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@article{1508637,
author = {Abt, D. and Besse, A. and Sedlarikova, L. and Kraus, M. and Bader, J. and Silzle, T. and Vodinská, Martina and Slabý, Ondřej and Schmid, H.P. and Engeler, D.S. and Driessen, C. and Besse, L.},
article_location = {HOBOKEN},
article_number = {4},
doi = {http://dx.doi.org/10.1111/bju.14083},
keywords = {bortezomib; carfilzomib; renal cell cancer; HIV-protease inhibitors; lopinavir; proteasome inhibitors; #KCSM; #KidneyCancer},
language = {eng},
issn = {1464-4096},
journal = {BJU INTERNATIONAL},
title = {Improving the efficacy of proteasome inhibitors in the treatment of renal cell carcinoma by combination with the human immunodeficiency virus (HIV)-protease inhibitors lopinavir or nelfinavir},
volume = {121},
year = {2018}
}
TY - JOUR
ID - 1508637
AU - Abt, D. - Besse, A. - Sedlarikova, L. - Kraus, M. - Bader, J. - Silzle, T. - Vodinská, Martina - Slabý, Ondřej - Schmid, H.P. - Engeler, D.S. - Driessen, C. - Besse, L.
PY - 2018
TI - Improving the efficacy of proteasome inhibitors in the treatment of renal cell carcinoma by combination with the human immunodeficiency virus (HIV)-protease inhibitors lopinavir or nelfinavir
JF - BJU INTERNATIONAL
VL - 121
IS - 4
SP - 600-609
EP - 600-609
PB - WILEY
SN - 14644096
KW - bortezomib
KW - carfilzomib
KW - renal cell cancer
KW - HIV-protease inhibitors
KW - lopinavir
KW - proteasome inhibitors
KW - #KCSM
KW - #KidneyCancer
N2 - Objectives To assess the potential of second-generation proteasome inhibition by carfilzomib and its combination with the human immunodeficiency virus (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 were assessed in three cell lines and primary cells derived from three ccRCC tumours by MTS assay, flow cytometry, quantitative reverse transcriptase-polymerase chain reaction and western blot, respectively. Proteasome activity was determined by activity based probes. Flow cytometry was used to assess apoptosis by annexin V/propidium iodide assay and ATP-binding cassette sub-family B member 1 (ABCB1) activity by MitoTracker Green FM efflux assay (Thermo Fisher Scientific, MA, USA). 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. Combined treatment led to unresolved protein stress, increased activation of pro-apoptotic UPR pathway, and a significant increase in apoptosis. Conclusion The combination of the proteasome inhibitor carfilzomib and the HIV-PIs lopinavir and nelfinavir has a strong synergistic cytotoxic activity against ccRCCin 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.
ER -
ABT, D., A. BESSE, L. SEDLARIKOVA, M. KRAUS, J. BADER, T. SILZLE, Martina VODINSKÁ, Ondřej SLABÝ, H.P. SCHMID, D.S. ENGELER, C. DRIESSEN and L. BESSE. Improving the efficacy of proteasome inhibitors in the treatment of renal cell carcinoma by combination with the human immunodeficiency virus (HIV)-protease inhibitors lopinavir or nelfinavir. \textit{BJU INTERNATIONAL}. HOBOKEN: WILEY, 2018, vol.~121, No~4, p.~600-609. ISSN~1464-4096. Available from: https://dx.doi.org/10.1111/bju.14083.
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