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Proteasome Inhibition in Multiple Myeloma: Head-to-Head Comparison of Currently Available Proteasome Inhibitors.

  • Besse A Experimental Oncology and Hematology, Department of Oncology and Hematology, Cantonal Hospital St. gallen, Rorschacher Strasse 95, St. Gallen 9007, Switzerland.
  • Besse L Experimental Oncology and Hematology, Department of Oncology and Hematology, Cantonal Hospital St. gallen, Rorschacher Strasse 95, St. Gallen 9007, Switzerland. Electronic address: lenka.besse@kssg.ch.
  • Kraus M Experimental Oncology and Hematology, Department of Oncology and Hematology, Cantonal Hospital St. gallen, Rorschacher Strasse 95, St. Gallen 9007, Switzerland.
  • Mendez-Lopez M Experimental Oncology and Hematology, Department of Oncology and Hematology, Cantonal Hospital St. gallen, Rorschacher Strasse 95, St. Gallen 9007, Switzerland.
  • Bader J Experimental Oncology and Hematology, Department of Oncology and Hematology, Cantonal Hospital St. gallen, Rorschacher Strasse 95, St. Gallen 9007, Switzerland.
  • Xin BT Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, 2333 CC Leiden, the Netherlands.
  • de Bruin G Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, 2333 CC Leiden, the Netherlands.
  • Maurits E Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, 2333 CC Leiden, the Netherlands.
  • Overkleeft HS Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, 2333 CC Leiden, the Netherlands.
  • Driessen C Experimental Oncology and Hematology, Department of Oncology and Hematology, Cantonal Hospital St. gallen, Rorschacher Strasse 95, St. Gallen 9007, Switzerland.
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  • 2019-01-08
Published in:
  • Cell chemical biology. - 2019
activity-based probes
bortezomib
carfilzomib
multiple myeloma
proteasome
proteasome inhibitors
resistance
Aged
Animals
Antineoplastic Agents
Apoptosis
Bortezomib
Drug Resistance, Neoplasm
Female
Humans
Male
Mice
Mice, Inbred BALB C
Middle Aged
Multiple Myeloma
Oligopeptides
Proteasome Endopeptidase Complex
Proteasome Inhibitors
Protein Subunits
Tissue Distribution
Tumor Cells, Cultured
English 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.
Language
  • English
Open access status
bronze
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Persistent URL
https://sonar.ch/global/documents/68655
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