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The mTOR inhibitor everolimus overcomes CXCR4-mediated resistance to histone deacetylase inhibitor panobinostat through inhibition of p21 and mitotic regulators
- Source :
- Biochemical pharmacology. 168
- Publication Year :
- 2019
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
rho GTP-Binding Proteins
Programmed cell death
Receptors, CXCR4
medicine.drug_class
Mitosis
Antineoplastic Agents
Bone Marrow Cells
Biochemistry
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Panobinostat
Cell Line, Tumor
medicine
Animals
Humans
Everolimus
PI3K/AKT/mTOR pathway
Cells, Cultured
Pharmacology
Dose-Response Relationship, Drug
Cell growth
TOR Serine-Threonine Kinases
Histone deacetylase inhibitor
Cell cycle
Xenograft Model Antitumor Assays
Histone Deacetylase Inhibitors
030104 developmental biology
chemistry
Apoptosis
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Cancer research
Multiple Myeloma
medicine.drug
Subjects
Details
- ISSN :
- 18732968
- Volume :
- 168
- Database :
- OpenAIRE
- Journal :
- Biochemical pharmacology
- Accession number :
- edsair.doi.dedup.....98533f2f17bdb27f1e83333a04a6e7aa