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HIV-protease inhibitors potentiate the activity of carfilzomib in triple-negative breast cancer.
Besse, Andrej; Sedlarikova, Lenka; Buechler, Lorina; Kraus, Marianne; Yang, Chieh-Hsiang; Strakova, Nicol; Soucek, Karel; Navratil, Jiri; Svoboda, Marek; Welm, Alana L; Joerger, Markus; Driessen, Christoph; Besse, Lenka.
Afiliación
  • Besse A; Laboratory of Experimental Oncology, Department of Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, 9000, Switzerland.
  • Sedlarikova L; Department of Biology, Faculty of Medicine, Masaryk University, Brno, 62500, Czech Republic.
  • Buechler L; Babak Myeloma Group, Department of Pathological Physiology, Masaryk University, Brno, 62500, Czech Republic.
  • Kraus M; Department of Biology, Faculty of Medicine, Masaryk University, Brno, 62500, Czech Republic.
  • Yang CH; Laboratory of Experimental Oncology, Department of Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, 9000, Switzerland.
  • Strakova N; Laboratory of Experimental Oncology, Department of Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, 9000, Switzerland.
  • Soucek K; Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA.
  • Navratil J; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
  • Svoboda M; Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, 612 00, Czech Republic.
  • Welm AL; Veterinary Research Institute, Brno, 62500, Czech Republic.
  • Joerger M; Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, 612 00, Czech Republic.
  • Driessen C; International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.
  • Besse L; Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Brno, 62500, Czech Republic.
Br J Cancer ; 131(5): 918-930, 2024 Sep.
Article en En | MEDLINE | ID: mdl-38969867
ABSTRACT

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 ß5 + ß2 inhibition, is more cytotoxic in TNBC than bortezomib, which inhibits ß5 + ß1 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oligopéptidos / Inhibidores de la Proteasa del VIH / Nelfinavir / Sinergismo Farmacológico / Respuesta de Proteína Desplegada / Lopinavir / Neoplasias de la Mama Triple Negativas / Bortezomib / Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 Límite: Female / Humans Idioma: En Revista: Br J Cancer Año: 2024 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Reino Unido
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oligopéptidos / Inhibidores de la Proteasa del VIH / Nelfinavir / Sinergismo Farmacológico / Respuesta de Proteína Desplegada / Lopinavir / Neoplasias de la Mama Triple Negativas / Bortezomib / Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 Límite: Female / Humans Idioma: En Revista: Br J Cancer Año: 2024 Tipo del documento: Article País de afiliación: Suiza Pais de publicación: Reino Unido