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Tumor treating fields increases membrane permeability in glioblastoma cells

Glioblastoma is the most common yet most lethal of primary brain cancers with a one-year post-diagnosis survival rate of 65% and a five-year survival rate of barely 5%. Recently the U.S. Food and Drug Administration approved a novel fourth approach (in addition to surgery, radiation therapy, and che...

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Autores principales: Chang, Edwin, Patel, Chirag B., Pohling, Christoph, Young, Caroline, Song, Jonathan, Flores, Thomas Anthony, Zeng, Yitian, Joubert, Lydia-Marie, Arami, Hamed, Natarajan, Arutselvan, Sinclair, Robert, Gambhir, Sanjiv S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281619/
https://www.ncbi.nlm.nih.gov/pubmed/30534421
http://dx.doi.org/10.1038/s41420-018-0130-x
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author Chang, Edwin
Patel, Chirag B.
Pohling, Christoph
Young, Caroline
Song, Jonathan
Flores, Thomas Anthony
Zeng, Yitian
Joubert, Lydia-Marie
Arami, Hamed
Natarajan, Arutselvan
Sinclair, Robert
Gambhir, Sanjiv S.
author_facet Chang, Edwin
Patel, Chirag B.
Pohling, Christoph
Young, Caroline
Song, Jonathan
Flores, Thomas Anthony
Zeng, Yitian
Joubert, Lydia-Marie
Arami, Hamed
Natarajan, Arutselvan
Sinclair, Robert
Gambhir, Sanjiv S.
author_sort Chang, Edwin
collection PubMed
description Glioblastoma is the most common yet most lethal of primary brain cancers with a one-year post-diagnosis survival rate of 65% and a five-year survival rate of barely 5%. Recently the U.S. Food and Drug Administration approved a novel fourth approach (in addition to surgery, radiation therapy, and chemotherapy) to treating glioblastoma; namely, tumor treating fields (TTFields). TTFields involves the delivery of alternating electric fields to the tumor but its mechanisms of action are not fully understood. Current theories involve TTFields disrupting mitosis due to interference with proper mitotic spindle assembly. We show that TTFields also alters cellular membrane structure thus rendering it more permeant to chemotherapeutics. Increased membrane permeability through the imposition of TTFields was shown by several approaches. For example, increased permeability was indicated through increased bioluminescence with TTFields exposure or with the increased binding and ingress of membrane-associating reagents such as Dextran-FITC or ethidium D or with the demonstration by scanning electron microscopy of augmented number and sizes of holes on the cellular membrane. Further investigations showed that increases in bioluminescence and membrane hole production with TTFields exposure disappeared by 24 h after cessation of alternating electric fields thus demonstrating that this phenomenom is reversible. Preliminary investigations showed that TTFields did not induce membrane holes in normal human fibroblasts thus suggesting that the phenomenom was specific to cancer cells. With TTFields, we present evidence showing augmented membrane accessibility by compounds such as 5-aminolevulinic acid, a reagent used intraoperatively to delineate tumor from normal tissue in glioblastoma patients. In addition, this mechanism helps to explain previous reports of additive and synergistic effects between TTFields and other chemotherapies. These findings have implications for the design of combination therapies in glioblastoma and other cancers and may significantly alter standard of care strategies for these diseases.
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spelling pubmed-62816192018-12-10 Tumor treating fields increases membrane permeability in glioblastoma cells Chang, Edwin Patel, Chirag B. Pohling, Christoph Young, Caroline Song, Jonathan Flores, Thomas Anthony Zeng, Yitian Joubert, Lydia-Marie Arami, Hamed Natarajan, Arutselvan Sinclair, Robert Gambhir, Sanjiv S. Cell Death Discov Article Glioblastoma is the most common yet most lethal of primary brain cancers with a one-year post-diagnosis survival rate of 65% and a five-year survival rate of barely 5%. Recently the U.S. Food and Drug Administration approved a novel fourth approach (in addition to surgery, radiation therapy, and chemotherapy) to treating glioblastoma; namely, tumor treating fields (TTFields). TTFields involves the delivery of alternating electric fields to the tumor but its mechanisms of action are not fully understood. Current theories involve TTFields disrupting mitosis due to interference with proper mitotic spindle assembly. We show that TTFields also alters cellular membrane structure thus rendering it more permeant to chemotherapeutics. Increased membrane permeability through the imposition of TTFields was shown by several approaches. For example, increased permeability was indicated through increased bioluminescence with TTFields exposure or with the increased binding and ingress of membrane-associating reagents such as Dextran-FITC or ethidium D or with the demonstration by scanning electron microscopy of augmented number and sizes of holes on the cellular membrane. Further investigations showed that increases in bioluminescence and membrane hole production with TTFields exposure disappeared by 24 h after cessation of alternating electric fields thus demonstrating that this phenomenom is reversible. Preliminary investigations showed that TTFields did not induce membrane holes in normal human fibroblasts thus suggesting that the phenomenom was specific to cancer cells. With TTFields, we present evidence showing augmented membrane accessibility by compounds such as 5-aminolevulinic acid, a reagent used intraoperatively to delineate tumor from normal tissue in glioblastoma patients. In addition, this mechanism helps to explain previous reports of additive and synergistic effects between TTFields and other chemotherapies. These findings have implications for the design of combination therapies in glioblastoma and other cancers and may significantly alter standard of care strategies for these diseases. Nature Publishing Group UK 2018-12-05 /pmc/articles/PMC6281619/ /pubmed/30534421 http://dx.doi.org/10.1038/s41420-018-0130-x Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Chang, Edwin
Patel, Chirag B.
Pohling, Christoph
Young, Caroline
Song, Jonathan
Flores, Thomas Anthony
Zeng, Yitian
Joubert, Lydia-Marie
Arami, Hamed
Natarajan, Arutselvan
Sinclair, Robert
Gambhir, Sanjiv S.
Tumor treating fields increases membrane permeability in glioblastoma cells
title Tumor treating fields increases membrane permeability in glioblastoma cells
title_full Tumor treating fields increases membrane permeability in glioblastoma cells
title_fullStr Tumor treating fields increases membrane permeability in glioblastoma cells
title_full_unstemmed Tumor treating fields increases membrane permeability in glioblastoma cells
title_short Tumor treating fields increases membrane permeability in glioblastoma cells
title_sort tumor treating fields increases membrane permeability in glioblastoma cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6281619/
https://www.ncbi.nlm.nih.gov/pubmed/30534421
http://dx.doi.org/10.1038/s41420-018-0130-x
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