Kinome profiling analysis identified Src pathway as a novel therapeutic target in combination with histone deacetylase inhibitors for cutaneous T-cell lymphoma

Jimura, Nozomi; Fujii, Kazuyasu; Qiao, Zhiwei; Tsuchiya, Ryuto; Yoshimatsu, Yuki; Kondo, Tadashi; Kanekura, Takuro

doi:10.1016/j.jdermsci.2021.01.004

Cited by 4 publications

(2 citation statements)

References 49 publications

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“…As expected, CTCL cell lines showed a dose-dependent sensitivity for HDAC inhibitors ( Figures 2A, B ). The EC 50 levels obtained ( Table 1 ) are in agreement with most EC 50 levels found in other studies ( Fantin et al, 2008 ; Heider et al, 2009 ; Chakraborty et al, 2013 ; Netchiporouk et al, 2017 ; Schcolnik-Cabrera et al, 2018 ; Li et al, 2019 ; Jimura et al, 2021 ). In order to account for any effects of the DMSO that is used to dissolve the inhibitors (maximum 0.2% DMSO), we tested cell viability of cells treated with or without DMSO.…”

Section: Resultssupporting

confidence: 90%

DOT1L inhibition does not modify the sensitivity of cutaneous T cell lymphoma to pan-HDAC inhibitors in vitro

et al. 2022

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Cutaneous T-cell lymphomas (CTCLs) are a subset of T-cell malignancies presenting in the skin. The treatment options for CTCL, in particular in advanced stages, are limited. One of the emerging therapies for CTCL is treatment with histone deacetylase (HDAC) inhibitors. We recently discovered an evolutionarily conserved crosstalk between HDAC1, one of the targets of HDAC inhibitors, and the histone methyltransferase DOT1L. HDAC1 negatively regulates DOT1L activity in yeast, mouse thymocytes, and mouse thymic lymphoma. Here we studied the functional relationship between HDAC inhibitors and DOT1L in two human CTCL cell lines, specifically addressing the question whether the crosstalk between DOT1L and HDAC1 observed in mouse T cells plays a role in the therapeutic effect of clinically relevant broad-acting HDAC inhibitors in the treatment of human CTCL. We confirmed that human CTCL cell lines were sensitive to treatment with pan-HDAC inhibitors. In contrast, the cell lines were not sensitive to DOT1L inhibitors. Combining both types of inhibitors did neither enhance nor suppress the inhibitory effect of HDAC inhibitors on CTCL cells. Thus our in vitro studies suggest that the effect of commonly used pan-HDAC inhibitors in CTCL cells relies on downstream effects other than DOT1L misregulation.

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Section: Resultssupporting

confidence: 90%

DOT1L inhibition does not modify the sensitivity of cutaneous T cell lymphoma to pan-HDAC inhibitors in vitro

et al. 2022

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“…No established combination therapies with HDACis have been administered for CTCL. However, many attempts, including preclinical trials, have been made to test combinations, such as vorinostat and a phosphoinositide-3 kinase inhibitor [ 12 ], vorinostat, interferon-α and extracorporeal photopheresis [ 13 ], vorinostat and bexarotene [ 14 ], romidepsin and azacytidine [ 15 ], romidepsin and lenalidomide [ 16 ], vorinostat and etretinate [ 17 ], and romidepsin and ponatinib [ 18 ], among others.…”

Section: Introductionmentioning

confidence: 99%

Functional Depletion of HSP72 by siRNA and Quercetin Enhances Vorinostat-Induced Apoptosis in an HSP72-Overexpressing Cutaneous T-Cell Lymphoma Cell Line, Hut78

Fujii

Idogawa

Suzuki

et al. 2021

IJMS

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Histone deacetylase inhibitors (HDACis) are one of the therapeutic options for cutaneous T-cell lymphoma (CTCL), but they have limited effects. We previously demonstrated that HSP72 overexpression is associated with chemoresistance to HDACis in lymphoma cells. The purpose of this study was to investigate whether the functional depletion of HSP72 enhances the effect of the HDACi vorinostat. First, we established a stable HSP72-knockdown CTCL cell line and confirmed the influence of HSP72 reduction on the antitumor effects of vorinostat. Next, we studied the effect of quercetin, an inhibitor of HSP72, on the antineoplastic effects of vorinostat. In five CTCL cell lines examined, HSP72 expression was highest in Hut78 cells, and HSP72 knockdown enhanced vorinostat-induced apoptosis in these cells. Low-dose quercetin reduced HSP72 expression, increased HDAC activity, and enhanced vorinostat-induced suppression of Hut78 cell proliferation. A single low dose of quercetin induced G2 arrest and only slightly increased the sub-G1 cell fraction. Quercetin also significantly enhanced vorinostat-induced apoptosis, caspase-3, caspase-8, and caspase-9 activity, and the loss of mitochondrial membrane potential. HSP72 knockdown enhanced vorinostat-induced apoptosis in an HSP72-overexpressing CTCL cell line, and thus, quercetin may be a suitable candidate for combination therapy with vorinostat in clinical settings.

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Ponatinib: An update on its drug targets, therapeutic potential and safety

Gao

Ding

Tai

et al. 2023

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Kinome profiling analysis identified Src pathway as a novel therapeutic target in combination with histone deacetylase inhibitors for cutaneous T-cell lymphoma

Cited by 4 publications

References 49 publications

DOT1L inhibition does not modify the sensitivity of cutaneous T cell lymphoma to pan-HDAC inhibitors in vitro

DOT1L inhibition does not modify the sensitivity of cutaneous T cell lymphoma to pan-HDAC inhibitors in vitro

Functional Depletion of HSP72 by siRNA and Quercetin Enhances Vorinostat-Induced Apoptosis in an HSP72-Overexpressing Cutaneous T-Cell Lymphoma Cell Line, Hut78

Ponatinib: An update on its drug targets, therapeutic potential and safety

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