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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F24%3A00603745" target="_blank" >RIV/68081707:_____/24:00603745 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216224:14110/24:00136690 RIV/00159816:_____/24:00081675 RIV/00209805:_____/24:00079855 RIV/00027162:_____/24:N0000114

Výsledek na webu

<a href="https://www.nature.com/articles/s41416-024-02774-9#citeas" target="_blank" >https://www.nature.com/articles/s41416-024-02774-9#citeas</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41416-024-02774-9" target="_blank" >10.1038/s41416-024-02774-9</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

BackgroundResistance 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.MethodsWe 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.ResultsCarfilzomib, via proteasome beta 5 + beta 2 inhibition, is more cytotoxic in TNBC than bortezomib, which inhibits beta 5 + beta 1 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.ConclusionProteasome inhibition by carfilzomib combined with nelfinavir/lopinavir represents a potential treatment option for TNBC, warranting further investigation.

Název v anglickém jazyce

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

Popis výsledku anglicky

BackgroundResistance 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.MethodsWe 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.ResultsCarfilzomib, via proteasome beta 5 + beta 2 inhibition, is more cytotoxic in TNBC than bortezomib, which inhibits beta 5 + beta 1 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.ConclusionProteasome inhibition by carfilzomib combined with nelfinavir/lopinavir represents a potential treatment option for TNBC, warranting further investigation.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30204 - Oncology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

British Journal of Cancer

ISSN

0007-0920

e-ISSN

1532-1827

Svazek periodika

5

Číslo periodika v rámci svazku

131

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

13

Strana od-do

918-930

Kód UT WoS článku

001263310800001

EID výsledku v databázi Scopus

2-s2.0-85197486685