Does the proteasome inhibitor bortezomib sensitize to DNA-damaging therapy in gastroenteropancreatic neuroendocrine neoplasms? - A preclinical assessment in vitro and in vivo.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
Bortezomib
/ pharmacology
Cell Cycle Checkpoints
Cell Line, Tumor
Cell Proliferation
/ drug effects
Chick Embryo
DNA Damage
/ drug effects
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Drug Synergism
Gastrointestinal Neoplasms
/ genetics
Gene Regulatory Networks
Humans
Immunohistochemistry
Mice
Molecular Targeted Therapy
Neuroendocrine Tumors
/ genetics
Proteasome Inhibitors
/ pharmacology
Bortezomib
Combination therapy
DNA repair
Neuroendocrine tumors
Peptide receptor radionuclide therapy (PRRT)
Proteasome inhibition
Journal
Neoplasia (New York, N.Y.)
ISSN: 1476-5586
Titre abrégé: Neoplasia
Pays: United States
ID NLM: 100886622
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
07
09
2020
revised:
01
11
2020
accepted:
03
11
2020
pubmed:
28
11
2020
medline:
5
10
2021
entrez:
27
11
2020
Statut:
ppublish
Résumé
Well-differentiated gastroenteropancreatic neuroendocrine neoplasms are rare tumors with a slow proliferation. They are virtually resistant to many DNA-damaging therapeutic approaches, such as chemo- and external beam therapy, which might be overcome by DNA damage inhibition induced by proteasome inhibitors such as bortezomib. In this study, we assessed several combined treatment modalities in vitro and in vivo. By cell-based functional analyses, in a 3D in ovo and an orthotopic mouse model, we demonstrated sensitizing effects of bortezomib combined with cisplatin, radiation and peptide receptor radionuclide therapy (PRRT). By gene expression profiling and western blot, we explored the underlying mechanisms, which resulted in an impaired DNA damage repair. Therapy-induced DNA damage triggered extrinsic proapoptotic signaling as well as the induction of cell cycle arrest, leading to a decreased vital tumor volume and altered tissue composition shown by magnetic resonance imaging and F-18-FDG-PET in vivo, however with no significant additional benefit related to PRRT alone. We demonstrated that bortezomib has short-term sensitizing effects when combined with DNA damaging therapy by interfering with DNA repair in vitro and in ovo. Nevertheless, due to high tumor heterogeneity after PRRT in long-term observations, we were not able to prove a therapeutic advantage of bortezomib-combined PRRT in an in vivo mouse model.
Sections du résumé
BACKGROUND
Well-differentiated gastroenteropancreatic neuroendocrine neoplasms are rare tumors with a slow proliferation. They are virtually resistant to many DNA-damaging therapeutic approaches, such as chemo- and external beam therapy, which might be overcome by DNA damage inhibition induced by proteasome inhibitors such as bortezomib.
METHODS AND RESULTS
In this study, we assessed several combined treatment modalities in vitro and in vivo. By cell-based functional analyses, in a 3D in ovo and an orthotopic mouse model, we demonstrated sensitizing effects of bortezomib combined with cisplatin, radiation and peptide receptor radionuclide therapy (PRRT). By gene expression profiling and western blot, we explored the underlying mechanisms, which resulted in an impaired DNA damage repair. Therapy-induced DNA damage triggered extrinsic proapoptotic signaling as well as the induction of cell cycle arrest, leading to a decreased vital tumor volume and altered tissue composition shown by magnetic resonance imaging and F-18-FDG-PET in vivo, however with no significant additional benefit related to PRRT alone.
CONCLUSIONS
We demonstrated that bortezomib has short-term sensitizing effects when combined with DNA damaging therapy by interfering with DNA repair in vitro and in ovo. Nevertheless, due to high tumor heterogeneity after PRRT in long-term observations, we were not able to prove a therapeutic advantage of bortezomib-combined PRRT in an in vivo mouse model.
Identifiants
pubmed: 33246310
pii: S1476-5586(20)30172-X
doi: 10.1016/j.neo.2020.11.004
pmc: PMC7701025
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Proteasome Inhibitors
0
Bortezomib
69G8BD63PP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
80-98Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
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