

216

142

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Background Within cells, there is a narrow concentration threshold that governs whether reactive oxygen species (ROS) induce toxicity or act as second messengers. Scope of review We discuss current understanding of how ROS arise, facilitate cell signaling, cause toxicities and disease related to abnormal cell differentiation and those (primarily) sulfur based pathways that provide nucleophilicity to offset these effects. Primary conclusions Cellular redox homeostasis mediates a plethora of cellular pathways that determine life and death events. For example, ROS intersect with GSH based enzyme pathways to influence cell differentiation, a process integral to normal hematopoiesis, but also affecting a number of diverse cell differentiation related human diseases. Recent attempts to manage such pathologies have focused on intervening in some of these pathways, with the consequence that differentiation therapy targeting redox homeostasis has provided a platform for drug discovery and development. General Significance The balance between electrophilic oxidative stress and protective biomolecular nucleophiles predisposes the evolution of modern life forms. Imbalances of the two can produce aberrant redox homeostasis with resultant pathologies. Understanding the pathways involved provides opportunities to consider interventional strategies.

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Section: Redox Active Drugs Used For Differentiation/redox Therapymentioning

confidence: 99%

Oxidative stress, redox regulation and diseases of cellular differentiation

Zhang

Townsend

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

216

142

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“…HDAC inhibitors promote cell-cycle arrest, growth inhibition, and apoptosis in multiple cell types, including leukaemia cell-lines 129 . In a phase II study 130 , the HDAC inhibitor vorinostat had minimal single-agent activity in patients with untreated or relapsed AML, leading to the initiation of combination studies this agent.…”

Section: Novel Therapies For Patients With Amlmentioning

confidence: 99%

Molecular therapy for acute myeloid leukaemia

2015

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Acute myeloid leukaemia (AML) is a heterogeneous disease that is, in general, associated with a very poor prognosis. Multiple cytogenetic and molecular abnormalities that characterize different forms of AML have been used to better prognosticate patients and inform treatment decisions. Indeed, risk status in patients with this disease has classically been based on cytogenetic findings; however, additional molecular characteristics have been shown to inform risk assessment, including FLT3, NPM1, KIT, and CEBPA mutation status. Advances in sequencing technology have led to the discovery of novel somatic mutations in tissue samples from patients with AML, providing deeper insight into the mutational landscape of the disease. The majority of patients with AML (>97%) are found to have a clonal somatic abnormality on mutational profiling. Nevertheless, our understanding of the utility of mutation profiling in clinical practice remains incomplete and is continually evolving, and evidence-based approaches to application of these data are needed. In this Review, we discuss the evidence-base for integrating mutational data into treatment decisions for patients with AML, and propose novel therapeutic algorithms in the era of molecular medicine.

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“…Histone deacetylase inhibitors, Vorinostat (SAHA) and Apicidin, have demonstrated promising anti-proliferation activity toward myeloid malignancies and solid tumors through acetylation of histones (45)(46)(47). Apicidin is a specific HDAC3/NCoR inhibitor (48).…”

Section: Proper Regulation Of Histone Acetylation Is Required For Monmentioning

confidence: 99%

Quantitative Proteomics Reveals a Role for Epigenetic Reprogramming During Human Monocyte Differentiation

Nicholas

Tang²,

Zhang

et al. 2015

Molecular & Cellular Proteomics

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The differentiation of monocytes into macrophages and dendritic cells involves mechanisms for activation of the innate immune system in response to inflammatory stimuli, such as pathogen infection and environmental cues. Epigenetic reprogramming is thought to play an important role during monocyte differentiation. Complementary to cell surface markers, the characterization of monocytic cell lineages by mass spectrometry based protein/histone expression profiling opens a new avenue for studying immune cell differentiation. Here, we report the application of mass spectrometry and bioinformatics to identify changes in human monocytes during their differentiation into macrophages and dendritic cells. Our data show that linker histone H1 proteins are significantly down-regulated during monocyte differentiation. Although highly enriched H3K9-methyl/S10-phos/K14-acetyl tri-modification forms of histone H3 were identified in monocytes and macrophages, they were dramatically reduced in dendritic cells. In contrast, histone H4 K16 acetylation was found to be markedly higher in dendritic cells than in monocytes and macrophages. We also found that global hyperacetylation generated by the nonspecific histone deacetylase HDAC inhibitor Apicidin induces monocyte differentiation. Together, our data suggest that specific regulation of inter-and intra-histone modifications including H3 K9 methylation, H3 S10 phosphorylation, H3 K14 acetylation, and H4 K16 acetylation must occur in concert with chromatin remodeling by linker histones for cell cycle progression and differentiation of human myeloid cells into macrophages and dendritic cells. Molecular & Cellular

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Vorinostat Induces Apoptosis and Differentiation in Myeloid Malignancies: Genetic and Molecular Mechanisms

Cited by 56 publications

References 63 publications

Oxidative stress, redox regulation and diseases of cellular differentiation

Oxidative stress, redox regulation and diseases of cellular differentiation

Molecular therapy for acute myeloid leukaemia

Quantitative Proteomics Reveals a Role for Epigenetic Reprogramming During Human Monocyte Differentiation

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