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Targeting the NF-κB Pathway as a Combination Therapy for Advanced Thyroid Cancer

NF-κB signaling plays an important role in tumor cell proliferation, cell survival, angiogenesis, invasion, metastasis and drug/radiation resistance. Combination therapy involving NF-κB pathway inhibition is an attractive strategy for the treatment of advanced forms of thyroid cancer. This study was...

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Autores principales: Pozdeyev, Nikita, Berlinberg, Adam, Zhou, Qiong, Wuensch, Kelsey, Shibata, Hiroyuki, Wood, William M., Haugen, Bryan R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532464/
https://www.ncbi.nlm.nih.gov/pubmed/26263379
http://dx.doi.org/10.1371/journal.pone.0134901
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author Pozdeyev, Nikita
Berlinberg, Adam
Zhou, Qiong
Wuensch, Kelsey
Shibata, Hiroyuki
Wood, William M.
Haugen, Bryan R.
author_facet Pozdeyev, Nikita
Berlinberg, Adam
Zhou, Qiong
Wuensch, Kelsey
Shibata, Hiroyuki
Wood, William M.
Haugen, Bryan R.
author_sort Pozdeyev, Nikita
collection PubMed
description NF-κB signaling plays an important role in tumor cell proliferation, cell survival, angiogenesis, invasion, metastasis and drug/radiation resistance. Combination therapy involving NF-κB pathway inhibition is an attractive strategy for the treatment of advanced forms of thyroid cancer. This study was designed to test the efficacy of NF-κB pathway inhibition in combination with cytotoxic chemotherapy, using docetaxel and ionizing radiation in in vitro models of thyroid cancer. We found that while both docetaxel and ionizing radiation activated NF-κB signaling in thyroid cancer cells, there was no synergistic effect on cell proliferation and/or programmed cell death with either genetic (transduction of a dominant negative mutant form of IκBα) or pharmacologic (proteasome inhibitor bortezomib and IKKβ inhibitor GO-Y030) inhibition of the NF-κB pathway in thyroid cancer cell lines BCPAP, 8505C, THJ16T and SW1736. Docetaxel plus bortezomib synergistically decreased in vitro invasion of 8505C cells, but not in the other cell lines. Screening of a panel of clinically relevant targeted therapies for synergy with genetic NF-κB inhibition in a proliferation/cytotoxicity assay identified the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) as a potential candidate. However, the synergistic effect was confirmed only in the BCPAP cells. These results indicate that NF-κB inhibitors are unlikely to be beneficial as combination therapy with taxane cytotoxic chemotherapy, external radiation therapy or radioiodine therapy. There may be unique circumstances where NF-κB inhibitors may be considered in combination with docetaxel to reduce tumor invasion or in combination with HDAC inhibitors to reduce tumor growth, but this does not appear to be a combination therapy that could be broadly applied to patients with advanced thyroid cancer. Further research may identify which subsets of patients/tumors may respond to this therapeutic approach.
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spelling pubmed-45324642015-08-20 Targeting the NF-κB Pathway as a Combination Therapy for Advanced Thyroid Cancer Pozdeyev, Nikita Berlinberg, Adam Zhou, Qiong Wuensch, Kelsey Shibata, Hiroyuki Wood, William M. Haugen, Bryan R. PLoS One Research Article NF-κB signaling plays an important role in tumor cell proliferation, cell survival, angiogenesis, invasion, metastasis and drug/radiation resistance. Combination therapy involving NF-κB pathway inhibition is an attractive strategy for the treatment of advanced forms of thyroid cancer. This study was designed to test the efficacy of NF-κB pathway inhibition in combination with cytotoxic chemotherapy, using docetaxel and ionizing radiation in in vitro models of thyroid cancer. We found that while both docetaxel and ionizing radiation activated NF-κB signaling in thyroid cancer cells, there was no synergistic effect on cell proliferation and/or programmed cell death with either genetic (transduction of a dominant negative mutant form of IκBα) or pharmacologic (proteasome inhibitor bortezomib and IKKβ inhibitor GO-Y030) inhibition of the NF-κB pathway in thyroid cancer cell lines BCPAP, 8505C, THJ16T and SW1736. Docetaxel plus bortezomib synergistically decreased in vitro invasion of 8505C cells, but not in the other cell lines. Screening of a panel of clinically relevant targeted therapies for synergy with genetic NF-κB inhibition in a proliferation/cytotoxicity assay identified the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) as a potential candidate. However, the synergistic effect was confirmed only in the BCPAP cells. These results indicate that NF-κB inhibitors are unlikely to be beneficial as combination therapy with taxane cytotoxic chemotherapy, external radiation therapy or radioiodine therapy. There may be unique circumstances where NF-κB inhibitors may be considered in combination with docetaxel to reduce tumor invasion or in combination with HDAC inhibitors to reduce tumor growth, but this does not appear to be a combination therapy that could be broadly applied to patients with advanced thyroid cancer. Further research may identify which subsets of patients/tumors may respond to this therapeutic approach. Public Library of Science 2015-08-11 /pmc/articles/PMC4532464/ /pubmed/26263379 http://dx.doi.org/10.1371/journal.pone.0134901 Text en © 2015 Pozdeyev et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Pozdeyev, Nikita
Berlinberg, Adam
Zhou, Qiong
Wuensch, Kelsey
Shibata, Hiroyuki
Wood, William M.
Haugen, Bryan R.
Targeting the NF-κB Pathway as a Combination Therapy for Advanced Thyroid Cancer
title Targeting the NF-κB Pathway as a Combination Therapy for Advanced Thyroid Cancer
title_full Targeting the NF-κB Pathway as a Combination Therapy for Advanced Thyroid Cancer
title_fullStr Targeting the NF-κB Pathway as a Combination Therapy for Advanced Thyroid Cancer
title_full_unstemmed Targeting the NF-κB Pathway as a Combination Therapy for Advanced Thyroid Cancer
title_short Targeting the NF-κB Pathway as a Combination Therapy for Advanced Thyroid Cancer
title_sort targeting the nf-κb pathway as a combination therapy for advanced thyroid cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532464/
https://www.ncbi.nlm.nih.gov/pubmed/26263379
http://dx.doi.org/10.1371/journal.pone.0134901
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