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Novel carfilzomib-based combinations as potential therapeutic strategies for liposarcomas.
- Source :
-
Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2021 Feb; Vol. 78 (4), pp. 1837-1851. Date of Electronic Publication: 2020 Aug 26. - Publication Year :
- 2021
-
Abstract
- Proteasome inhibitors, such as bortezomib and carfilzomib, have shown efficacy in anti-cancer therapy in hematological diseases but not in solid cancers. Here, we found that liposarcomas (LPS) are susceptible to proteasome inhibition, and identified drugs that synergize with carfilzomib, such as selinexor, an inhibitor of XPO1-mediated nuclear export. Through quantitative nuclear protein profiling and phospho-kinase arrays, we identified potential mode of actions of this combination, including interference with ribosome biogenesis and inhibition of pro-survival kinase PRAS40. Furthermore, by assessing global protein levels changes, FADS2, a key enzyme regulating fatty acids synthesis, was found down-regulated after proteasome inhibition. Interestingly, SC26196, an inhibitor of FADS2, synergized with carfilzomib. Finally, to identify further combinational options, we performed high-throughput drug screening and uncovered novel drug interactions with carfilzomib. For instance, cyclosporin A, a known immunosuppressive agent, enhanced carfilzomib's efficacy in vitro and in vivo. Altogether, these results demonstrate that carfilzomib and its combinations could be repurposed for LPS clinical management.
- Subjects :
- Antineoplastic Combined Chemotherapy Protocols pharmacology
Bortezomib pharmacology
Cell Line, Tumor
Cell Nucleus drug effects
Drug Resistance, Neoplasm genetics
Drug Synergism
Fatty Acid Desaturases antagonists & inhibitors
Gene Expression Regulation, Neoplastic drug effects
Humans
Hydrazines pharmacology
Liposarcoma genetics
Liposarcoma pathology
Piperazines pharmacology
Proteasome Endopeptidase Complex drug effects
Proteasome Inhibitors pharmacology
Triazoles pharmacology
Exportin 1 Protein
Fatty Acid Desaturases genetics
Karyopherins genetics
Liposarcoma drug therapy
Oligopeptides pharmacology
Receptors, Cytoplasmic and Nuclear genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1420-9071
- Volume :
- 78
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cellular and molecular life sciences : CMLS
- Publication Type :
- Academic Journal
- Accession number :
- 32851475
- Full Text :
- https://doi.org/10.1007/s00018-020-03620-w