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 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.
Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States of America.
Nikita
N
Pozdeyev
Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States of America.
Adam
A
Berlinberg
Department of Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States of America.
Qiong
Q
Zhou
Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States of America.
Kelsey
K
Wuensch
Department of Clinical Oncology, Faculty of Medicine, Akita University, Akita, Japan.
Hiroyuki
H
Shibata
Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States of America.
William M
WM
Wood
Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States of America; University of Colorado Cancer Center, Anschutz Medical Campus, Aurora, CO, United States of America.
Bryan R
BR
Haugen
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D000077143:Docetaxel; D006801:Humans; D020128:Inhibitory Concentration 50; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism*; D009367:Neoplasm Staging; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000187:drug effects* / Q000528:radiation effects; D043823:Taxoids / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy
D000970:Antineoplastic Agents; D016328:NF-kappa B; D043823:Taxoids; D000077143:Docetaxel; D000069286:Bortezomib; D053148:Caspase 3; D053179:Caspase 7