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MON-513 Suppressing the Growth of Human Medullary Thyroid Cancer Cells Using FDA-Approved Drug
Medullary thyroid carcinoma (MTC) is a solid tumor of the parafollicular cells in the thyroid gland. MTC has worse prognosis, when compared with other differentiated thyroid cancers, and MTC patients with distant metastases have a low survival rate unless thyroidectomy is performed at an early stage...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207445/ http://dx.doi.org/10.1210/jendso/bvaa046.1639 |
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author | Ramachandran, Ilangovan Ramadoss, Sivakumar Nathan, Lauren Kumaran, R Ileng Chaudhuri, Gautam |
author_facet | Ramachandran, Ilangovan Ramadoss, Sivakumar Nathan, Lauren Kumaran, R Ileng Chaudhuri, Gautam |
author_sort | Ramachandran, Ilangovan |
collection | PubMed |
description | Medullary thyroid carcinoma (MTC) is a solid tumor of the parafollicular cells in the thyroid gland. MTC has worse prognosis, when compared with other differentiated thyroid cancers, and MTC patients with distant metastases have a low survival rate unless thyroidectomy is performed at an early stage. Furthermore, conventional treatments have only marginal benefits. Therefore, there is a need to develop novel therapeutics for MTC. Several drugs that are developed and tested in preclinical trials fail in clinical trials. Therefore, repurposing the already US Food and Drug Administration (FDA)-approved drugs towards the treatment of cancers may have potential benefits, like saving the lives of cancer patients and lowering the investment cost of drug development. Here, we explored a novel precision treatment for thyroid cancers by repurposing the FDA-approved small molecule anti-parasitic drug Nitazoxanide (NTZ). In our study, we examined the anticancer effects of NTZ on human MTC cells using the TT cell line. We treated the TT cells with different concentrations of NTZ and assessed the cell proliferation by water-soluble tetrazolium salt (WST-1) assay and oxygen consumption rate (OCR) by Seahorse extracellular flux analysis (Seahorse XFe24 Analyzer). Additionally, we determined the effects of NTZ on the protein expression of key signaling molecules that regulate MTC cell growth by western blot analysis. Our results indicated that NTZ significantly suppressed the growth of TT cells at 24 h treatment. Very importantly, NTZ reduced the basal OCR demonstrating the inhibition of mitochondrial respiration. Moreover, protein expression studies revealed that NTZ markedly reduced the key Hippo signaling pathway effector molecule TAZ and the oncogene c-myc. Interestingly, NTZ decreased the expression of epidermal growth factor receptor (EGFR) that plays an important role for RET activation in MTC. Importantly, NTZ increased the expression of p53 upregulated modulator of apoptosis (Puma). Taken together, our findings demonstrate for the first time that NTZ inhibits the growth of MTC cells and decreases the cancer cell metabolism. The mechanisms by which NTZ targets the MTC cells involve the suppression of key oncogenic proteins and upregulation of tumor suppressor molecule. Thus, our study highlights that repurposing this FDA-approved currently used drug may have a greater advantage of being tested in preclinical models of MTC, and therefore, for the rapid consideration of NTZ as a potential therapeutic drug to treat MTC patients in the near future. |
format | Online Article Text |
id | pubmed-7207445 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-72074452020-05-13 MON-513 Suppressing the Growth of Human Medullary Thyroid Cancer Cells Using FDA-Approved Drug Ramachandran, Ilangovan Ramadoss, Sivakumar Nathan, Lauren Kumaran, R Ileng Chaudhuri, Gautam J Endocr Soc Thyroid Medullary thyroid carcinoma (MTC) is a solid tumor of the parafollicular cells in the thyroid gland. MTC has worse prognosis, when compared with other differentiated thyroid cancers, and MTC patients with distant metastases have a low survival rate unless thyroidectomy is performed at an early stage. Furthermore, conventional treatments have only marginal benefits. Therefore, there is a need to develop novel therapeutics for MTC. Several drugs that are developed and tested in preclinical trials fail in clinical trials. Therefore, repurposing the already US Food and Drug Administration (FDA)-approved drugs towards the treatment of cancers may have potential benefits, like saving the lives of cancer patients and lowering the investment cost of drug development. Here, we explored a novel precision treatment for thyroid cancers by repurposing the FDA-approved small molecule anti-parasitic drug Nitazoxanide (NTZ). In our study, we examined the anticancer effects of NTZ on human MTC cells using the TT cell line. We treated the TT cells with different concentrations of NTZ and assessed the cell proliferation by water-soluble tetrazolium salt (WST-1) assay and oxygen consumption rate (OCR) by Seahorse extracellular flux analysis (Seahorse XFe24 Analyzer). Additionally, we determined the effects of NTZ on the protein expression of key signaling molecules that regulate MTC cell growth by western blot analysis. Our results indicated that NTZ significantly suppressed the growth of TT cells at 24 h treatment. Very importantly, NTZ reduced the basal OCR demonstrating the inhibition of mitochondrial respiration. Moreover, protein expression studies revealed that NTZ markedly reduced the key Hippo signaling pathway effector molecule TAZ and the oncogene c-myc. Interestingly, NTZ decreased the expression of epidermal growth factor receptor (EGFR) that plays an important role for RET activation in MTC. Importantly, NTZ increased the expression of p53 upregulated modulator of apoptosis (Puma). Taken together, our findings demonstrate for the first time that NTZ inhibits the growth of MTC cells and decreases the cancer cell metabolism. The mechanisms by which NTZ targets the MTC cells involve the suppression of key oncogenic proteins and upregulation of tumor suppressor molecule. Thus, our study highlights that repurposing this FDA-approved currently used drug may have a greater advantage of being tested in preclinical models of MTC, and therefore, for the rapid consideration of NTZ as a potential therapeutic drug to treat MTC patients in the near future. Oxford University Press 2020-05-08 /pmc/articles/PMC7207445/ http://dx.doi.org/10.1210/jendso/bvaa046.1639 Text en © Endocrine Society 2020. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Thyroid Ramachandran, Ilangovan Ramadoss, Sivakumar Nathan, Lauren Kumaran, R Ileng Chaudhuri, Gautam MON-513 Suppressing the Growth of Human Medullary Thyroid Cancer Cells Using FDA-Approved Drug |
title | MON-513 Suppressing the Growth of Human Medullary Thyroid Cancer Cells Using FDA-Approved Drug |
title_full | MON-513 Suppressing the Growth of Human Medullary Thyroid Cancer Cells Using FDA-Approved Drug |
title_fullStr | MON-513 Suppressing the Growth of Human Medullary Thyroid Cancer Cells Using FDA-Approved Drug |
title_full_unstemmed | MON-513 Suppressing the Growth of Human Medullary Thyroid Cancer Cells Using FDA-Approved Drug |
title_short | MON-513 Suppressing the Growth of Human Medullary Thyroid Cancer Cells Using FDA-Approved Drug |
title_sort | mon-513 suppressing the growth of human medullary thyroid cancer cells using fda-approved drug |
topic | Thyroid |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207445/ http://dx.doi.org/10.1210/jendso/bvaa046.1639 |
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