Synthetic Cannabinoids Induce Autophagy and Mitochondrial Apoptotic Pathways in Human Glioblastoma Cells Independently of Deficiency in <i>TP53</i> or <i>PTEN</i> Tumor Suppressors
Glioblastomas (GBMs) are aggressive brain tumors with frequent genetic alterations in <i>TP53</i> and <i>PTEN </i>tumor suppressor genes rendering resistance to standard chemotherapeutics. Cannabinoid type 1 and 2 (CB1/CB2) receptor expression in GBMs and antitumor activity o...
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MDPI AG
2021-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/3/419 |
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| author | Aleksandra Ellert-Miklaszewska Iwona Anna Ciechomska Bozena Kaminska |
| author_facet | Aleksandra Ellert-Miklaszewska Iwona Anna Ciechomska Bozena Kaminska |
| author_sort | Aleksandra Ellert-Miklaszewska |
| collection | DOAJ |
| description | Glioblastomas (GBMs) are aggressive brain tumors with frequent genetic alterations in <i>TP53</i> and <i>PTEN </i>tumor suppressor genes rendering resistance to standard chemotherapeutics. Cannabinoid type 1 and 2 (CB1/CB2) receptor expression in GBMs and antitumor activity of cannabinoids in glioma cells and animal models, raised promises for a targeted treatment of these tumors. The susceptibility of human glioma cells to CB2-agonists and their mechanism of action are not fully elucidated. We determined CB1 and CB2 expression in 14 low-grade and 21 high-grade tumor biopsies, GBM-derived primary cultures and established cell lines. The non-selective CB receptor agonist WIN55,212-2 (but not its inactive enantiomer) or the CB2-selective agonist JWH133 induced apoptosis in patient-derived glioma cultures and five established glioma cell lines despite p53 and/or PTEN deficiency. Growth inhibitory efficacy of cannabinoids correlated with CB1/CB2 expression (EC<sub>50</sub> WIN55,212-2: 7.36–15.70 µM, JWH133: 12.15–143.20 µM). Treatment with WIN55,212-2 or JWH133 led to activation of the apoptotic mitochondrial pathway and DNA fragmentation. Synthetic cannabinoid action was associated with the induction of autophagy and knockdown of autophagy genes augmented cannabinoid-induced apoptotic cell death. The high susceptibility of human glioblastoma cells to synthetic cannabinoids, despite genetic defects contributing to apoptosis resistance, makes cannabinoids promising anti-glioma therapeutics. |
| first_indexed | 2024-03-09T03:55:39Z |
| format | Article |
| id | doaj.art-7bdcd5db84ab4346bac3b5134f7f182e |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T03:55:39Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-7bdcd5db84ab4346bac3b5134f7f182e2023-12-03T14:21:48ZengMDPI AGCancers2072-66942021-01-0113341910.3390/cancers13030419Synthetic Cannabinoids Induce Autophagy and Mitochondrial Apoptotic Pathways in Human Glioblastoma Cells Independently of Deficiency in <i>TP53</i> or <i>PTEN</i> Tumor SuppressorsAleksandra Ellert-Miklaszewska0Iwona Anna Ciechomska1Bozena Kaminska2Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, PolandLaboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, PolandLaboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, PolandGlioblastomas (GBMs) are aggressive brain tumors with frequent genetic alterations in <i>TP53</i> and <i>PTEN </i>tumor suppressor genes rendering resistance to standard chemotherapeutics. Cannabinoid type 1 and 2 (CB1/CB2) receptor expression in GBMs and antitumor activity of cannabinoids in glioma cells and animal models, raised promises for a targeted treatment of these tumors. The susceptibility of human glioma cells to CB2-agonists and their mechanism of action are not fully elucidated. We determined CB1 and CB2 expression in 14 low-grade and 21 high-grade tumor biopsies, GBM-derived primary cultures and established cell lines. The non-selective CB receptor agonist WIN55,212-2 (but not its inactive enantiomer) or the CB2-selective agonist JWH133 induced apoptosis in patient-derived glioma cultures and five established glioma cell lines despite p53 and/or PTEN deficiency. Growth inhibitory efficacy of cannabinoids correlated with CB1/CB2 expression (EC<sub>50</sub> WIN55,212-2: 7.36–15.70 µM, JWH133: 12.15–143.20 µM). Treatment with WIN55,212-2 or JWH133 led to activation of the apoptotic mitochondrial pathway and DNA fragmentation. Synthetic cannabinoid action was associated with the induction of autophagy and knockdown of autophagy genes augmented cannabinoid-induced apoptotic cell death. The high susceptibility of human glioblastoma cells to synthetic cannabinoids, despite genetic defects contributing to apoptosis resistance, makes cannabinoids promising anti-glioma therapeutics.https://www.mdpi.com/2072-6694/13/3/419cannabinoidsglioblastomaapoptosisautophagymitochondrial apoptotic pathwaymTOR |
| spellingShingle | Aleksandra Ellert-Miklaszewska Iwona Anna Ciechomska Bozena Kaminska Synthetic Cannabinoids Induce Autophagy and Mitochondrial Apoptotic Pathways in Human Glioblastoma Cells Independently of Deficiency in <i>TP53</i> or <i>PTEN</i> Tumor Suppressors Cancers cannabinoids glioblastoma apoptosis autophagy mitochondrial apoptotic pathway mTOR |
| title | Synthetic Cannabinoids Induce Autophagy and Mitochondrial Apoptotic Pathways in Human Glioblastoma Cells Independently of Deficiency in <i>TP53</i> or <i>PTEN</i> Tumor Suppressors |
| title_full | Synthetic Cannabinoids Induce Autophagy and Mitochondrial Apoptotic Pathways in Human Glioblastoma Cells Independently of Deficiency in <i>TP53</i> or <i>PTEN</i> Tumor Suppressors |
| title_fullStr | Synthetic Cannabinoids Induce Autophagy and Mitochondrial Apoptotic Pathways in Human Glioblastoma Cells Independently of Deficiency in <i>TP53</i> or <i>PTEN</i> Tumor Suppressors |
| title_full_unstemmed | Synthetic Cannabinoids Induce Autophagy and Mitochondrial Apoptotic Pathways in Human Glioblastoma Cells Independently of Deficiency in <i>TP53</i> or <i>PTEN</i> Tumor Suppressors |
| title_short | Synthetic Cannabinoids Induce Autophagy and Mitochondrial Apoptotic Pathways in Human Glioblastoma Cells Independently of Deficiency in <i>TP53</i> or <i>PTEN</i> Tumor Suppressors |
| title_sort | synthetic cannabinoids induce autophagy and mitochondrial apoptotic pathways in human glioblastoma cells independently of deficiency in i tp53 i or i pten i tumor suppressors |
| topic | cannabinoids glioblastoma apoptosis autophagy mitochondrial apoptotic pathway mTOR |
| url | https://www.mdpi.com/2072-6694/13/3/419 |
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