The mTOR inhibitor everolimus overcomes CXCR4-mediated resistance to histone deacetylase inhibitor panobinostat through inhibition of p21 and mitotic regulators
| Autor: | Lola Weiss, Valeria Voevoda-Dimenshtein, Avichai Shimoni, Evgenia Rosenberg, Jonathan Canaani, Michal Abraham, Amnon Peled, Hila Magen, Yaarit Sirovsky, Arnon Nagler, Olga Ostrovsky, Noya Shilo, Katia Beider, Michael Milyavsky, Hanna Bitner |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
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 |
| Zdroj: | Biochemical pharmacology. 168 |
| ISSN: | 1873-2968 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect