Mechanisms of HDAC inhibitor-induced thrombocytopenia

Matsuoka, Hiroaki; Unami, Akira; Fujimura, Takao; Noto, Takahisa; Takata, Yoko; Yoshizawa, Katsuhiko; Mori, Hajime; Aramori, Ichiro; Mutoh, Seitaro

doi:10.1016/j.ejphar.2007.06.015

Cited by 47 publications

(33 citation statements)

References 35 publications

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“…This finding is also consistent with a model of thrombocytopenia involving temporary disruption of nuclear factor-kB signaling, as the NFkB transcription factor is important in megakaryocyte maturation, 8 and panobinostat is known to block nuclear translocation of NFkB. 6 A study by Matsuoka et al 12 also found that megakaryocyte numbers in rat spleen increase in response to the histone deacetylase inhibitor FR235225, and that inhibition of GATA-1 in megakaryocytes is associated with histone deacetylase inhibitor-induced thrombocytopenia. Thus, our data show that megakaryocytes are neither lost nor undergo prolonged morphological changes because of therapy, and that enhanced megakaryocytopoiesis ensues following induction of thrombocytopenia.…”

supporting

confidence: 82%

Rapid recovery from panobinostat (LBH589)-induced thrombocytopenia in mice involves a rebound effect of bone marrow megakaryocytes

et al. 2010

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supporting

confidence: 82%

Rapid recovery from panobinostat (LBH589)-induced thrombocytopenia in mice involves a rebound effect of bone marrow megakaryocytes

et al. 2010

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“…In this experiment, variances of platelet counts in each group were very small as previously reported. 21) Regarding a difference in the compounds' treatment protocol between the transplant experiment and the haematologic study (14 consecutive days vs. 7 consecutive days), we have confirmed that there is no difference in the platelet depletion rates between the 7-d treatment and the 14-d treatment.…”

Section: Resultssupporting

confidence: 58%

“…[16][17][18][19][20] We recently reported that HDAC inhibitors inhibit GATA binding protein-1 (GATA-1) gene expression in megakaryocytes by decreasing the transactivation function of GATA-1 itself and that this may in turn lead to a delay in megakaryocyte maturation and initiate thrombocytopenia. 21) In this study, nine HDAC inhibitors compounds were administered at an immunosuppressive dose in vivo to investigate the correlation between a ratio of IC 50 value in GATA-1 reporter gene assay to IC 50 value in IL-2 reporter gene assay (G/I ratio) and a HDAC inhibitor's thrombocytopenic effect. [1,4,7,10]tetraazacyclododecine-1,4,7,10(3H,12H)-tetrone.…”

mentioning

confidence: 99%

Novel Method for Selecting Immunosuppressive Histone Deacetylase (HDAC) Inhibitors with Minimal Thrombocytopenia

Matsuoka

Fujimura

Unami

et al. 2008

Biological & Pharmaceutical Bulletin

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Histone deacetylase (HDAC) inhibitors repress interleukin-2 (IL-2) gene expression in T cells and possess immunosuppressive activity in vivo.In addition to its immunosuppressive activity, HDAC inhibitors block GATA binding protein-1 (GATA-1) gene expression in megakaryocytes and elicit thrombocytopenia. In this report we state that for a given immunosuppressive dose of HDAC inhibitor, the ratio of GATA-1 reporter gene activity relative to IL-2 reporter gene assay (G/I ratio of measured IC 50 ) can be predictive of a HDAC inhibitor's thrombocytopenic effect. This study utilized nine HDAC inhibitors at a minimal effective dose in a rat heterotopic cardiac transplantation model and the resultant G/I ratios and platelet depletion rates were highly correlated (r‫.)339.0؍‬ These results indicate that calculation of G/I ratio can be a novel method for selecting immunosuppressive HDAC inhibitor having minimal thrombocytopenic effect which will benefit the search for new immunosuppressants of greater safety and efficacy.

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“…The mechanism by which belinostat causes thrombocytopenia is not fully understood, but one theory has been explained previously. 24 The HDACi decrease the transactivation function of GATA-1, an erythroid transcription factor, and this has the potential to affect posttranslational modification of GATA-1, leading to a delay in megakaryocyte maturation. Ultimately, thrombocytopenia can occur due to this interaction.…”

Section: Safetymentioning

confidence: 99%

Critical appraisal of belinostat in the management of T-cell lymphoma – patient considerations

Bodiford¹,

Talbott²,

Reddy³

2015

BLCTT

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Abstract:The histone deacetylase inhibitor (HDACi), belinostat, is an emerging and novel therapeutic option for patients diagnosed with relapsed/refractory peripheral T-cell lymphoma (PTCL). The PTCLs are comprised of multiple subtypes that occur in less than one per 100,000 cases in the USA. The incidence of these malignancies is rare, thus limited evidence is available. The most appropriate treatment modality has not been established. The most current recommended option is combination chemotherapy or enrollment in a clinical trial. T-cell lymphomas have emerged as a disease with marked epigenetic dysregulation. HDACi are an innovative and emerging medication class gaining increased attention in the treatment of T-cell lymphomas. There is a need to evaluate their potential place in the treatment of patients diagnosed with PTCL. Currently, the largest study evaluating belinostat use in this patient population is the BELIEF study. The BELIEF study is a single-arm, Phase II clinical trial, evaluating the use of belinostat in patients with refractory or relapsed PTCL. The primary outcome, objective response rate, was 26%, with 11% achieving a complete response and 15% a partial response. This study presents a potential novel therapeutic option in the treatment of these patients. In this paper, we review therapeutic options for PTCL and present the recent data on the role of HDACi, specifically belinostat, in the treatment of patients with relapsed/refractory PTCL.

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Mechanisms of HDAC inhibitor-induced thrombocytopenia

Cited by 47 publications

References 35 publications

Rapid recovery from panobinostat (LBH589)-induced thrombocytopenia in mice involves a rebound effect of bone marrow megakaryocytes

Rapid recovery from panobinostat (LBH589)-induced thrombocytopenia in mice involves a rebound effect of bone marrow megakaryocytes

Novel Method for Selecting Immunosuppressive Histone Deacetylase (HDAC) Inhibitors with Minimal Thrombocytopenia

Critical appraisal of belinostat in the management of T-cell lymphoma – patient considerations

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Mechanisms of HDAC inhibitor-induced thrombocytopenia

Cited by 47 publications

References 35 publications

Rapid recovery from panobinostat (LBH589)-induced thrombocytopenia in mice involves a rebound effect of bone marrow megakaryocytes

Rapid recovery from panobinostat (LBH589)-induced thrombocytopenia in mice involves a rebound effect of bone marrow megakaryocytes

Novel Method for Selecting Immunosuppressive Histone Deacetylase (HDAC) Inhibitors with Minimal Thrombocytopenia

Critical appraisal of belinostat in the management of T-cell lymphoma &ndash; patient considerations

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Critical appraisal of belinostat in the management of T-cell lymphoma – patient considerations