The mTOR inhibitor everolimus overcomes CXCR4-mediated resistance to histone deacetylase inhibitor panobinostat through inhibition of p21 and mitotic regulators.
Animals
Antineoplastic Agents
/ administration & dosage
Bone Marrow Cells
/ drug effects
Cell Line, Tumor
Cells, Cultured
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
/ drug effects
Everolimus
/ administration & dosage
Histone Deacetylase Inhibitors
/ administration & dosage
Humans
Mice
Mitosis
/ drug effects
Multiple Myeloma
/ drug therapy
Panobinostat
/ administration & dosage
Receptors, CXCR4
/ antagonists & inhibitors
TOR Serine-Threonine Kinases
/ antagonists & inhibitors
Xenograft Model Antitumor Assays
/ methods
rho GTP-Binding Proteins
/ antagonists & inhibitors
CXCR4
HDACi resistance
Multiple myeloma
mTOR
Journal
Biochemical pharmacology
ISSN: 1873-2968
Titre abrégé: Biochem Pharmacol
Pays: England
ID NLM: 0101032
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
14
05
2019
accepted:
15
07
2019
pubmed:
22
7
2019
medline:
2
7
2020
entrez:
21
7
2019
Statut:
ppublish
Résumé
Although having promising anti-myeloma properties, the pan-histone deacetylase inhibitor (HDACi) panobinostat lacks therapeutic activity as a single agent. The aim of the current study was to elucidate the mechanisms underlying multiple myeloma (MM) resistance to panobinostat monotherapy and to define strategies to overcome it. Sensitivity of MM cell lines and primary CD138+ cells from MM patients to panobinostat correlated with reduced expression of the chemokine receptor CXCR4, whereas overexpression of CXCR4 in MM cell lines increased their resistance to panobinostat. Decreased sensitivity to HDACi was associated with reversible G0/G1 cell growth arrest while response was characterized by apoptotic cell death. Analysis of intra-cellular signaling mediators revealed the pro-survival mTOR pathway to be regulated by CXCR4 overexpression. Combining panobinostat with mTOR inhibitor everolimus abrogated the resistance to HDACi and induced synergistic cell death. The combination of panobinostat/everolimus resulted in sustained DNA damage and irreversible suppression of proliferation accompanied by robust apoptosis. Gene expression analysis revealed distinct genetic profiles of single versus combined agent exposure. Whereas panobinostat increased the expression of the cell cycle inhibitor p21, co-treatment with everolimus abrogated the increase in p21 and synergistically downregulated the expression of DNA repair genes and mitotic checkpoint regulators. Importantly, the combination of panobinostat with everolimus effectively targeted CXCR4-expressing resistant MM cells in vivo in the BM niche. In summary, our results uncover the mechanism responsible for the strong synergistic anti-MM activity of dual HDAC and mTOR inhibition and provide the rationale for a novel potential therapeutic approach to treat MM.
Identifiants
pubmed: 31325448
pii: S0006-2952(19)30271-0
doi: 10.1016/j.bcp.2019.07.016
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
CXCR4 protein, human
0
Histone Deacetylase Inhibitors
0
Receptors, CXCR4
0
Panobinostat
9647FM7Y3Z
Everolimus
9HW64Q8G6G
MTOR protein, human
EC 2.7.1.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
rho GTP-Binding Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
412-428Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.