BACKGROUND: Resistance to chemotherapy is a major problem in the treatment of patients with triple-negative breast cancer (TNBC). Preclinical data suggest that TNBC is dependent on proteasomes; however, clinical observations indicate that the efficacy of proteasome inhibitors in TNBC may be limited, suggesting the need for combination therapies. METHODS: We compared bortezomib and carfilzomib and their combinations with nelfinavir and lopinavir in TNBC cell lines and primary cells with regard to their cytotoxic activity, functional proteasome inhibition, and induction of the unfolded protein response (UPR). Furthermore, we evaluated the involvement of sXBP1, ABCB1, and ABCG2 in the cytotoxic activity of drug combinations. RESULTS: Carfilzomib, via proteasome β5 + β2 inhibition, is more cytotoxic in TNBC than bortezomib, which inhibits β5 + β1 proteasome subunits. The cytotoxicity of carfilzomib was significantly potentiated by nelfinavir or lopinavir. Carfilzomib with lopinavir induced endoplasmic reticulum stress and pro-apoptotic UPR through the accumulation of excess proteasomal substrate protein in TNBC in vitro. Moreover, lopinavir increased the intracellular availability of carfilzomib by inhibiting carfilzomib export from cells that express high levels and activity of ABCB1, but not ABCG2. CONCLUSION: Proteasome inhibition by carfilzomib combined with nelfinavir/lopinavir represents a potential treatment option for TNBC, warranting further investigation.

Babak Myeloma Group Department of Pathological Physiology Masaryk University Brno 62500 Czech Republic

Department of Biology Faculty of Medicine Masaryk University Brno 62500 Czech Republic

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute Brno 62500 Czech Republic

Department of Cytokinetics Institute of Biophysics of the Czech Academy of Sciences Brno 612 00 Czech Republic

Department of Oncological Sciences University of Utah Salt Lake City UT USA

Department of Oncology and Hematology Cantonal Hospital St Gallen St Gallen 9000 Switzerland

Faculty of Medicine Masaryk University Brno 62500 Czech Republic

Huntsman Cancer Institute University of Utah Salt Lake City UT USA

International Clinical Research Center St Anne's University Hospital Brno Brno Czech Republic

Laboratory of Experimental Oncology Department of Oncology and Hematology Cantonal Hospital St Gallen St Gallen 9000 Switzerland

Veterinary Research Institute Brno 62500 Czech Republic

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