Proteasome Inhibition in Multiple Myeloma: Head-to-Head Comparison of Currently Available Proteasome Inhibitors.
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Besse A
Experimental Oncology and Hematology, Department of Oncology and Hematology, Cantonal Hospital St. gallen, Rorschacher Strasse 95, St. Gallen 9007, Switzerland.
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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.
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Kraus M
Experimental Oncology and Hematology, Department of Oncology and Hematology, Cantonal Hospital St. gallen, Rorschacher Strasse 95, St. Gallen 9007, Switzerland.
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Mendez-Lopez M
Experimental Oncology and Hematology, Department of Oncology and Hematology, Cantonal Hospital St. gallen, Rorschacher Strasse 95, St. Gallen 9007, Switzerland.
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Bader J
Experimental Oncology and Hematology, Department of Oncology and Hematology, Cantonal Hospital St. gallen, Rorschacher Strasse 95, St. Gallen 9007, Switzerland.
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Xin BT
Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, 2333 CC Leiden, the Netherlands.
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de Bruin G
Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, 2333 CC Leiden, the Netherlands.
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Maurits E
Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, 2333 CC Leiden, the Netherlands.
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Overkleeft HS
Gorlaeus Laboratories, Leiden Institute of Chemistry and Netherlands Proteomics Centre, 2333 CC Leiden, the Netherlands.
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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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Published in:
- Cell chemical biology. - 2019
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.
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bronze
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https://folia.unifr.ch/global/documents/68655
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