A novel NF-κB inhibitor improves glucocorticoid sensitivity of canine neoplastic lymphoid cells by up-regulating expression of glucocorticoid receptors

Matsuda, Akihisa; Tanaka, Akane; Muto, Shoshi; Ohmori, Kitaro; Furusaka, Tohru; Jung, Kyungsook; Karasawa, Kaoru; Okamoto, Nobuhiko; Oida, Kumiko; Itai, Akiko; Matsuda, Hiroshi

doi:10.1016/j.rvsc.2010.03.017

Cited by 16 publications

(23 citation statements)

References 19 publications

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“…Several studies on pathogenic roles of NF-κB have been reported in human lymphoid neoplasms [2,16,18], whereas few studies have been reported in canine counterparts. The sole previous study in canine lymphoid neoplasms described a part of similar results to the present study that the NF-κB subunit of p65 was detected in the nuclear fraction of GL-1 and CL-1 cell lines [12]. Since the present study revealed that NF-κB subunits of p65 and p50 were apparently expressed in the nuclear fraction of canine neoplastic lymphoid cell lines (GL-1, CLBL-1 and CL-1), NF-κB could be spontaneously activated in canine cases with lymphoid neoplasms.…”

Section: Discussionsupporting

confidence: 90%

Analyses on Activation of NF-κB and Effect of Bortezomib in Canine Neoplastic Lymphoid Cell Lines

Kojima

Fujino

Goto‐Koshino

et al. 2013

The Journal of Veterinary Medical Science

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ABSTRACT. Lymphoid malignancies, such as leukemia, and many types of lymphoma are common and severe disorders in dogs. Since shortening remission duration caused by resistance to chemotherapy often becomes clinically critical problems, development of novel and effective therapy should be required. The present study investigated the status of NF-κB and effect of its inhibitor, bortezomib, in six canine neoplastic lymphoid cell lines. NF-κB p65 and p50 were detected in the nuclear fraction of GL-1, CLBL-1 and CL-1, suggesting that NF-κB was constitutively activated in the cells. NF-κB p65 was detected in the cytoplasmic fraction of UL-1 and Ema. After incubation with bortezomib, NF-κB p50 and p65 became undetectable in the nuclear fraction of GL-1, CLBL-1 and CL-1, and CLBL-1, respectively, and p65 was clearly degraded in the cytoplasmic fraction of CLBL-1 and CL-1. Bortezomib inhibited the proliferation of all cell lines except Nody-1 in a concentration-dependent manner. The results indicated that constitutive activation of NF-κB could contribute to the proliferation of canine neoplastic lymphoid cells, and bortezomib would have suppressive effects on the NF-κB activation and the proliferation of neoplastic lymphoid cells in dogs.

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Section: Discussionsupporting

confidence: 90%

Analyses on Activation of NF-κB and Effect of Bortezomib in Canine Neoplastic Lymphoid Cell Lines

Kojima

Fujino

Goto‐Koshino

et al. 2013

The Journal of Veterinary Medical Science

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“…Inhibition of the canonical NFκB pathway may therefore prove relevant in ABC-DLBCL treatment (4). Matsuda et al (12) showed that inhibition of NFκB transcription factor restored the glucocorticoid receptor expression and the sensitivity of CL-1 and GL-1 cells to the effects of dexamethasone.…”

Section: Discussionmentioning

confidence: 99%

In vitro drug sensitivity in canine lymphoma

Pawlak¹,

Obmińska-Mrukowicz²,

Zbyryt³

et al. 2016

Journal of Veterinary Research

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Introduction: Due to the high heterogeneity of canine lymphoma, the aim of the present study was to test in vitro the chemosensitivity of canine high-grade primary lymphoma cells to various cytostatic drugs commonly used to treat dogs: 4-HO-cyclophosphamide, doxorubicin, dexamethasone, prednisolone, vincristine, etoposide, chlorambucil, lomustine, and cytosine arabinoside. Material and Methods: To determine the cell viability and drug ability to induce apoptosis two different tests were used: an MTT assay and annexin V/propidium iodide staining. Results: Both in vitro tests were found to be useful tools. Significant differences in the sensitivity, depending on the drug type, between B-, T-and mixed/null-type lymphoma cells were found for the majority of the tested drugs. B-type cells were the most sensitive in vitro, whereas T-type cells seemed to be the most resistant. Doxorubicin, chlorambucil, etoposide, and vincristine most strongly reduced the cell viability and induced apoptosis. Conclusion: In vitro assays, such as the MTT test and especially the annexin V/PI assay, may be useful tools for predicting a response to the treatment of high-grade lymphoma in dogs or improving the treatment outcomes in individual animals.

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“…Proteasome inhibitor Bortezomib suppresses NF‐κB pathway activation and inhibits cell proliferation of canine DLBCL cell lines . A synthetic NF‐κB inhibitor IMD‐0354 improves glucocorticoid sensitivity of canine malignant lymphoid cells by upregulating expression of glucocorticoid receptors . Constitutively activated NF‐κB signalling can also be inhibited by NEMO Binding Domain (NBD) peptide, which blocks NF‐κB signalling .…”

Section: Discussionmentioning

confidence: 99%

Targeting NEDD8‐activating enzyme is a new approach to treat canine diffuse large B‐cell lymphoma

Assumpção

Marlowe

et al. 2018

Vet Comparative Oncology

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Canine diffuse large B-cell lymphoma (DLBCL), the most common hematologic malignancy of dogs, is associated with poor overall survival. The lack of conventional chemotherapies with sustainable efficacy warrants investigation of novel therapies. Pevonedistat (MLN4924) is a potent and selective small molecule NEDD8-activating enzyme inhibitor. In human activated B-cell-like (ABC) diffuse large B-cell lymphoma, pevonedistat induces lymphoma cell apoptosis, DNA damage and G1 cell cycle arrest by inhibiting the nuclear factor-κB (NF-κB) pathway. Genomic and transcriptomic studies showed that the NF-κB pathway is deregulated in canine DLBCL. Our results showed that pevonedistat treatment significantly reduces the viability of canine DLBCL cells by inducing G1 cell cycle arrest and apoptosis. Pevonedistat treatment inhibits NF-κB pathway activation and downregulates NF-κB target genes in canine DLBCL. Moreover, administration of pevonedistat to mice bearing canine DLBCL xenograft tumours resulted in tumour regression. Our in vivo and in vitro studies provide justification for future clinical application of pevonedistat as a potential new anti-cancer therapy that may benefit both canine and human species.

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A novel NF-κB inhibitor improves glucocorticoid sensitivity of canine neoplastic lymphoid cells by up-regulating expression of glucocorticoid receptors

Cited by 16 publications

References 19 publications

Analyses on Activation of NF-κB and Effect of Bortezomib in Canine Neoplastic Lymphoid Cell Lines

Analyses on Activation of NF-κB and Effect of Bortezomib in Canine Neoplastic Lymphoid Cell Lines

In vitro drug sensitivity in canine lymphoma

Targeting NEDD8‐activating enzyme is a new approach to treat canine diffuse large B‐cell lymphoma

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