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Proteasome activity was determined by activity based probes. Flow cytometry was used to assess apoptosis by annexin V\/propidium iodide assay and\n ATP<\/jats:styled-content>\n \u2010binding cassette sub\u2010family B member 1 (\n ABCB<\/jats:styled-content>\n 1) activity by MitoTracker\u2122 Green\n FM<\/jats:styled-content>\n efflux assay (Thermo Fisher Scientific, MA, USA).\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Lopinavir and nelfinavir significantly increased the cytotoxic effect of carfilzomib in all cell lines and primary cells.\n ABCB<\/jats:styled-content>\n 1 efflux pump inhibition, induction of\n ROS<\/jats:styled-content>\n production, and\n UPR<\/jats:styled-content>\n pre\u2010activation by lopinavir were identified as underlying mechanisms of this strong synergistic effect. Combined treatment led to unresolved protein stress, increased activation of pro\u2010apoptotic\n UPR<\/jats:styled-content>\n pathway, and a significant increase in apoptosis.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n The combination of the proteasome inhibitor carfilzomib and the\n HIV<\/jats:styled-content>\n \u2010\n PI<\/jats:styled-content>\n s lopinavir and nelfinavir has a strong synergistic cytotoxic activity against cc\n RCC<\/jats:styled-content>\n in vitro<\/jats:italic>\n at therapeutically relevant drug concentrations. This effect is most likely explained by synergistic\n UPR<\/jats:styled-content>\n triggering and\n ABCB<\/jats:styled-content>\n 1\u2010modulation caused by\n HIV<\/jats:styled-content>\n \u2010\n PI<\/jats:styled-content>\n s. Our findings suggest that combined treatment of second\u2010generation proteasome inhibitors and\n HIV<\/jats:styled-content>\n \u2010\n PI<\/jats:styled-content>\n s should be investigated in patients with metastatic\n RCC<\/jats:styled-content>\n within a clinical trial.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/bju.14083","type":"journal-article","created":{"date-parts":[[2017,11,21]],"date-time":"2017-11-21T17:52:42Z","timestamp":1511286762000},"page":"600-609","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Improving the efficacy of proteasome inhibitors in the treatment of renal cell carcinoma by combination with the human immunodeficiency virus (\n HIV<\/scp>\n )\u2010protease inhibitors lopinavir or nelfinavir"],"prefix":"10.1111","volume":"121","author":[{"given":"Dominik","family":"Abt","sequence":"first","affiliation":[{"name":"Department of Urology Cantonal Hospital St. Gallen St. Gallen 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