The novel dual BET/HDAC inhibitor TW09 mediates cell death by mitochondrial apoptosis in rhabdomyosarcoma cells.
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Caspases
/ physiology
Cell Line, Tumor
Histone Deacetylase Inhibitors
/ pharmacology
Humans
Membrane Potential, Mitochondrial
/ drug effects
Mitochondria
/ drug effects
Proteins
/ antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2
/ physiology
Rhabdomyosarcoma
/ drug therapy
bcl-2-Associated X Protein
/ physiology
Apoptosis
BET proteins
Cell death
HDAC
Rhabdomyosarcoma
Journal
Cancer letters
ISSN: 1872-7980
Titre abrégé: Cancer Lett
Pays: Ireland
ID NLM: 7600053
Informations de publication
Date de publication:
28 08 2020
28 08 2020
Historique:
received:
27
02
2020
revised:
24
04
2020
accepted:
11
05
2020
pubmed:
24
5
2020
medline:
28
1
2021
entrez:
24
5
2020
Statut:
ppublish
Résumé
Targeting the epigenome of cancer cells with the combination of Bromodomain and Extra Terminal (BET) protein inhibitors and histone deacetylase (HDAC) inhibitors has shown synergistic antitumor effects in several cancer types. In this study, we investigate the antitumor potential of the novel dual BET/HDAC inhibitor TW09 in rhabdomyosarcoma (RMS) cells. TW09 reduces cell viability, suppresses long-term clonogenic survival and induces cell death in RMS cells in a dose-dependent manner. Compared to BET/HDAC co-inhibition using JQ1 and MS-275, TW09 induces similar cell death at equimolar concentrations and regulates BET and HDAC target proteins (e.g. c-MYC, H3 acetylation). Mechanistic studies revealed that TW09 upregulates BIM, NOXA, PUMA and BMF, while downregulating BCL-X
Identifiants
pubmed: 32445837
pii: S0304-3835(20)30245-7
doi: 10.1016/j.canlet.2020.05.008
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
BAX protein, human
0
Histone Deacetylase Inhibitors
0
Proteins
0
Proto-Oncogene Proteins c-bcl-2
0
bcl-2-Associated X Protein
0
bromodomain and extra-terminal domain protein, human
0
Caspases
EC 3.4.22.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
46-57Informations de copyright
Copyright © 2020 Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest None to declare.