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Valproic acid overcomes hypoxia-induced resistance to apoptosis

Valproic acid (VPA), a histone deacetylase inhibitor (HDACi), has been shown to be an effective tool in cancer treatment. Although its ability to induce apoptosis has been described in many cancer types, the data come from experiments performed in normoxic (21% O(2)) conditions only. Therefore, we q...

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Autores principales: CIPRO, ŠIMON, HŘEBAČKOVÁ, JANA, HRABĚTA, JAN, POLJAKOVÁ, JITKA, ECKSCHLAGER, TOMÁŠ
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583540/
https://www.ncbi.nlm.nih.gov/pubmed/22159638
http://dx.doi.org/10.3892/or.2011.1577
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author CIPRO, ŠIMON
HŘEBAČKOVÁ, JANA
HRABĚTA, JAN
POLJAKOVÁ, JITKA
ECKSCHLAGER, TOMÁŠ
author_facet CIPRO, ŠIMON
HŘEBAČKOVÁ, JANA
HRABĚTA, JAN
POLJAKOVÁ, JITKA
ECKSCHLAGER, TOMÁŠ
author_sort CIPRO, ŠIMON
collection PubMed
description Valproic acid (VPA), a histone deacetylase inhibitor (HDACi), has been shown to be an effective tool in cancer treatment. Although its ability to induce apoptosis has been described in many cancer types, the data come from experiments performed in normoxic (21% O(2)) conditions only. Therefore, we questioned whether VPA would be equally effective under hypoxic conditions (1% O(2)), which is known to induce resistance to apoptosis. Four neuroblastoma cell lines were used: UKF-NB-3, SK-N-AS, plus one cisplatin-resistant subline derived from each of the two original sensitive lines. All were treated with VPA and incubated under hypoxic conditions. Measurement of apoptosis and viability using TUNEL assay and Annexin V/propidium iodide labeling revealed that VPA was even more effective under hypoxic conditions. We show here that hypoxia-induced resistance to chemotherapeutic agents such as cisplatin could be overcome using VPA. We also demonstrated that apoptosis pathways induced by VPA do not differ between normoxic and hypoxic conditions. VPA-induced apoptosis proceeds through the mitochondrial pathway, not the extrinsic pathway (under both normoxia and hypoxia), since inhibition of caspase-8 failed to decrease apoptosis or influence bid cleavage. Our data demonstrated that VPA is more efficient in triggering apoptosis under hypoxic conditions and overcomes hypoxia-induced resistance to cisplatin. The results provide additional evidence for the use of VPA in neuroblastoma (NBL) treatment.
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spelling pubmed-35835402013-02-28 Valproic acid overcomes hypoxia-induced resistance to apoptosis CIPRO, ŠIMON HŘEBAČKOVÁ, JANA HRABĚTA, JAN POLJAKOVÁ, JITKA ECKSCHLAGER, TOMÁŠ Oncol Rep Articles Valproic acid (VPA), a histone deacetylase inhibitor (HDACi), has been shown to be an effective tool in cancer treatment. Although its ability to induce apoptosis has been described in many cancer types, the data come from experiments performed in normoxic (21% O(2)) conditions only. Therefore, we questioned whether VPA would be equally effective under hypoxic conditions (1% O(2)), which is known to induce resistance to apoptosis. Four neuroblastoma cell lines were used: UKF-NB-3, SK-N-AS, plus one cisplatin-resistant subline derived from each of the two original sensitive lines. All were treated with VPA and incubated under hypoxic conditions. Measurement of apoptosis and viability using TUNEL assay and Annexin V/propidium iodide labeling revealed that VPA was even more effective under hypoxic conditions. We show here that hypoxia-induced resistance to chemotherapeutic agents such as cisplatin could be overcome using VPA. We also demonstrated that apoptosis pathways induced by VPA do not differ between normoxic and hypoxic conditions. VPA-induced apoptosis proceeds through the mitochondrial pathway, not the extrinsic pathway (under both normoxia and hypoxia), since inhibition of caspase-8 failed to decrease apoptosis or influence bid cleavage. Our data demonstrated that VPA is more efficient in triggering apoptosis under hypoxic conditions and overcomes hypoxia-induced resistance to cisplatin. The results provide additional evidence for the use of VPA in neuroblastoma (NBL) treatment. D.A. Spandidos 2011-12-06 2012-04 /pmc/articles/PMC3583540/ /pubmed/22159638 http://dx.doi.org/10.3892/or.2011.1577 Text en Copyright © 2012, Spandidos Publications http://creativecommons.org/licenses/by/3.0 This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.
spellingShingle Articles
CIPRO, ŠIMON
HŘEBAČKOVÁ, JANA
HRABĚTA, JAN
POLJAKOVÁ, JITKA
ECKSCHLAGER, TOMÁŠ
Valproic acid overcomes hypoxia-induced resistance to apoptosis
title Valproic acid overcomes hypoxia-induced resistance to apoptosis
title_full Valproic acid overcomes hypoxia-induced resistance to apoptosis
title_fullStr Valproic acid overcomes hypoxia-induced resistance to apoptosis
title_full_unstemmed Valproic acid overcomes hypoxia-induced resistance to apoptosis
title_short Valproic acid overcomes hypoxia-induced resistance to apoptosis
title_sort valproic acid overcomes hypoxia-induced resistance to apoptosis
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583540/
https://www.ncbi.nlm.nih.gov/pubmed/22159638
http://dx.doi.org/10.3892/or.2011.1577
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