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Bcl-XL but Not Bcl-2 Is a Potential Target in Medulloblastoma Therapy

Medulloblastoma (MB) is the most common solid tumour in children and, despite current treatment with a rather aggressive combination therapy, accounts for 10% of all deaths associated with paediatric cancer. Breaking the tumour cells’ intrinsic resistance to therapy-induced cell death should lead to...

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Autores principales: Westhoff, Mike-Andrew, Schuler-Ortoli, Marie, Zerrinius, Daniela, Hadzalic, Amina, Schuster, Andrea, Strobel, Hannah, Scheuerle, Angelika, Wong, Tiana, Wirtz, Christian Rainer, Debatin, Klaus-Michael, Peraud, Aurelia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8779796/
https://www.ncbi.nlm.nih.gov/pubmed/35056150
http://dx.doi.org/10.3390/ph15010091
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author Westhoff, Mike-Andrew
Schuler-Ortoli, Marie
Zerrinius, Daniela
Hadzalic, Amina
Schuster, Andrea
Strobel, Hannah
Scheuerle, Angelika
Wong, Tiana
Wirtz, Christian Rainer
Debatin, Klaus-Michael
Peraud, Aurelia
author_facet Westhoff, Mike-Andrew
Schuler-Ortoli, Marie
Zerrinius, Daniela
Hadzalic, Amina
Schuster, Andrea
Strobel, Hannah
Scheuerle, Angelika
Wong, Tiana
Wirtz, Christian Rainer
Debatin, Klaus-Michael
Peraud, Aurelia
author_sort Westhoff, Mike-Andrew
collection PubMed
description Medulloblastoma (MB) is the most common solid tumour in children and, despite current treatment with a rather aggressive combination therapy, accounts for 10% of all deaths associated with paediatric cancer. Breaking the tumour cells’ intrinsic resistance to therapy-induced cell death should lead to less aggressive and more effective treatment options. In other tumour entities, this has been achieved by modulating the balance between the various pro- and anti-apoptotic members of the Bcl-2 family with small molecule inhibitors. To evaluate the therapeutic benefits of ABT-199 (Venetoclax), a Bcl-2 inhibitor, and ABT-263 (Navitoclax), a dual Bcl-XL/Bcl-2 inhibitor, increasingly more relevant model systems were investigated. Starting from established MB cell lines, progressing to primary patient-derived material and finally an experimental tumour system imbedded in an organic environment were chosen. Assessment of the metabolic activity (a surrogate readout for population viability), the induction of DNA fragmentation (apoptosis) and changes in cell number (the combined effect of alterations in proliferation and cell death induction) revealed that ABT-263, but not ABT-199, is a promising candidate for combination therapy, synergizing with cell death-inducing stimuli. Interestingly, in the experimental tumour setting, the sensitizing effect of ABT-263 seems to be predominantly mediated via an anti-proliferative and not a pro-apoptotic effect, opening a future line of investigation. Our data show that modulation of specific members of the Bcl-2 family might be a promising therapeutic addition for the treatment of MB.
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spelling pubmed-87797962022-01-22 Bcl-XL but Not Bcl-2 Is a Potential Target in Medulloblastoma Therapy Westhoff, Mike-Andrew Schuler-Ortoli, Marie Zerrinius, Daniela Hadzalic, Amina Schuster, Andrea Strobel, Hannah Scheuerle, Angelika Wong, Tiana Wirtz, Christian Rainer Debatin, Klaus-Michael Peraud, Aurelia Pharmaceuticals (Basel) Article Medulloblastoma (MB) is the most common solid tumour in children and, despite current treatment with a rather aggressive combination therapy, accounts for 10% of all deaths associated with paediatric cancer. Breaking the tumour cells’ intrinsic resistance to therapy-induced cell death should lead to less aggressive and more effective treatment options. In other tumour entities, this has been achieved by modulating the balance between the various pro- and anti-apoptotic members of the Bcl-2 family with small molecule inhibitors. To evaluate the therapeutic benefits of ABT-199 (Venetoclax), a Bcl-2 inhibitor, and ABT-263 (Navitoclax), a dual Bcl-XL/Bcl-2 inhibitor, increasingly more relevant model systems were investigated. Starting from established MB cell lines, progressing to primary patient-derived material and finally an experimental tumour system imbedded in an organic environment were chosen. Assessment of the metabolic activity (a surrogate readout for population viability), the induction of DNA fragmentation (apoptosis) and changes in cell number (the combined effect of alterations in proliferation and cell death induction) revealed that ABT-263, but not ABT-199, is a promising candidate for combination therapy, synergizing with cell death-inducing stimuli. Interestingly, in the experimental tumour setting, the sensitizing effect of ABT-263 seems to be predominantly mediated via an anti-proliferative and not a pro-apoptotic effect, opening a future line of investigation. Our data show that modulation of specific members of the Bcl-2 family might be a promising therapeutic addition for the treatment of MB. MDPI 2022-01-14 /pmc/articles/PMC8779796/ /pubmed/35056150 http://dx.doi.org/10.3390/ph15010091 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
Westhoff, Mike-Andrew
Schuler-Ortoli, Marie
Zerrinius, Daniela
Hadzalic, Amina
Schuster, Andrea
Strobel, Hannah
Scheuerle, Angelika
Wong, Tiana
Wirtz, Christian Rainer
Debatin, Klaus-Michael
Peraud, Aurelia
Bcl-XL but Not Bcl-2 Is a Potential Target in Medulloblastoma Therapy
title Bcl-XL but Not Bcl-2 Is a Potential Target in Medulloblastoma Therapy
title_full Bcl-XL but Not Bcl-2 Is a Potential Target in Medulloblastoma Therapy
title_fullStr Bcl-XL but Not Bcl-2 Is a Potential Target in Medulloblastoma Therapy
title_full_unstemmed Bcl-XL but Not Bcl-2 Is a Potential Target in Medulloblastoma Therapy
title_short Bcl-XL but Not Bcl-2 Is a Potential Target in Medulloblastoma Therapy
title_sort bcl-xl but not bcl-2 is a potential target in medulloblastoma therapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8779796/
https://www.ncbi.nlm.nih.gov/pubmed/35056150
http://dx.doi.org/10.3390/ph15010091
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