BET inhibition therapy counteracts cancer cell survival, clonogenic potential and radioresistance mechanisms in rhabdomyosarcoma cells.
Acetanilides
/ pharmacology
Animals
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Cell Movement
/ drug effects
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
GTP-Binding Proteins
/ genetics
Gene Expression Regulation, Neoplastic
/ drug effects
Heterocyclic Compounds, 3-Ring
/ pharmacology
Humans
Mice
Nuclear Proteins
/ genetics
Proteins
/ antagonists & inhibitors
Radiation Tolerance
/ drug effects
Rhabdomyosarcoma, Alveolar
/ genetics
BET inhibitors
GNL3
OTX015
Radiotherapy
Rhabdomyosarcoma
Journal
Cancer letters
ISSN: 1872-7980
Titre abrégé: Cancer Lett
Pays: Ireland
ID NLM: 7600053
Informations de publication
Date de publication:
01 06 2020
01 06 2020
Historique:
received:
17
01
2020
revised:
04
03
2020
accepted:
10
03
2020
pubmed:
23
3
2020
medline:
15
12
2020
entrez:
23
3
2020
Statut:
ppublish
Résumé
The antitumour effects of OTX015, a first-in-class BET inhibitor (BETi), were investigated as a single agent or in combination with ionizing radiation (IR) in preclinical in vitro models of rhabdomyosarcoma (RMS), the most common childhood soft tissue sarcoma. Herein, we demonstrated the upregulation of BET Bromodomain gene expression in RMS tumour biopsies and cell lines compared to normal skeletal muscle. In vitro experiments showed that OTX015 significantly reduced RMS cell proliferation by altering cell cycle modulators and apoptotic related proteins due to the accumulation of DNA breaks that cells are unable to repair. Interestingly, OTX015 also impaired migration capacity and tumour-sphere architecture by downregulating pro-stemness genes and was able to potentiate ionizing radiation effects by reducing the expression of different drivers of tumour dissemination and resistance mechanisms, including the GNL3 gene, that we correlated for the first time with the RMS phenotype. In conclusion, our research sheds further light on the molecular events of OTX015 action against RMS cells and indicates this novel BETi as an effective option to improve therapeutic strategies and overcome the development of resistant cancer cells in patients with RMS.
Identifiants
pubmed: 32200036
pii: S0304-3835(20)30130-0
doi: 10.1016/j.canlet.2020.03.011
pii:
doi:
Substances chimiques
Acetanilides
0
Antineoplastic Agents
0
GNL3 protein, human
0
Heterocyclic Compounds, 3-Ring
0
Nuclear Proteins
0
OTX015
0
Proteins
0
bromodomain and extra-terminal domain protein, human
0
GTP-Binding Proteins
EC 3.6.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
71-88Informations de copyright
Copyright © 2020 Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest All authors have no conflict of interest to declare.