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

J 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.

Základní údaje

Originální název

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

Autoři

ABT, D.; A. BESSE; L. SEDLARIKOVA; M. KRAUS; J. BADER; T. SILZLE; Martina VODINSKÁ; Ondřej SLABÝ; H.P. SCHMID; D.S. ENGELER; C. DRIESSEN a L. BESSE

Vydání

BJU INTERNATIONAL, HOBOKEN, WILEY, 2018, 1464-4096

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30204 Oncology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 4.524

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14740/18:00106679

Organizační jednotka

Středoevropský technologický institut

Klíčová slova anglicky

bortezomib; carfilzomib; renal cell cancer; HIV-protease inhibitors; lopinavir; proteasome inhibitors; #KCSM; #KidneyCancer

Štítky

rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 21. 3. 2019 08:43, Mgr. Pavla Foltynová, Ph.D.

Anotace

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.

Návaznosti

LQ1601, projekt VaV

Název: CEITEC 2020 (Akronym: CEITEC2020)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CEITEC 2020

Citovat

ABT, D.; A. BESSE; L. SEDLARIKOVA; M. KRAUS; J. BADER; T. SILZLE; Martina VODINSKÁ; Ondřej SLABÝ; H.P. SCHMID; D.S. ENGELER; C. DRIESSEN a 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. BJU INTERNATIONAL. HOBOKEN: WILEY, 2018, roč. 121, č. 4, s. 600-609. ISSN 1464-4096. Dostupné z: https://doi.org/10.1111/bju.14083.

@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 = {https://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 a 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, roč.~121, č.~4, s.~600-609. ISSN~1464-4096. Dostupné z: https://doi.org/10.1111/bju.14083.

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