ASTEMIZOLE, AN INHIBITOR OF ETHER-À-GO-GO-1 POTASSIUM CHANNEL, INCREASES THE ACTIVITY OF THE TYROSINE KINASE INHIBITOR GEFITINIB IN BREAST CANCER CELLS.
Antineoplastic Agents
/ administration & dosage
Astemizole
/ administration & dosage
Breast Neoplasms
/ drug therapy
Cell Line, Tumor
Cell Proliferation
/ drug effects
Dose-Response Relationship, Drug
Drug Synergism
ErbB Receptors
/ antagonists & inhibitors
Ether-A-Go-Go Potassium Channels
/ antagonists & inhibitors
Female
Gefitinib
/ administration & dosage
Gene Expression Regulation, Neoplastic
Humans
Inhibitory Concentration 50
Protein Kinase Inhibitors
/ administration & dosage
Astemizole
Breast cancer
Combination index
Epidermal growth factor receptor
Gefitinib
Journal
Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion
ISSN: 0034-8376
Titre abrégé: Rev Invest Clin
Pays: Mexico
ID NLM: 9421552
Informations de publication
Date de publication:
2019
2019
Historique:
entrez:
12
6
2019
pubmed:
12
6
2019
medline:
28
12
2019
Statut:
ppublish
Résumé
Expression and activity of the potassium channel ether-à-go-go-1 (EAG1) are strongly related to carcinogenesis and tumor progression, which can be exploited for therapeutic purposes. EAG1 activity may be reduced by preventing its phosphorylation with epidermal growth factor receptor (EGFR) kinase inhibitors and by astemizole, which blocks the channel pore and downregulates its gene expression. We aimed to study the potential cooperative antiproliferative effect of the EGFR inhibitor gefitinib and the EAG1-blocker astemizole, in breast cancer cells. The cells were characterized by immunocytochemistry. Inhibitory concentrations were determined by non-linear regression analysis using dose-response curves. The nature of the pharmacological effect was evaluated by the combination index equation while cell cycle analysis was studied by flow cy-tometry. Astemizole and gefitinib inhibited cell proliferation in a concentration-dependent manner, with inhibitory concentrations (IC 50) values of 1.72 µM and 0.51 µM, respectively. All combinations resulted in a synergistic antiproliferative effect. The combination of astemizole and gefitinib diminished the percentage of cells in G2/M and S phases, while increased accumulation in G0/G1 of the cell cycle. Astemizole and gefitinib synergistically inhibited proliferation in breast cancer cells expressing both EGFR and EAG1. Our results suggest that the combined treatment increased cell death by targeting the oncogenic activity of EAG1.
Sections du résumé
BACKGROUND
BACKGROUND
Expression and activity of the potassium channel ether-à-go-go-1 (EAG1) are strongly related to carcinogenesis and tumor progression, which can be exploited for therapeutic purposes. EAG1 activity may be reduced by preventing its phosphorylation with epidermal growth factor receptor (EGFR) kinase inhibitors and by astemizole, which blocks the channel pore and downregulates its gene expression.
OBJECTIVE
OBJECTIVE
We aimed to study the potential cooperative antiproliferative effect of the EGFR inhibitor gefitinib and the EAG1-blocker astemizole, in breast cancer cells.
MATERIALS AND METHODS
METHODS
The cells were characterized by immunocytochemistry. Inhibitory concentrations were determined by non-linear regression analysis using dose-response curves. The nature of the pharmacological effect was evaluated by the combination index equation while cell cycle analysis was studied by flow cy-tometry.
RESULTS
RESULTS
Astemizole and gefitinib inhibited cell proliferation in a concentration-dependent manner, with inhibitory concentrations (IC 50) values of 1.72 µM and 0.51 µM, respectively. All combinations resulted in a synergistic antiproliferative effect. The combination of astemizole and gefitinib diminished the percentage of cells in G2/M and S phases, while increased accumulation in G0/G1 of the cell cycle.
CONCLUSIONS
CONCLUSIONS
Astemizole and gefitinib synergistically inhibited proliferation in breast cancer cells expressing both EGFR and EAG1. Our results suggest that the combined treatment increased cell death by targeting the oncogenic activity of EAG1.
Identifiants
pubmed: 31184333
pii: j71/3/186
doi: 10.24875/RIC.18002840
doi:
Substances chimiques
Antineoplastic Agents
0
Ether-A-Go-Go Potassium Channels
0
KCNH1 protein, human
0
Protein Kinase Inhibitors
0
Astemizole
7HU6337315
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Gefitinib
S65743JHBS
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
186-194Informations de copyright
Copyright: © 2019 Permanyer.