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Celecoxib Blocks Vasculogenic Mimicry via an Off-Target Effect to Radiosensitize Lung Cancer Cells: An Experimental Study

The resistance to radiotherapy in lung cancer can be attributed to vasculogenic mimicry (VM) to some extent. Celecoxib (CXB), a selective inhibitor of cyclooxygenase-2 (COX-2), is reported as a radiosensitizer in non-small cell lung cancer (NSCLC). However, whether CXB can regulate VM formation via...

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Autores principales: Niu, Kai, Chen, Xie-Wan, Qin, Yu, Zhang, Lu-Ping, Liao, Rong-Xia, Sun, Jian-Guo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461170/
https://www.ncbi.nlm.nih.gov/pubmed/34568026
http://dx.doi.org/10.3389/fonc.2021.697227
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author Niu, Kai
Chen, Xie-Wan
Qin, Yu
Zhang, Lu-Ping
Liao, Rong-Xia
Sun, Jian-Guo
author_facet Niu, Kai
Chen, Xie-Wan
Qin, Yu
Zhang, Lu-Ping
Liao, Rong-Xia
Sun, Jian-Guo
author_sort Niu, Kai
collection PubMed
description The resistance to radiotherapy in lung cancer can be attributed to vasculogenic mimicry (VM) to some extent. Celecoxib (CXB), a selective inhibitor of cyclooxygenase-2 (COX-2), is reported as a radiosensitizer in non-small cell lung cancer (NSCLC). However, whether CXB can regulate VM formation via an off-target effect to radiosensitize NSCLC remains unclear. This study aimed to elucidate the mechanism underlying the radiosensitizing effect of CXB on NSCLC, i.e., whether CXB can inhibit VM formation via binding to newly identified targets other than COX-2. CXB radiosensitivity assay was performed in BALB/c mice bearing H460 xenografts and C57 mice bearing Lewis lung cancer (LLC) xenografts, which were divided into the control, CXB, irradiation (IR) treatment, and IR plus CXB groups. VM formation was observed using 3D Matrigel, periodic acid solution (PAS) staining, and immunofluorescence staining. The potential off-targets of CXB were screened using Protein Data Bank (PDB) database, MGLTools 1.5.6, and AutoDock Vina 1.1.2 and confirmed by Western blotting, enzyme activity assay, and RNA interference in vitro experiments and by immunohistochemistry in vivo experiments. CXB treatment almost eliminated the enhancement of VM formation by IR in vitro and in vivo, partially due to COX-2 inhibition. Four potential off-targets were predicted by molecular docking. Among them, aminopeptidase N (APN) and integrin alpha-V (ITAV) were remarkably inhibited in protein expression and enzyme activity in vitro or in vivo, consistent with the remarkable reduction of VM formation in H460 xenografts in BALB/c mice. In conclusion, CXB dramatically blocked VM through inhibiting newly identified off-targets APN and ITAV, other than COX-2, then radiosensitizing NSCLC.
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spelling pubmed-84611702021-09-25 Celecoxib Blocks Vasculogenic Mimicry via an Off-Target Effect to Radiosensitize Lung Cancer Cells: An Experimental Study Niu, Kai Chen, Xie-Wan Qin, Yu Zhang, Lu-Ping Liao, Rong-Xia Sun, Jian-Guo Front Oncol Oncology The resistance to radiotherapy in lung cancer can be attributed to vasculogenic mimicry (VM) to some extent. Celecoxib (CXB), a selective inhibitor of cyclooxygenase-2 (COX-2), is reported as a radiosensitizer in non-small cell lung cancer (NSCLC). However, whether CXB can regulate VM formation via an off-target effect to radiosensitize NSCLC remains unclear. This study aimed to elucidate the mechanism underlying the radiosensitizing effect of CXB on NSCLC, i.e., whether CXB can inhibit VM formation via binding to newly identified targets other than COX-2. CXB radiosensitivity assay was performed in BALB/c mice bearing H460 xenografts and C57 mice bearing Lewis lung cancer (LLC) xenografts, which were divided into the control, CXB, irradiation (IR) treatment, and IR plus CXB groups. VM formation was observed using 3D Matrigel, periodic acid solution (PAS) staining, and immunofluorescence staining. The potential off-targets of CXB were screened using Protein Data Bank (PDB) database, MGLTools 1.5.6, and AutoDock Vina 1.1.2 and confirmed by Western blotting, enzyme activity assay, and RNA interference in vitro experiments and by immunohistochemistry in vivo experiments. CXB treatment almost eliminated the enhancement of VM formation by IR in vitro and in vivo, partially due to COX-2 inhibition. Four potential off-targets were predicted by molecular docking. Among them, aminopeptidase N (APN) and integrin alpha-V (ITAV) were remarkably inhibited in protein expression and enzyme activity in vitro or in vivo, consistent with the remarkable reduction of VM formation in H460 xenografts in BALB/c mice. In conclusion, CXB dramatically blocked VM through inhibiting newly identified off-targets APN and ITAV, other than COX-2, then radiosensitizing NSCLC. Frontiers Media S.A. 2021-09-10 /pmc/articles/PMC8461170/ /pubmed/34568026 http://dx.doi.org/10.3389/fonc.2021.697227 Text en Copyright © 2021 Niu, Chen, Qin, Zhang, Liao and Sun https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Niu, Kai
Chen, Xie-Wan
Qin, Yu
Zhang, Lu-Ping
Liao, Rong-Xia
Sun, Jian-Guo
Celecoxib Blocks Vasculogenic Mimicry via an Off-Target Effect to Radiosensitize Lung Cancer Cells: An Experimental Study
title Celecoxib Blocks Vasculogenic Mimicry via an Off-Target Effect to Radiosensitize Lung Cancer Cells: An Experimental Study
title_full Celecoxib Blocks Vasculogenic Mimicry via an Off-Target Effect to Radiosensitize Lung Cancer Cells: An Experimental Study
title_fullStr Celecoxib Blocks Vasculogenic Mimicry via an Off-Target Effect to Radiosensitize Lung Cancer Cells: An Experimental Study
title_full_unstemmed Celecoxib Blocks Vasculogenic Mimicry via an Off-Target Effect to Radiosensitize Lung Cancer Cells: An Experimental Study
title_short Celecoxib Blocks Vasculogenic Mimicry via an Off-Target Effect to Radiosensitize Lung Cancer Cells: An Experimental Study
title_sort celecoxib blocks vasculogenic mimicry via an off-target effect to radiosensitize lung cancer cells: an experimental study
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461170/
https://www.ncbi.nlm.nih.gov/pubmed/34568026
http://dx.doi.org/10.3389/fonc.2021.697227
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