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.

• MeSH
• ABC transportér z rodiny G, člen 2 * metabolismus   antagonisté a inhibitory   MeSH
• apoptóza účinky léků   MeSH
• bortezomib * farmakologie   MeSH
• inhibitory HIV-proteasy * farmakologie   MeSH
• inhibitory proteasomu farmakologie   MeSH
• lidé MeSH
• Lopinavir * farmakologie   MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny antagonisté a inhibitory   metabolismus   MeSH
• nelfinavir * farmakologie   MeSH
• oligopeptidy * farmakologie   MeSH
• P-glykoproteiny metabolismus   MeSH
• protokoly protinádorové kombinované chemoterapie farmakologie   MeSH
• signální dráha UPR * účinky léků   MeSH
• stres endoplazmatického retikula účinky léků   MeSH
• synergismus léků * MeSH
• triple-negativní karcinom prsu * farmakoterapie   patologie   MeSH
• XBP1 metabolismus   genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH