Specific inhibitor of Notch3 enhances the sensitivity of NSCLC cells to gemcitabine.
Oncol Rep
; 40(1): 155-164, 2018 Jul.
Article
em En
| MEDLINE
| ID: mdl-29781034
ABSTRACT
Notch3 is a receptor of the Notch signaling pathway and plays an important role in regulating selfrenewal, differentiation and apoptosis in cancer cells. Overexpression of Notch3 has been proved to be associated with resistance to gemcitabine (GEM) and poor patient prognosis for various malignant tumors. In the present study, two nonsmall cell lung cancer (NSCLC) cell lines, H1299 and A549, were induced with GEM for two months and then were treated with various concentrations of a Notch signaling blocker, N[N(3,5difluorophenacetyl)Lalanyl]Sphenylglycine tbutyl ester (DAPT), with the goal of reducing expression of Notch intracellular domain 3 (NICD3). Both cell lines were subsequently treated with either DAPT or DAPT combined with GEM and then viability, apoptosis, colony formation and cell count assays were performed. DAPT treatment effectively downregulated the expression of NICD3 in both cell lines. DAPT combined with GEM also significantly reduced the percentage of viable cells in both cell lines, while increasing the percentage of apoptotic cells, compared with GEM alone. In the clonogenicity assays, the combination of DAPT and GEM led to a decrease in clone numbers and significantly greater inhibition of the H1299 and A549 cells compared to treatment with DAPT or GEM alone. Meanwhile, levels of the apoptosisrelated proteins, Bcl2 and Bax, were found to be affected by the various treatments. Thus Notch3 appears to be a promising target for gene therapy and DAPT is able to mediate a strong antitumor effect in NSCLC cells that overexpress Notch3. Further studies of a combined treatment regimen with DAPT and GEM are warranted and may provide greater efficacy and safety in the treatment of NSCLC patients.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tiazóis
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Carcinoma Pulmonar de Células não Pequenas
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Desoxicitidina
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Diaminas
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Receptor Notch3
Tipo de estudo:
Diagnostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article