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A novel approach to target hypoxic cancer cells via combining β-oxidation inhibitor etomoxir with radiation

BACKGROUND: Hypoxia in tumors is associated with resistance towards various therapies including radiotherapy. In this study, we assessed if hypoxia in cancer spheres could be effectively reduced by adding etomoxir (a β-oxidation inhibitor) immediately after cell irradiation. METHODS: We employed can...

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Autores principales: Dheeraj, Arpit, Agarwal, Chapla, Schlaepfer, Isabel R, Raben, David, Singh, Rana, Agarwal, Rajesh, Deep, Gagan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109663/
https://www.ncbi.nlm.nih.gov/pubmed/30175155
http://dx.doi.org/10.2147/HP.S163115
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author Dheeraj, Arpit
Agarwal, Chapla
Schlaepfer, Isabel R
Raben, David
Singh, Rana
Agarwal, Rajesh
Deep, Gagan
author_facet Dheeraj, Arpit
Agarwal, Chapla
Schlaepfer, Isabel R
Raben, David
Singh, Rana
Agarwal, Rajesh
Deep, Gagan
author_sort Dheeraj, Arpit
collection PubMed
description BACKGROUND: Hypoxia in tumors is associated with resistance towards various therapies including radiotherapy. In this study, we assessed if hypoxia in cancer spheres could be effectively reduced by adding etomoxir (a β-oxidation inhibitor) immediately after cell irradiation. METHODS: We employed cancer cells’ sphere model to target hypoxia. Confocal imaging was used to analyze hypoxia and expression of specific biomarkers in spheres following various treatments (radiation and/or etomoxir). RESULTS: Etomoxir (32.5 μM) treatment improved the radiation (2.5 Gy) efficacy against growth of lung adenocarcinoma H460 spheres. More importantly, radiation and etomoxir combination significantly reduced the hypoxic regions (pimonidazole+ areas) in H460 spheres compared to either treatment alone. Also, etomoxir and radiation combination treatment reduced the protein level of biomarkers for proliferation (Ki-67 and cyclin D1), stemness (CD44) and β-oxidation (CPT1A) in H460 spheres. We observed similar efficacy of etomoxir against growth of prostate cancer LNCaP cells’ spheres when combined with radiation. Further, radiation treatment strongly reduced the hypoxic regions (pimonidazole+ areas) in CPT1 knockdown LNCaP cells’ spheres. CONCLUSIONS: Together, these results offer a unique approach to target hypoxia in solid tumors via combining etomoxir with radiation, thereby improving therapeutic efficacy.
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spelling pubmed-61096632018-08-31 A novel approach to target hypoxic cancer cells via combining β-oxidation inhibitor etomoxir with radiation Dheeraj, Arpit Agarwal, Chapla Schlaepfer, Isabel R Raben, David Singh, Rana Agarwal, Rajesh Deep, Gagan Hypoxia (Auckl) Original Research BACKGROUND: Hypoxia in tumors is associated with resistance towards various therapies including radiotherapy. In this study, we assessed if hypoxia in cancer spheres could be effectively reduced by adding etomoxir (a β-oxidation inhibitor) immediately after cell irradiation. METHODS: We employed cancer cells’ sphere model to target hypoxia. Confocal imaging was used to analyze hypoxia and expression of specific biomarkers in spheres following various treatments (radiation and/or etomoxir). RESULTS: Etomoxir (32.5 μM) treatment improved the radiation (2.5 Gy) efficacy against growth of lung adenocarcinoma H460 spheres. More importantly, radiation and etomoxir combination significantly reduced the hypoxic regions (pimonidazole+ areas) in H460 spheres compared to either treatment alone. Also, etomoxir and radiation combination treatment reduced the protein level of biomarkers for proliferation (Ki-67 and cyclin D1), stemness (CD44) and β-oxidation (CPT1A) in H460 spheres. We observed similar efficacy of etomoxir against growth of prostate cancer LNCaP cells’ spheres when combined with radiation. Further, radiation treatment strongly reduced the hypoxic regions (pimonidazole+ areas) in CPT1 knockdown LNCaP cells’ spheres. CONCLUSIONS: Together, these results offer a unique approach to target hypoxia in solid tumors via combining etomoxir with radiation, thereby improving therapeutic efficacy. Dove Medical Press 2018-08-21 /pmc/articles/PMC6109663/ /pubmed/30175155 http://dx.doi.org/10.2147/HP.S163115 Text en © 2018 Dheeraj et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Original Research
Dheeraj, Arpit
Agarwal, Chapla
Schlaepfer, Isabel R
Raben, David
Singh, Rana
Agarwal, Rajesh
Deep, Gagan
A novel approach to target hypoxic cancer cells via combining β-oxidation inhibitor etomoxir with radiation
title A novel approach to target hypoxic cancer cells via combining β-oxidation inhibitor etomoxir with radiation
title_full A novel approach to target hypoxic cancer cells via combining β-oxidation inhibitor etomoxir with radiation
title_fullStr A novel approach to target hypoxic cancer cells via combining β-oxidation inhibitor etomoxir with radiation
title_full_unstemmed A novel approach to target hypoxic cancer cells via combining β-oxidation inhibitor etomoxir with radiation
title_short A novel approach to target hypoxic cancer cells via combining β-oxidation inhibitor etomoxir with radiation
title_sort novel approach to target hypoxic cancer cells via combining β-oxidation inhibitor etomoxir with radiation
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109663/
https://www.ncbi.nlm.nih.gov/pubmed/30175155
http://dx.doi.org/10.2147/HP.S163115
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