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Proteasome Inhibition in Multiple Myeloma: Head-to-Head Comparison of Currently Available Proteasome Inhibitors
- Source :
- Cell Chemical Biology, 26(3), 340-351
- Publication Year :
- 2018
-
Abstract
- Proteasome inhibitors (PIs) are a backbone of multiple myeloma (MM) therapy. The proteasome harbors six proteolytically active subunits (β1, β2, β5), while β5 was identified as rate-limiting and is a primary target of clinically available PIs. The most effective pattern of subunit inhibition provided by these PIs for cytotoxic activity in MM is unknown. A head-to-head comparison of clinically available PIs shows that in the clinically relevant setting only the co-inhibition of β1 or β2 with β5 activity achieves meaningful functional proteasome inhibition and cytotoxicity, while the selective β2/β5 inhibition of both constitutive and immunoproteasome is the most cytotoxic. In the long-term setting, selective inhibition of β5 subunit is sufficient to induce cytotoxicity in PI-sensitive, but not in PI-resistant MM, and the β5/β2 co-inhibition is the most cytotoxic in PI-resistant MM. These results give a rational basis for selecting individual PIs for the treatment of MM.
- Subjects :
- Male
Proteasome Endopeptidase Complex
Proteasome Inhibition
Protein subunit
Clinical Biochemistry
Antineoplastic Agents
Apoptosis
Pharmacology
Biology
01 natural sciences
Biochemistry
Bortezomib
chemistry.chemical_compound
Mice
Drug Discovery
medicine
Tumor Cells, Cultured
Cytotoxic T cell
Animals
Humans
Tissue Distribution
Cytotoxicity
Molecular Biology
Multiple myeloma
Aged
Mice, Inbred BALB C
010405 organic chemistry
Middle Aged
medicine.disease
Carfilzomib
0104 chemical sciences
Protein Subunits
Proteasome
chemistry
Drug Resistance, Neoplasm
Molecular Medicine
Female
Multiple Myeloma
Oligopeptides
Proteasome Inhibitors
medicine.drug
Subjects
Details
- ISSN :
- 24519448
- Volume :
- 26
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Cell chemical biology
- Accession number :
- edsair.doi.dedup.....6dba17fffa011712c90a5984246b06f7