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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
Language English Country England, Great Britain
Document type Journal Article
Grant support
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)
NLK
Free Medical Journals
from 1947 to 1 year ago
Freely Accessible Journals
from 1947 to 1 year ago
PubMed Central
from 1947 to 1 year ago
Europe PubMed Central
from 1947 to 1 year ago
ProQuest Central
from 2000-01-01 to 1 year ago
Open Access Digital Library
from 1947-01-01
Open Access Digital Library
from 1999-01-01
Nursing & Allied Health Database (ProQuest)
from 2000-01-01 to 1 year ago
Health & Medicine (ProQuest)
from 2000-01-01 to 1 year ago
Public Health Database (ProQuest)
from 2000-01-01 to 1 year ago
- MeSH
- ATP Binding Cassette Transporter, Subfamily G, Member 2 * metabolism antagonists & inhibitors MeSH
- Apoptosis drug effects MeSH
- Bortezomib * pharmacology MeSH
- HIV Protease Inhibitors * pharmacology MeSH
- Proteasome Inhibitors pharmacology MeSH
- Humans MeSH
- Lopinavir * pharmacology MeSH
- Cell Line, Tumor MeSH
- Neoplasm Proteins antagonists & inhibitors metabolism MeSH
- Nelfinavir * pharmacology MeSH
- Oligopeptides * pharmacology MeSH
- ATP Binding Cassette Transporter, Subfamily B metabolism MeSH
- Antineoplastic Combined Chemotherapy Protocols pharmacology MeSH
- Unfolded Protein Response * drug effects MeSH
- Endoplasmic Reticulum Stress drug effects MeSH
- Drug Synergism * MeSH
- Triple Negative Breast Neoplasms * drug therapy pathology MeSH
- X-Box Binding Protein 1 metabolism genetics MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
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.
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 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
References provided by Crossref.org
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