Targeted blocking of EGFR and GLUT1 by compound H reveals a new strategy for treatment of triple-negative breast cancer and nasopharyngeal carcinoma.
Eur J Pharm Sci
; 198: 106789, 2024 Jul 01.
Article
em En
| MEDLINE
| ID: mdl-38710335
ABSTRACT
BACKGROUND:
Cytoplasmic epidermal growth factor receptor (EGFR) is overexpressed in both nasopharyngeal carcinoma (NPC) and triple-negative breast cancer (TNBC), while clinical outcome and prognosis vary greatly among patients treated with gefitinib, and all patients eventually develop resistance to this agent. Therefore, we propose a new concept for synthesizing multitarget compounds and reveal new therapeutic strategies for NPC and TNBC expressing EGFR.METHODS:
Compound H was synthesized in our previous study. Molecular docking, and cell thermal shift assays (CETSAs) and drug affinity responsive target stability(DARTS) were used to confirm the binding of compound H to EGFR and GLUT1. Methylthiazolyldiphenyl-tetrazolium bromide(MTT), annexin V-PE assays, mitochondrial membrane potential (MMP) assays, and animal models were used to evaluate the inhibitory effect of compound H on TNBC cell lines. Energy metabolism tests, Western blotting, and immunofluorescence staining were performed to evaluate the synergistic effects on EGFR- and glucose transporter type 1(GLUT1)-mediated energy metabolism.RESULTS:
Compound H can simultaneously act on the EGFR tyrosine kinase ATP-binding site and inhibit GLUT1-mediated energy metabolism, resulting in reductions in ATP, MMP, intra-cellular lactic acid, and EGFR nuclear transfer. The anti-tumor activity of compound H is significantly superior to the combination of GLUT1 inhibitor BAY876 and EGFR inhibitor gefitinib. Compound H has remarkable anti-proliferative effects on TNBC MDA-MB231 cells, and importantly, no obvious toxicity effects of compound H were found in vivo.CONCLUSIONS:
Synergistic effects of inhibition of EGFR- and GLUT1-mediated energy metabolism by compound H may present a new strategy for the treatment of TNBC and NPC.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transportador de Glucose Tipo 1
/
Neoplasias de Mama Triplo Negativas
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Receptores ErbB
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Carcinoma Nasofaríngeo
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Antineoplásicos
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Eur J Pharm Sci
Assunto da revista:
FARMACIA
/
FARMACOLOGIA
/
QUIMICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China
País de publicação:
HOLANDA
/
HOLLAND
/
NETHERLANDS
/
NL
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PAISES BAJOS
/
THE NETHERLANDS