Cargando…

NPI-0052 and γ-radiation induce a synergistic apoptotic effect in medulloblastoma

Medulloblastoma (MB) is the most common malignant solid paediatric brain tumour. The standard treatment for MB is surgical resection of the tumour, radiation and chemotherapy. This therapy is associated with high morbidity and adverse side effects. Hence, more targeted and less toxic therapies are v...

Descripción completa

Detalles Bibliográficos
Autores principales: Frisira, Eleni, Rashid, Fatima, Varma, Swastina Nath, Badodi, Sara, Benjamin-Ombo, Valentine Ayodele, Michod, David, Niklison-Chirou, Maria Victoria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795856/
https://www.ncbi.nlm.nih.gov/pubmed/31619667
http://dx.doi.org/10.1038/s41419-019-2026-y
_version_ 1783459519363284992
author Frisira, Eleni
Rashid, Fatima
Varma, Swastina Nath
Badodi, Sara
Benjamin-Ombo, Valentine Ayodele
Michod, David
Niklison-Chirou, Maria Victoria
author_facet Frisira, Eleni
Rashid, Fatima
Varma, Swastina Nath
Badodi, Sara
Benjamin-Ombo, Valentine Ayodele
Michod, David
Niklison-Chirou, Maria Victoria
author_sort Frisira, Eleni
collection PubMed
description Medulloblastoma (MB) is the most common malignant solid paediatric brain tumour. The standard treatment for MB is surgical resection of the tumour, radiation and chemotherapy. This therapy is associated with high morbidity and adverse side effects. Hence, more targeted and less toxic therapies are vitally needed to improve the quality of life of survivors. NPI-0052 is a novel proteasome inhibitor that irreversibly binds the 20S proteasome subunit. This compound has anti-tumour activity in metastatic solid tumours, glioblastoma and multiple myeloma with a good safety profile. Importantly, NPI-0052 has a lipophilic structure and can penetrate the blood–brain barrier, making it a suitable treatment for brain tumours. In the present study, we performed an in silico gene expression analysis to evaluate the proteasome subunit expression in MB. To evaluate the anticancer activity of NPI-0052, we used a range of MB patient-derived MB cells and cell lines. The synergistic cell death of NPI-0052 with γ-radiation was evaluated in tumour organoids derived from patient-derived MB cells. We show that high expression of proteasome subunits is a poor prognostic factor for MB patients. Also, our preclinical work demonstrated that NPI-0052 can inhibit proteasome activity and activate apoptosis in MB cells. Moreover, we observe that NPI-0052 has a synergistic apoptotic effect with γ-radiation, a component of the current MB therapy. Here, we present compelling preclinical evidence that NPI-0052 can be used as an adjuvant treatment for p53-family-expressing MB tumours.
format Online
Article
Text
id pubmed-6795856
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-67958562019-10-17 NPI-0052 and γ-radiation induce a synergistic apoptotic effect in medulloblastoma Frisira, Eleni Rashid, Fatima Varma, Swastina Nath Badodi, Sara Benjamin-Ombo, Valentine Ayodele Michod, David Niklison-Chirou, Maria Victoria Cell Death Dis Article Medulloblastoma (MB) is the most common malignant solid paediatric brain tumour. The standard treatment for MB is surgical resection of the tumour, radiation and chemotherapy. This therapy is associated with high morbidity and adverse side effects. Hence, more targeted and less toxic therapies are vitally needed to improve the quality of life of survivors. NPI-0052 is a novel proteasome inhibitor that irreversibly binds the 20S proteasome subunit. This compound has anti-tumour activity in metastatic solid tumours, glioblastoma and multiple myeloma with a good safety profile. Importantly, NPI-0052 has a lipophilic structure and can penetrate the blood–brain barrier, making it a suitable treatment for brain tumours. In the present study, we performed an in silico gene expression analysis to evaluate the proteasome subunit expression in MB. To evaluate the anticancer activity of NPI-0052, we used a range of MB patient-derived MB cells and cell lines. The synergistic cell death of NPI-0052 with γ-radiation was evaluated in tumour organoids derived from patient-derived MB cells. We show that high expression of proteasome subunits is a poor prognostic factor for MB patients. Also, our preclinical work demonstrated that NPI-0052 can inhibit proteasome activity and activate apoptosis in MB cells. Moreover, we observe that NPI-0052 has a synergistic apoptotic effect with γ-radiation, a component of the current MB therapy. Here, we present compelling preclinical evidence that NPI-0052 can be used as an adjuvant treatment for p53-family-expressing MB tumours. Nature Publishing Group UK 2019-10-16 /pmc/articles/PMC6795856/ /pubmed/31619667 http://dx.doi.org/10.1038/s41419-019-2026-y Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Frisira, Eleni
Rashid, Fatima
Varma, Swastina Nath
Badodi, Sara
Benjamin-Ombo, Valentine Ayodele
Michod, David
Niklison-Chirou, Maria Victoria
NPI-0052 and γ-radiation induce a synergistic apoptotic effect in medulloblastoma
title NPI-0052 and γ-radiation induce a synergistic apoptotic effect in medulloblastoma
title_full NPI-0052 and γ-radiation induce a synergistic apoptotic effect in medulloblastoma
title_fullStr NPI-0052 and γ-radiation induce a synergistic apoptotic effect in medulloblastoma
title_full_unstemmed NPI-0052 and γ-radiation induce a synergistic apoptotic effect in medulloblastoma
title_short NPI-0052 and γ-radiation induce a synergistic apoptotic effect in medulloblastoma
title_sort npi-0052 and γ-radiation induce a synergistic apoptotic effect in medulloblastoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795856/
https://www.ncbi.nlm.nih.gov/pubmed/31619667
http://dx.doi.org/10.1038/s41419-019-2026-y
work_keys_str_mv AT frisiraeleni npi0052andgradiationinduceasynergisticapoptoticeffectinmedulloblastoma
AT rashidfatima npi0052andgradiationinduceasynergisticapoptoticeffectinmedulloblastoma
AT varmaswastinanath npi0052andgradiationinduceasynergisticapoptoticeffectinmedulloblastoma
AT badodisara npi0052andgradiationinduceasynergisticapoptoticeffectinmedulloblastoma
AT benjaminombovalentineayodele npi0052andgradiationinduceasynergisticapoptoticeffectinmedulloblastoma
AT michoddavid npi0052andgradiationinduceasynergisticapoptoticeffectinmedulloblastoma
AT niklisonchiroumariavictoria npi0052andgradiationinduceasynergisticapoptoticeffectinmedulloblastoma