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The Sesquiterpene Lactone Cynaropicrin Manifests Strong Cytotoxicity in Glioblastoma Cells U-87 MG by Induction of Oxidative Stress

Cynaropicrin has shown a wide range of pharmacological properties, such as antitumor action. Here, we showed the inhibitory effect of Cyn on human glioblastoma cell U-87 MG growth. According to the IC50 values, Cyn 4, 8 and 10 µM displayed a significant cytotoxicity, as confirmed by the cell count a...

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Autores principales: Rotondo, Rossella, Oliva, Maria Antonietta, Arcella, Antonietta
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9312546/
https://www.ncbi.nlm.nih.gov/pubmed/35884887
http://dx.doi.org/10.3390/biomedicines10071583
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author Rotondo, Rossella
Oliva, Maria Antonietta
Arcella, Antonietta
author_facet Rotondo, Rossella
Oliva, Maria Antonietta
Arcella, Antonietta
author_sort Rotondo, Rossella
collection PubMed
description Cynaropicrin has shown a wide range of pharmacological properties, such as antitumor action. Here, we showed the inhibitory effect of Cyn on human glioblastoma cell U-87 MG growth. According to the IC50 values, Cyn 4, 8 and 10 µM displayed a significant cytotoxicity, as confirmed by the cell count and MTT assay. Furthermore, Cyn completely abolished the ability of U-87 MG to form colonies and induced drastic morphological changes. Interestingly, pretreatment with ROS scavenger N-acetylcysteine 3 mM reversed the cytotoxicity induced by Cyn 25 µM and preserved the cells by morphological changes. Therefore, oxidative stress induction was evaluated at low 8- and high 25-µM concentrations in U-87 MG, as demonstrated by the quantitative and qualitative analysis of ROS. A prolonged increase in ROS generation under Cyn 25 µM exposure was followed by the loss of the mitochondrial membrane potential in treated U-87 MG cells. An acute treatment with Cyn 25 µM induced Cyt c release, as revealed by immunofluorescence staining and the activation of cell death pathways, apoptosis and autophagy. On the other hand, chronic treatment with Cyn 8 µM induced senescence, as revealed by the increase in SA-β-Gal activity. Moreover, at this concentration, Cyn led to ERK dephosphorylation accompanied by a relevant reduction of the NF-κB p65 subunit. Finally, the combined effect of TMZ and Cyn resulted in synergistic cytotoxicity, as evaluated by the Bliss additivity model. The strong cytotoxicity of Cyn was also confirmed on IDH1 mutant U-87 MG cells and patient-derived IDH wild-type glioblastoma cell lines NULU and ZAR. In conclusion, given the high toxicity at minimal concentrations, the high inhibition of tumor cell growth and synergy with the standard drug for glioblastoma TMZ, Cyn could be proposed as a potential adjuvant for the treatment of glioblastoma.
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spelling pubmed-93125462022-07-26 The Sesquiterpene Lactone Cynaropicrin Manifests Strong Cytotoxicity in Glioblastoma Cells U-87 MG by Induction of Oxidative Stress Rotondo, Rossella Oliva, Maria Antonietta Arcella, Antonietta Biomedicines Article Cynaropicrin has shown a wide range of pharmacological properties, such as antitumor action. Here, we showed the inhibitory effect of Cyn on human glioblastoma cell U-87 MG growth. According to the IC50 values, Cyn 4, 8 and 10 µM displayed a significant cytotoxicity, as confirmed by the cell count and MTT assay. Furthermore, Cyn completely abolished the ability of U-87 MG to form colonies and induced drastic morphological changes. Interestingly, pretreatment with ROS scavenger N-acetylcysteine 3 mM reversed the cytotoxicity induced by Cyn 25 µM and preserved the cells by morphological changes. Therefore, oxidative stress induction was evaluated at low 8- and high 25-µM concentrations in U-87 MG, as demonstrated by the quantitative and qualitative analysis of ROS. A prolonged increase in ROS generation under Cyn 25 µM exposure was followed by the loss of the mitochondrial membrane potential in treated U-87 MG cells. An acute treatment with Cyn 25 µM induced Cyt c release, as revealed by immunofluorescence staining and the activation of cell death pathways, apoptosis and autophagy. On the other hand, chronic treatment with Cyn 8 µM induced senescence, as revealed by the increase in SA-β-Gal activity. Moreover, at this concentration, Cyn led to ERK dephosphorylation accompanied by a relevant reduction of the NF-κB p65 subunit. Finally, the combined effect of TMZ and Cyn resulted in synergistic cytotoxicity, as evaluated by the Bliss additivity model. The strong cytotoxicity of Cyn was also confirmed on IDH1 mutant U-87 MG cells and patient-derived IDH wild-type glioblastoma cell lines NULU and ZAR. In conclusion, given the high toxicity at minimal concentrations, the high inhibition of tumor cell growth and synergy with the standard drug for glioblastoma TMZ, Cyn could be proposed as a potential adjuvant for the treatment of glioblastoma. MDPI 2022-07-02 /pmc/articles/PMC9312546/ /pubmed/35884887 http://dx.doi.org/10.3390/biomedicines10071583 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rotondo, Rossella
Oliva, Maria Antonietta
Arcella, Antonietta
The Sesquiterpene Lactone Cynaropicrin Manifests Strong Cytotoxicity in Glioblastoma Cells U-87 MG by Induction of Oxidative Stress
title The Sesquiterpene Lactone Cynaropicrin Manifests Strong Cytotoxicity in Glioblastoma Cells U-87 MG by Induction of Oxidative Stress
title_full The Sesquiterpene Lactone Cynaropicrin Manifests Strong Cytotoxicity in Glioblastoma Cells U-87 MG by Induction of Oxidative Stress
title_fullStr The Sesquiterpene Lactone Cynaropicrin Manifests Strong Cytotoxicity in Glioblastoma Cells U-87 MG by Induction of Oxidative Stress
title_full_unstemmed The Sesquiterpene Lactone Cynaropicrin Manifests Strong Cytotoxicity in Glioblastoma Cells U-87 MG by Induction of Oxidative Stress
title_short The Sesquiterpene Lactone Cynaropicrin Manifests Strong Cytotoxicity in Glioblastoma Cells U-87 MG by Induction of Oxidative Stress
title_sort sesquiterpene lactone cynaropicrin manifests strong cytotoxicity in glioblastoma cells u-87 mg by induction of oxidative stress
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9312546/
https://www.ncbi.nlm.nih.gov/pubmed/35884887
http://dx.doi.org/10.3390/biomedicines10071583
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