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Improving the efficacy of proteasome inhibitors in the treatment of renal cell carcinoma by combination with the HIV-protease inhibitors lopinavir or nelfinavir.

Improving the efficacy of proteasome inhibitors in the treatment of renal cell carcinoma by combination with the HIV-protease inhibitors lopinavir or nelfinavir.
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Abt D, Besse A, Sedlarikova L, Kraus M, Bader J, Silzle T, Vodinska M, Slaby O, Schmid HP, Engeler DS, Driessen C, Besse L,


Abt D, Besse A, Sedlarikova L, Kraus M, Bader J, Silzle T, Vodinska M, Slaby O, Schmid HP, Engeler DS, Driessen C, Besse L, (click to view)

Abt D, Besse A, Sedlarikova L, Kraus M, Bader J, Silzle T, Vodinska M, Slaby O, Schmid HP, Engeler DS, Driessen C, Besse L,

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BJU international 2017 11 21() doi 10.1111/bju.14083

Abstract
OBJECTIVES
To assess the potential of second-generation proteasome inhibition by carfilzomib and its combination with the HIV-protease inhibitors (HIV-PIs) lopinavir and nelfinavir in vitro for improved treatment of clear cell renal cell cancer (ccRCC).

MATERIALS AND METHODS
Cytotoxicity, reactive oxygen species (ROS) production and unfolded protein response (UPR) activation of proteasome inhibitors, HIV-PIs and their combination was assessed in 3 cell lines and primary cells derived from 3 ccRCC tumors by MTS assay, flow cytometry, quantitative PCR and western blot, respectively. Proteasome activity was determined by activity based probes. Flow cytometry was used to assess apoptosis by Annexin V/PI assay and ABCB1 activity by Mitotracker Green FM efflux assay.

RESULTS
Lopinavir and nelfinavir significantly increased the cytotoxic effect of carfilzomib in all cell lines and primary cells. ABCB1 efflux pump inhibition, induction of ROS production and UPR pre-activation by lopinavir were identified as underlying mechanisms of this strong synergistic effect. Combination treatment led to unresolved protein stress, increased activation of pro-apoptotic UPR pathway and significant increase of apoptosis.

CONCLUSION
The combination of the proteasome inhibitor carfilzomib and the HIV-PIs lopinavir and nelfinavir has a strong synergistic cytotoxic activity against ccRCC in vitro at therapeutically relevant drug concentrations. This effect is most likely explained by synergistic UPR triggering and ABCB1-modulation caused by HIV-PIs. Our findings suggest that combined treatment of second-generation proteasome inhibitors and HIV-PIs should be investigated in patients with metastatic RCC within a clinical trial. This article is protected by copyright. All rights reserved.

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