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HIV-protease inhibitors potentiate the activity of carfilzomib in triple-negative breast cancer

A. Besse, L. Sedlarikova, L. Buechler, M. Kraus, CH. Yang, N. Strakova, K. Soucek, J. Navratil, M. Svoboda, AL. Welm, M. Joerger, C. Driessen, L. Besse

. 2024 ; 131 (5) : 918-930. [pub] 20240705

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc24019120

Grantová podpora
U54 CA224076 NCI NIH HHS - United States
NU-21-08-00023 Agentura Pro Zdravotnický Výzkum České Republiky (Czech Health Research Council)
KFS-4990-02-2020 Krebsliga Schweiz (Ligue Suisse Contre le Cancer)
U54CA224076 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)

E-zdroje Online Plný text

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Odkazy

PubMed 38969867
DOI 10.1038/s41416-024-02774-9
Knihovny.cz E-zdroje

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.

Citace poskytuje Crossref.org

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