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
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
29161753
DOI
10.1111/bju.14083
Knihovny.cz E-resources
- Keywords
- #KCSM, #KidneyCancer, HIV-protease inhibitors, bortezomib, carfilzomib, lopinavir, proteasome inhibitors, renal cell cancer,
- MeSH
- Drug Resistance, Neoplasm MeSH
- HIV Protease Inhibitors therapeutic use MeSH
- Proteasome Inhibitors therapeutic use MeSH
- Carcinoma, Renal Cell drug therapy MeSH
- Humans MeSH
- Lopinavir therapeutic use MeSH
- Cell Line, Tumor MeSH
- Kidney Neoplasms drug therapy MeSH
- Nelfinavir therapeutic use MeSH
- Antineoplastic Agents therapeutic use MeSH
- Endoplasmic Reticulum Stress drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- HIV Protease Inhibitors MeSH
- Proteasome Inhibitors MeSH
- Lopinavir MeSH
- Nelfinavir MeSH
- Antineoplastic Agents MeSH
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.
Central European Institute of Technology Masaryk University Brno Czech Republic
Department of Pathological Physiology Babak Myeloma Group Masaryk University Brno Czech Republic
Department of Urology Cantonal Hospital St Gallen St Gallen Switzerland
References provided by Crossref.org
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