Detailed Information on Publication Record
2018
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
ABT, D., A. BESSE, L. SEDLARIKOVA, M. KRAUS, J. BADER et. al.Basic information
Original name
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
Authors
ABT, D. (756 Switzerland), A. BESSE (756 Switzerland), L. SEDLARIKOVA (203 Czech Republic), M. KRAUS (756 Switzerland), J. BADER (756 Switzerland), T. SILZLE (756 Switzerland), Martina VODINSKÁ (203 Czech Republic, belonging to the institution), Ondřej SLABÝ (203 Czech Republic, guarantor, belonging to the institution), H.P. SCHMID (756 Switzerland), D.S. ENGELER (756 Switzerland), C. DRIESSEN (756 Switzerland) and L. BESSE (756 Switzerland)
Edition
BJU INTERNATIONAL, HOBOKEN, WILEY, 2018, 1464-4096
Other information
Language
English
Type of outcome
Článek v odborném periodiku
Field of Study
30204 Oncology
Country of publisher
United States of America
Confidentiality degree
není předmětem státního či obchodního tajemství
Impact factor
Impact factor: 4.524
RIV identification code
RIV/00216224:14740/18:00106679
Organization unit
Central European Institute of Technology
UT WoS
000428845400017
Keywords in English
bortezomib; carfilzomib; renal cell cancer; HIV-protease inhibitors; lopinavir; proteasome inhibitors; #KCSM; #KidneyCancer
Tags
Tags
International impact, Reviewed
Změněno: 21/3/2019 08:43, Mgr. Pavla Foltynová, Ph.D.
Abstract
V originále
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.
Links
| LQ1601, research and development project |
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