Combination of retinoid and histone deacetylase inhibitor produced an anti-tumor effect in cutaneous T-cell lymphoma by restoring tumor suppressor gene, retinoic acid receptorβ2, via histone acetylation

Kato, Yukihiko; Egusa, Chizu; Maeda, Takeyasu; Tsuboi, Ryoji

doi:10.1016/j.jdermsci.2015.10.016

Cited by 11 publications

(12 citation statements)

References 35 publications

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“…Furthermore, our study provides first evidence for the in vivo relevance of Bcl-2 inhibition, especially in combination with NF-kB inhibition, in CTCL. The SeAx xenograft mouse model we used for that purpose was different from the models described in the literature so far in some aspects: in contrast to other groups working on SeAx xenografts, [49][50][51] we intradermally injected a high number of cells at a high density (1 3 10 8 /mL intradermally) in the presence of Matrigel into NSG mice from different sources and, thus, achieved stable and significant xenograft tumor growth. Of note, only SeAx cell batches with basal apoptotic levels of ,5% to 10% were inoculated.…”

Section: Discussionmentioning

confidence: 99%

Combined inhibition of Bcl-2 and NFκB synergistically induces cell death in cutaneous T-cell lymphoma

Froehlich

Müller‐Decker²,

Braun

et al. 2019

Blood

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Therapeutic options for cutaneous T-cell lymphoma (CTCL) are limited and curative treatment regimens are not available. Thus, new targeted and well-tolerated therapeutic approaches are urgently needed. In this respect, we have recently shown that dimethyl fumerate (DMF) inhibits NF-κB acting as a survival factor in CTCL. Similarly, inhibition of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) has been shown to induce cell death in CTCL especially when combined with histone deacetylase inhibitors. Therefore, we hypothesized that inhibition of Bcl-2 should potentiate NF-κB inhibition in a novel combination treatment of CTCL. We show that, in vitro, the Bcl-2 inhibitors ABT-199 and ABT-263 induced specific cell death in primary CD4+ cells from CTCL patients as well as in the CTCL cell line SeAx, but not in T cells of healthy donors nor in the CTCL cell line HH, which lacks Bcl-2. Combined treatment with ABT-199 and DMF caused synergistic cell death specifically in CTCL cells engaging 2 independent signaling pathways. To verify these findings in vivo, we performed combined ABT-199 and DMF treatment in a xenograft mouse model for CTCL. The combined treatment effectively reduced tumor growth and increased overall survival via synergistic induction of CTCL cell death and suppression of tumor cell proliferation. Essentially, the combination treatment was superior to ABT-199 monotherapy with respect to both efficacy and tolerability. To sum up, our data provide proof of principle for the therapeutic potential of combining Bcl-2 and NF-κB inhibitors in treating CTCL. Next, this potential should be explored further in a clinical study.

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Section: Discussionmentioning

confidence: 99%

Combined inhibition of Bcl-2 and NFκB synergistically induces cell death in cutaneous T-cell lymphoma

Froehlich

Müller‐Decker²,

Braun

et al. 2019

Blood

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“…Retinoids are effective in treating the CTCLs through anti-proliferative and apoptosis-inducing effects 56 , 57 . Retinoic acid receptor β2 works as a tumor suppressor gene 56 .…”

Section: Managementmentioning

confidence: 99%

“…Retinoids are effective in treating the CTCLs through anti-proliferative and apoptosis-inducing effects 56 , 57 . Retinoic acid receptor β2 works as a tumor suppressor gene 56 . Among topical retinoids, bexarotene, also known as Targretin, is approved by the US Food and Drug Administration (FDA) for treating stage I MF 1 , 58 , 59 and relapsed refractory CTCLs 58 .…”

Section: Managementmentioning

confidence: 99%

An overview of cutaneous T cell lymphomas

Bagherani¹,

Smoller

2016

F1000Res

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Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of extranodal non-Hodgkin’s lymphomas that are characterized by a cutaneous infiltration of malignant monoclonal T lymphocytes. They typically afflict adults with a median age of 55 to 60 years, and the annual incidence is about 0.5 per 100,000. Mycosis fungoides, Sézary syndrome, and primary cutaneous peripheral T cell lymphomas not otherwise specified are the most important subtypes of CTCL. CTCL is a complicated concept in terms of etiopathogenesis, diagnosis, therapy, and prognosis. Herein, we summarize advances which have been achieved in these fields.

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“…Recently, more and more evidences on correlation between acetylation and tumorigenesis are emerging 4 - 6 . Acetylation is the reaction that introduces an acetyl functional group into the substrate.…”

Section: Introductionmentioning

confidence: 99%

Tat-interactive Protein-60KDA (TIP60) Regulates the Tumorigenesis of Lung Cancer In Vitro

Yang¹,

Sun²,

Chen³

et al. 2017

J. Cancer

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Histone acetyltransferases (HATs) play vital functions in the tumorigenesis of many solid organ malignancies. We previously screened a human HATs cDNA library and identified Tat-interactive protein-60KDa (TIP60) as a candidate critical HATs in the origination of lung cancer. In this study, our data suggested that overexpression of TIP60 inhibited the cell viability of A549 and H1299 cells since day 2. Compared to the control group, the viability of these two lung cancer cells was inhibited by 25% and 19% at day 6 with the overexpression of TIP60. It increased by 36% and 26% when TIP60 was knockdown for 6 days. The invasion ability of these two cells was also restrained when TIP60 was overexpressed. While knockdown of TIP60 had the opposite effect. Inhibition of TIP60 significantly promoted the expression of molecules in AKT signaling pathway especially c-Myc. Furthermore, compared to paired tumor-adjacent tissue, lung cancer tumors had low expression of TIP60. Therefore, we concluded that TIP60 might inhibit the viability and invasion ability of lung cancer cells through down-regulation of AKT signaling pathway.

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Combination of retinoid and histone deacetylase inhibitor produced an anti-tumor effect in cutaneous T-cell lymphoma by restoring tumor suppressor gene, retinoic acid receptorβ2, via histone acetylation

Cited by 11 publications

References 35 publications

Combined inhibition of Bcl-2 and NFκB synergistically induces cell death in cutaneous T-cell lymphoma

Combined inhibition of Bcl-2 and NFκB synergistically induces cell death in cutaneous T-cell lymphoma

An overview of cutaneous T cell lymphomas

Tat-interactive Protein-60KDA (TIP60) Regulates the Tumorigenesis of Lung Cancer In Vitro

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