Bcl-XL but Not Bcl-2 Is a Potential Target in Medulloblastoma Therapy.
ABT-199 (Venetoclax)
ABT-263 (Navitoclax)
Bcl-2
Bcl-XL
apoptosis
chemotherapy
medulloblastoma
Journal
Pharmaceuticals (Basel, Switzerland)
ISSN: 1424-8247
Titre abrégé: Pharmaceuticals (Basel)
Pays: Switzerland
ID NLM: 101238453
Informations de publication
Date de publication:
14 Jan 2022
14 Jan 2022
Historique:
received:
02
12
2021
revised:
29
12
2021
accepted:
05
01
2022
entrez:
21
1
2022
pubmed:
22
1
2022
medline:
22
1
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35056150
pii: ph15010091
doi: 10.3390/ph15010091
pmc: PMC8779796
pii:
doi:
Types de publication
Journal Article
Langues
eng
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