Valproic acid for the treatment of myeloid malignancies

Kuendgen, Andrea; Gattermann, Norbert

doi:10.1002/cncr.22891

Cited by 122 publications

(83 citation statements)

References 71 publications

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“…Since the clinical use of HDAC inhibitors is increasing, it is important to define the effects of this family of compounds on the normal hematopoietic compartment. While results of phase I clinical trials with HDAC inhibitors suggest no unfavorable effects on the normal progenitor compartment, 24,35,37,38 our data clearly show that both the choice and concentration of HDAC inhibitor can greatly affect the proliferative and differentiation capacity of CD34 + hematopoietic progenitor cells. Furthermore, our results suggest that these effects may be mediated by non-histone targets.…”

Section: Discussionmentioning

confidence: 65%

“…23 Valproic acid (VPA), a short chain fatty acid and potent class I/IIa HDAC inhibitor, has been extensively studied in preclinical and clinical trials involving hematologic malignancies. 24,25 Studies in patients with advanced myeloid leukemia and myelodysplastic syndromes have shown that treatment with VPA, as monotherapy or in combination with retinoic acid, results in a reduction of malignant blast cells and hematologic improvement. [26][27][28] In addition, in an ex vivo model of acute leukemia, it has been demonstrated that VPA has the potential to relieve transcriptional repression resulting in cellular differentiation of leukemic blast cells.…”

Section: Introductionmentioning

confidence: 99%

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Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation

Bartels¹,

Geest²,

Bierings³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundThe clinical use of chromatin-modulating drugs, such as histone deacetylase inhibitors, for the treatment of bone marrow failure and hematopoietic malignancies has increased dramatically over the last few years. Nonetheless, little is currently known concerning their effects on myelopoiesis. Design and MethodsWe utilized an ex vivo differentiation system in which umbilical cord blood-derived CD34 + cells were treated with trichostatin A, sodium butyrate and valproic acid to evaluate the effect of histone deacetylase inhibitor treatment on myeloid lineage development, colony-forming potential, proliferation, and terminal neutrophil differentiation. ResultsTrichostatin A treatment modestly reduced progenitor proliferation, while sodium butyrate and valproic acid resulted in concentration-dependent effects on proliferation and apoptosis. Addition of valproic acid uniquely stimulated CD34 + proliferation. Sodium butyrate treatment inhibited terminal neutrophil differentiation both quantitatively and qualitatively. Addition of 100 μM valproic acid resulted in increased numbers of mature neutrophils with a block in differentiation at increasing concentrations. Sodium butyrate and valproic acid treatment resulted in increased acetylation of histones 3 and 4 while trichostatin A, sodium butyrate and valproic acid had differential effects on the acetylation of non-histone proteins. ConclusionsIndividual histone deacetylase inihibitors had specific effects on cell fate decisions during myeloid development. These data provide novel insights into the effects of histone deacetylase inhibitors on the regulation of normal hematopoiesis, which is of importance when considering utilizing these compounds for the treatment of myeloid malignancies and bone marrow failure syndromes.Key words: hematopoiesis, HDAC inhibitors, neutrophil. Haematologica 2010;95:1052-1060. doi:10.3324/haematol.2009 This is an open-access paper. Citation: Bartels M, Geest CR, Bierings M, Buitenhuis M, and Coffer PJ. Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation. Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation

Bartels¹,

Geest²,

Bierings³

et al. 2010

Haematologica

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“…Indeed, VPA has been shown to induce the death of chronic lymphocytic leukemia cells, 47 and several trials are currently exploring its activity against various types of cancer, including hematologic malignancies. 48 Depsipeptide, another HDAC inhibitor, has demonstrated efficacy against primary ATL cells. 49 Moreover, in a murine model of human ATL, 50 HDAC inhibitors are able to trigger growth arrest and death of HTLV-1-infected cell lines and ATL cells via activation of the death-receptor pathway and potentialization of tumor necrosis factor-related apoptosis-inducing ligand response.…”

Section: Discussionmentioning

confidence: 99%

Effects of valproate on Tax and HBZ expression in HTLV-1 and HAM/TSP T lymphocytes

Belrose

Gross

Olindo

et al. 2011

Blood

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IntroductionHuman T-lymphotropic virus-1 (HTLV-1) is the etiologic agent of adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP). 1,2 Although the majority of HTLV-1-infected individuals remain asymptomatic carriers (ACs), the lifetime cumulative risk of developing ATL or HAM/ TSP is Ͻ 5%. HTLV-1-provirus integrates into the genome of infected cells, predominantly CD4 ϩ CD25 ϩ T lymphocytes, which represent the main reservoir in peripheral blood. 3 HAM/TSP, a central nervous system neuroinflammatory disease, is associated with perivascular and parenchymal infiltration of HTLV-1-infected T cells and activated cytotoxic T lymphocytes (CTLs). 4 A major determinant of HAM/TSP development is the HTLV-1-infected cell burden. The peripheral blood HTLV-1-proviral load is higher in HAM/TSP patients than AC. 5,6 Follow-up studies of HAM/TSP cohorts showed that high provirus loads were associated with rapid disease progression. [7][8][9] Those studies also demonstrated a relative stability of the HTLV-1-proviral load throughout the disease. Set-point provirus load and subsequent HAM/TSP risk are influenced by the cellular immune-response efficiency, 10 although excessive activation of HTLV-1-specific CTLs might become deleterious and contribute to central nervous system tissue damage. 4 Host-pathogen interplay is characterized by very dynamic kinetics, resulting in an equilibrium between the virus-driven clonal expansion of infected T cells 11 and tight control exerted by the immune response. 10 Tax, a transactivator protein encoded by the pX region of the HTLV-1 genome, plays a central role in disease pathogenesis. Tax activates viral transcription and also modulates many cellular signaling pathways involved in T cell activation, cycling, apoptosis or a combination. 12 Tax expression is promitotic and drives CD4 ϩ T-cell proliferation. 13 At the same time, Tax is the immunodominant target recognized by the CTL response. 14 Rapid immune elimination of Tax-expressing cells may explain the poor detection of Tax-gene products (ie, mRNA or protein) in freshly isolated peripheral blood mononuclear cells (PBMCs) from infected patients. 15-18 Short-term culture enables Tax detection and ex vivo conditions might allow Tax-expressing cells to escape immune selective pressure. 19 The current model of HTLV-1 accumulation and persistence supposes 2 steps: first, Tax expression propels CD4 ϩ T cells into cell cycling, which is well documented; and second, silencing of virus expression allows escape from immune surveillance, which remains to be elucidated. Epigenetic mechanisms might participate in silencing of HTLV-1 gene transcription. 20 Use of histone deacetylase (HDAC) inhibitors, such as valproate (2-npropylpentanoic acid, VPA), was postulated to transiently activate virus expression and thereby expose the latent virus reservoir to immune destruction. 21,22 Another avenue of research focuses on negative posttranscriptional regulators of virus expression, eg, pX-encoded Rex and p30 II...

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“…12 The anti-tumor properties of VPA have been observed in many cancer types, such as prostate cancer, 13 breast cancer, 14 glioma, 15 neuroblastoma 16 and in hematological malignancies. [17][18][19] Recently, our group showed that VPA at low pharmacological concentration could induce apoptosis of CLL B cells in vitro. 20 Bokelmann and Mahlknecht 21 showed decrease in the BCL-2/Bax ratio in CLL B cells treated with VPA in vitro and Bouzar et al 22 reported that valproate synergizes with purine nucleoside analogues to induce apoptosis of CLL B cells.…”

Section: Introductionmentioning

confidence: 99%

Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis

et al. 2009

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Valproic acid for the treatment of myeloid malignancies

Cited by 122 publications

References 71 publications

Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation

Histone deacetylase inhibition modulates cell fate decisions during myeloid differentiation

Effects of valproate on Tax and HBZ expression in HTLV-1 and HAM/TSP T lymphocytes

Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis

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