Differential effects of montelukast and zafirlukast on MDAMB231 triplenegative breast cancer cells: Cell cycle regulation, apoptosis, autophagy, DNA damage and endoplasmic reticulum stress.
Mol Med Rep
; 30(2)2024 Aug.
Article
en En
| MEDLINE
| ID: mdl-38904207
ABSTRACT
Montelukast and zafirlukast, cysteinyl leukotriene receptor antagonists (LTRAs), trigger apoptosis and inhibit cell proliferation of triplenegative breast cancer MDAMB231 cells. By contrast, only zafirlukast induces G0/G1 cell cycle arrest. The present study compared the effects of these drugs on proteins regulating cell proliferation, apoptosis, autophagy, and endoplasmic reticulum (ER) and oxidative stress using reverse transcriptionquantitative PCR, western blotting and flow cytometry. The expression of proliferating markers, Ki67 and proliferating cell nuclear antigen, was decreased by both drugs. Zafirlukast, but not montelukast, decreased the expression of cyclin D1 and CDK4, disrupting progression from G1 to S phase. Zafirlukast also increased the expression of p27, a cell cycle inhibitor. Both drugs decreased the expression of antiapoptotic protein Bcl2 and ERK1/2 phosphorylation, and increased levels of the autophagy marker LC3II and DNA damage markers, including cleaved PARP1, phosphorylated (p)ATM and phistone H2AX. The number of caspase 3/7positive cells was greater in montelukasttreated cells compared with zafirlukasttreated cells. Montelukast induced higher levels of the ER stress marker CHOP compared with zafirlukast. Montelukast activated PERK, activating transcription factor 6 (ATF6) and inositolrequiring enzyme type 1 (IRE1) pathways, while zafirlukast only stimulated ATF6 and IRE1 pathways. GSK2606414, a PERK inhibitor, decreased apoptosis mediated by montelukast, but did not affect zafirlukastinduced cell death. The knockdown of CHOP by small interfering RNA reduced apoptosis triggered by montelukast and zafirlukast. In conclusion, the effects on cell cycle regulator proteins may contribute to cell cycle arrest caused by zafirlukast. The greater apoptotic effects of montelukast may be caused by the higher levels of activated caspase enzymes and the activation of three pathways of ER stress PERK, ATF6, and IRE1.
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Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Quinolinas
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Autofagia
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Sulfuros
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Sulfonamidas
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Daño del ADN
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Apoptosis
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Ciclopropanos
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Estrés del Retículo Endoplásmico
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Indoles
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Acetatos
Límite:
Female
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Humans
Idioma:
En
Año:
2024
Tipo del documento:
Article