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The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells

Wang, Xin (author)
Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Linkoping Univ, Dept Med Hlth Sci IMH, S-75185 Linkoping, Sweden.
Mazurkiewicz, Magdalena (author)
Karolinska Institutet,Karolinska Inst, Dept Pathol & Oncol, Canc Ctr Karolinska, S-17176 Stockholm, Sweden.,Karolinska Institute, Sweden
Hillert, Ellin-Kristina (author)
Karolinska Institutet,Karolinska Inst, Dept Pathol & Oncol, Canc Ctr Karolinska, S-17176 Stockholm, Sweden.,Karolinska Institute, Sweden
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Hägg Olofsson, Maria (author)
Karolinska Institute, Sweden,Karolinska Inst, Dept Pathol & Oncol, Canc Ctr Karolinska, S-17176 Stockholm, Sweden.
Pierrou, Stefan (author)
ESP Life Science Consulting AB, Sweden,ESP Life Sci Consulting AB, Box 119, S-43122 Molndal, Sweden.
Hillertz, Per (author)
Biosynchro West AB, Karl Johansgatan 142, S-41451 Gothenburg, Sweden.
Gullbo, Joachim (author)
Uppsala universitet,Experimentell och klinisk onkologi,Cancerfarmakologi och beräkningsmedicin,Uppsala University, Sweden
Selvaraju, Karthik (author)
Linköpings universitet,Medicinska fakulteten,Avdelningen för läkemedelsforskning,Linkoping Univ, Dept Med Hlth Sci IMH, S-75185 Linkoping, Sweden.
Paulus, Aneel (author)
Mayo Clin, Dept Hematol & Oncol, Jacksonville, FL 32224 USA.
Akhtar, Sharoon (author)
Mayo Clin, Dept Canc Biol, Jacksonville, FL 32224 USA.
Bossler, Felicitas (author)
DKFZ, German Canc Res Ctr, Heidelberg, Germany.
Chanan Khan, Asher (author)
Mayo Clin, Dept Hematol & Oncol, Jacksonville, FL 32224 USA.;Mayo Clin, Dept Canc Biol, Jacksonville, FL 32224 USA.
Linder, Stig (author)
Karolinska Institutet,Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden,Linkoping Univ, Dept Med Hlth Sci IMH, S-75185 Linkoping, Sweden.;Karolinska Inst, Dept Pathol & Oncol, Canc Ctr Karolinska, S-17176 Stockholm, Sweden.
D´arcy, Padraig (author)
Karolinska Institutet,Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Linkoping Univ, Dept Med Hlth Sci IMH, S-75185 Linkoping, Sweden.
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 (creator_code:org_t)
2016-06-06
2016
English.
In: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 6, s. 1-14
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • Inhibition of deubiquitinase (DUB) activity is a promising strategy for cancer therapy. VLX1570 is an inhibitor of proteasome DUB activity currently in clinical trials for relapsed multiple myeloma. Here we show that VLX1570 binds to and inhibits the activity of ubiquitin-specific protease-14 (USP14) in vitro, with comparatively weaker inhibitory activity towards UCHL5 (ubiquitin-C-terminal hydrolase-5). Exposure of multiple myeloma cells to VLX1570 resulted in thermostabilization of USP14 at therapeutically relevant concentrations. Transient knockdown of USP14 or UCHL5 expression by electroporation of siRNA reduced the viability of multiple myeloma cells. Treatment of multiple myeloma cells with VLX1570 induced the accumulation of proteasome-bound high molecular weight polyubiquitin conjugates and an apoptotic response. Sensitivity to VLX1570 was moderately affected by altered drug uptake, but was unaffected by overexpression of BCL2-family proteins or inhibitors of caspase activity. Finally, treatment with VLX1570 was found to lead to extended survival in xenograft models of multiple myeloma. Our findings demonstrate promising antiproliferative activity of VLX1570 in multiple myeloma, primarily associated with inhibition of USP14 activity.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

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