Histone deacetylase inhibitor romidepsin induces efficient tumor cell lysis via selective down-regulation of LMP1 and c-myc expression in EBV-positive diffuse large B-cell lymphoma

Shin, Dong‐Yeop; Kim, Areumnuri; Kang, Hye Jin; Park, Sunhoo; Kim, Dong Wan; Lee, Seung-Sook

doi:10.1016/j.canlet.2015.03.016

Cited by 25 publications

(16 citation statements)

References 41 publications

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“…Myc target gene expression is perturbed through direct downregulation of Myc and/or modulation of Mycmediated transcription. Downregulation of Myc expression has been observed in a wide range of tumor types [137][138][139][140][141][142][143]. Furthermore, Myc interacts with a number of HDACs including HDAC1 [144], HDAC2 [145], and HDAC3 [146,147].…”

Section: Hdacis Can Regulate the Expression And Stability Of Oncoprotmentioning

confidence: 99%

How do tumor cells respond to HDAC inhibition?

et al. 2016

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It is now well recognized that mutations, deregulated expression, and aberrant recruitment of epigenetic readers, writers, and erasers are fundamentally important processes in the onset and maintenance of many human tumors. The molecular, biological, and biochemical characteristics of a particular class of epigenetic erasers, the histone deacetylases (HDACs), have been extensively studied and small-molecule HDAC inhibitors (HDACis) have now been clinically approved for the treatment of human hemopoietic malignancies. This review explores our current understanding of the biological and molecular effects on tumor cells following HDACi treatment. The predominant responses include induction of tumor cell death and inhibition of proliferation that in experimental models have been linked to therapeutic efficacy. However, tumor cell-intrinsic responses to HDACi, including modulating tumor immunogenicity have also been described and may have substantial roles in mediating the antitumor effects of HDACi. We posit that the field has failed to fully reconcile the biological consequences of exposure to HDACis with the molecular events that underpin these responses, however progress is being made. Understanding the pleiotrophic activities of HDACis on tumor cells will hopefully fast track the development of more potent and selective HDACi that may be used alone or in combination to improve patient outcomes.

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Section: Hdacis Can Regulate the Expression And Stability Of Oncoprotmentioning

confidence: 99%

How do tumor cells respond to HDAC inhibition?

et al. 2016

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“…The cyclic peptide family included more HDACi like apicidin, romidepsin (FK228), the irreversible HDACi trapoxin A, and CHAP, a hybrid molecule composed of TSA and trapoxin A. A study revealed that the underlying mechanism that mediated the greater induction of cytotoxicity in Epstein–Barr virus (EBV)‐positive versus and Epstein–Barr virus (EBV)‐negative diffuse large B‐cell lymphoma by romidepsin involves the dual inhibition of located membrane protein 1 and c‐myc …”

Section: Histone Deacetylase Inhibitorsmentioning

confidence: 99%

Histone deacetylases function as novel potential therapeutic targets for cancer

Zhang

Shang

Chen

et al. 2016

Hepatology Research

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Diverse cellular functions, including tumor suppressor gene expression, DNA repair, cell proliferation and apoptosis, are regulated by histone acetylation and deacetylation. Histone deacetylases (HDACs) are enzymes involved in remodeling of chromatin by deacetylating the lysine residues. They play a pivotal role in epigenetic regulation of gene expression. Dysregulation of HDACs and aberrant chromatin acetylation and deacetylation have been implicated in the pathogenesis of various diseases, including cancer. Histone deacetylases have become a target for the development of drugs for treating cancer because of their major contribution to oncogenic cell transformation. Overexpression of HDACs correlates with tumorigenesis. Previous work showed that inhibition of HDACs results in apoptosis and the inhibition of cell proliferation in multiple cells. A significant number of HDAC inhibitors have been developed in the past decade. These inhibitors have strong anticancer effects in vitro and in vivo, inducing growth arrest, differentiation, and programmed cell death, inhibiting cell migration, invasion, and metastasis, and suppressing angiogenesis. In addition, HDAC-mediated deacetylation alters the transcriptional activity of nuclear transcription factors, including p53, E2F, c-Myc, and nuclear factor-κB, as well as the extracellular signal-regulated kinase1/2, phosphatidylinositol 3-kinase, Notch, and Wnt signaling pathways. This review highlights the role of HDACs in cancer pathogenesis and, more importantly, that HDACs are potential novel therapeutic targets.

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“…Previous studies have elucidated pathways regulated by HDACs and counteracted by HDAC inhibitors in cancer, including PTEN/Akt/mTor, p53, p21, p27 as well as cyclin/Cdk complexes, which when inhibited lead to the enhancement of cell cycle arrest and apoptosis that is observed with HDAC inhibitors [15, 18, 19]. Treatment of cancer cell lines with HDAC inhibitors frequently also leads to the downregulation of Myc, thereby enhancing cell death in diverse cancer cell types [19–21]. Given that MM cells show addiction to Myc [10], these data suggest a mechanistic link by which HDAC inhibitors could enhance cytotoxicity of MM cells through regulation of Myc expression.…”

Section: Introductionmentioning

confidence: 99%

Enhancement of pomalidomide anti-tumor response with ACY-241, a selective HDAC6 inhibitor

et al. 2017

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Thalidomide-based Immunomodulatory Drugs (IMiDs®), including lenalidomide and pomalidomide, are effective therapeutics for multiple myeloma. These agents have been approved with, or are under clinical development with, other targeted therapies including proteasome inhibitors, αCD38 monoclonal antibodies, as well as histone deacetylase (HDAC) inhibitors for combination therapy. HDAC inhibitors broadly targeting Class I and IIb HDACs have shown potent preclinical efficacy but have frequently demonstrated an undesirable safety profile in combination therapy approaches in clinical studies. Therefore, development of more selective HDAC inhibitors could provide enhanced efficacy with reduced side effects in combination with IMiDs® for the treatment of B-cell malignancies, including multiple myeloma. Here, the second generation selective HDAC6 inhibitor citarinostat (ACY-241), with a more favorable safety profile than non-selective pan-HDAC inhibitors, is shown to synergize with pomalidomide in in vitro assays through promoting greater apoptosis and cell cycle arrest. Furthermore, utilizing a multiple myeloma in vivo murine xenograft model, combination treatment with pomalidomide and ACY-241 leads to increased tumor growth inhibition. At the molecular level, combination treatment with ACY-241 and pomalidomide leads to greater suppression of the pro-survival factors survivin, Myc, and IRF4. The results presented here demonstrate synergy between pomalidomide and ACY-241 in both in vitro and in vivo preclinical models, providing further impetus for clinical development of ACY-241 for use in combination with IMiDs for patients with multiple myeloma and potentially other B-cell malignancies.

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Histone deacetylase inhibitor romidepsin induces efficient tumor cell lysis via selective down-regulation of LMP1 and c-myc expression in EBV-positive diffuse large B-cell lymphoma

Cited by 25 publications

References 41 publications

How do tumor cells respond to HDAC inhibition?

How do tumor cells respond to HDAC inhibition?

Histone deacetylases function as novel potential therapeutic targets for cancer

Enhancement of pomalidomide anti-tumor response with ACY-241, a selective HDAC6 inhibitor

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