New insights into cytotoxic mechanisms of bozepinib against glioblastoma
Copyright © 2021 Elsevier B.V. All rights reserved..
Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults and the current treatments only have a modest effect on patient survival. Recent studies show that bozepinib (BZP), a purine derivative, has potential applications in cancer treatment. The aim of this study was to evaluate the effect of BZP against GBM cells, specially concerning the purinergic system. Thus, GBM cells (C6 and U138 cell lines) were treated with BZP and cell viability, cell cycle, and annexin/PI assays, and active caspase-3 measurements were carried out. Besides, the effect of BZP over the purinergic system was also evaluated in silico and in vitro. Finally, we evaluate the action of BZP against important markers related to cancer progression, such as Akt, NF-κB, and CD133. We demonstrate here that BZP reduces GBM cell viability (IC50 = 5.7 ± 0.3 µM and 12.7 ± 1.5 µM, in C6 and U138 cells, respectively), inducing cell death through caspase-dependent apoptosis, autophagosome formation, activation of NF-κB, without any change in cell cycle progression or on the Akt pathway. Also, BZP modulates the purinergic system, inducing an increase in CD39 enzyme expression and activity, while inhibiting CD73 activity and adenosine formation, without altering CD73 enzyme expression. Curiously, one cycle of treatment resulted in enrichment of GBM cells expressing NF-κB and CD133+, suggesting resistant cells selection. However, after another treatment round, the resistant cells were eliminated. Altogether, BZP presented in vitro anti-glioma activity, encouraging further in vivo studies in order to better understand its mechanism of action.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:162 |
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| Enthalten in: |
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences - 162(2021) vom: 01. Juli, Seite 105823 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dias, Amanda de Fraga [VerfasserIn] |
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| Links: |
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| Themen: |
2,6-dichloro-9-(1-(p-nitrobenzenesulfonyl)-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)-9H-purine |
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| Anmerkungen: |
Date Completed 21.06.2021 Date Revised 21.06.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejps.2021.105823 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults and the current treatments only have a modest effect on patient survival. Recent studies show that bozepinib (BZP), a purine derivative, has potential applications in cancer treatment. The aim of this study was to evaluate the effect of BZP against GBM cells, specially concerning the purinergic system. Thus, GBM cells (C6 and U138 cell lines) were treated with BZP and cell viability, cell cycle, and annexin/PI assays, and active caspase-3 measurements were carried out. Besides, the effect of BZP over the purinergic system was also evaluated in silico and in vitro. Finally, we evaluate the action of BZP against important markers related to cancer progression, such as Akt, NF-κB, and CD133. We demonstrate here that BZP reduces GBM cell viability (IC50 = 5.7 ± 0.3 µM and 12.7 ± 1.5 µM, in C6 and U138 cells, respectively), inducing cell death through caspase-dependent apoptosis, autophagosome formation, activation of NF-κB, without any change in cell cycle progression or on the Akt pathway. Also, BZP modulates the purinergic system, inducing an increase in CD39 enzyme expression and activity, while inhibiting CD73 activity and adenosine formation, without altering CD73 enzyme expression. Curiously, one cycle of treatment resulted in enrichment of GBM cells expressing NF-κB and CD133+, suggesting resistant cells selection. However, after another treatment round, the resistant cells were eliminated. Altogether, BZP presented in vitro anti-glioma activity, encouraging further in vivo studies in order to better understand its mechanism of action | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Kagami, Luciano Porto |e verfasserin |4 aut | |
| 700 | 1 | |a das Neves, Gustavo Machado |e verfasserin |4 aut | |
| 700 | 1 | |a Eifler-Lima, Vera Lúcia |e verfasserin |4 aut | |
| 700 | 1 | |a Cruz-López, Olga |e verfasserin |4 aut | |
| 700 | 1 | |a Conejo-García, Ana |e verfasserin |4 aut | |
| 700 | 1 | |a Sévigny, Jean |e verfasserin |4 aut | |
| 700 | 1 | |a Battastini, Ana Maria Oliveira |e verfasserin |4 aut | |
| 700 | 1 | |a Campos, Joaquin María |e verfasserin |4 aut | |
| 700 | 1 | |a Figueiró, Fabrício |e verfasserin |4 aut | |
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