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01.06.2014 | Original Article | Ausgabe 6/2014

Cancer Chemotherapy and Pharmacology 6/2014

Effects of a novel proteasome inhibitor BU-32 on multiple myeloma cells

Zeitschrift:
Cancer Chemotherapy and Pharmacology > Ausgabe 6/2014
Autoren:
Sudipa S. Roy, Nameer B. Kirma, Bindu Santhamma, Rajeshwar R. Tekmal, Joseph K. Agyin
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s00280-014-2463-3) contains supplementary material, which is available to authorized users.

Abstract

Proteasome inhibition is associated with substantial antitumor effects in preclinical models of multiple myeloma (MM) as well as in patients. However, results of recent clinical trials to evaluate the effect of the proteasome inhibitor Bortezomib (Velcade®, also called PS-341) in MM patients have shown limited activity when used as a single agent. This underscores the need to find new efficacious and less toxic proteasome inhibitors. Recently, carfilzomib was approved for the treatment of refractory/relapsed MM and several new agents have been introduced into the clinic, including marizomib and MLN9708, and trials investigating these second-generation proteasome inhibitors have demonstrated promising results. We have recently synthesized a novel proteasome inhibitor, BU-32, and tested its growth inhibitory effects in different human MM cells including RPMI8226, MM.1S, MM.1R, and U266. In this study, we evaluate the efficacy of the novel proteasome inhibitor BU-32 (NSC D750499) using an in vitro MM model. BU-32 exhibits strong cytotoxicity in a panel of MM cell lines—RPMI8226, MM1S, MM1R, and U266. In addition, we demonstrate by proteasome inhibition assay that BU-32 potently inhibits the chymotryptic- and caspase-like activities of the 26S proteasome. We further show from Annexin V-FITC binding studies that BU-32, like Bortezomib, induces apoptosis in a panel of MM cell lines but the effect is more pronounced with BU-32-treated cells. Invasion assay with the MM.1S cell line indicates that BU-32 inhibits the invasiveness of myeloma cells. Results from our studies using real-time PCR array analyses show that BU-32 effectively downregulates an array of angiogenesis and inflammatory markers. Our results suggest that BU-32 might be a potential chemotherapeutic agent with promising antitumor activity for the treatment of MM.

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Zusatzmaterial
Supplementary material 1 (DOCX 14 kb)
280_2014_2463_MOESM1_ESM.docx
Supplementary material 2 (PPTX 166 kb)
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Supplementary material 3 (PPTX 385 kb)
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Supplementary material 4 (PPTX 247 kb)
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Supplementary material 5 (PPTX 278 kb)
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Supplementary material 6 (PPTX 277 kb)
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Supplementary material 7 (PPTX 257 kb)
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Supplementary material 8 (PPTX 267 kb)
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Literatur
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