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Specific inhibitor of Notch‑3 enhances the sensitivity of NSCLC cells to gemcitabine

Citation

Hu, B-D and Guo, J and Ye, Y-Z and Du, T and Cheng, C-S and Jiang, Q and Liu, R-N and Zhang, Y-B, Specific inhibitor of Notch‑3 enhances the sensitivity of NSCLC cells to gemcitabine, Oncology Reports, 40, (1) pp. 155-164. ISSN 1021-335X (2018) [Refereed Article]


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Copyright 2018 The Authors. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) https://creativecommons.org/licenses/by-nc-nd/4.0/

DOI: doi:10.3892/or.2018.6448

Abstract

Notch‑3 is a receptor of the Notch signaling pathway and plays an important role in regulating self‑renewal, differentiation and apoptosis in cancer cells. Overexpression of Notch‑3 has been proved to be associated with resistance to gemcitabine (GEM) and poor patient prognosis for various malignant tumors. In the present study, two non‑small 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‑(3,5‑difluorophenacetyl)‑L‑alanyl]‑S‑phenylglycine t‑butyl 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 apoptosis‑related proteins, Bcl‑2 and Bax, were found to be affected by the various treatments. Thus Notch‑3 appears to be a promising target for gene therapy and DAPT is able to mediate a strong antitumor effect in NSCLC cells that overexpress Notch‑3. 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.

Item Details

Item Type:Refereed Article
Keywords:non‑small cell lung cancer, Notch signaling, DAPT, gemcitabine, chemoresistance
Research Division:Biomedical and Clinical Sciences
Research Group:Oncology and carcinogenesis
Research Field:Cancer cell biology
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Ye, Y-Z (Ms Yuanzi Ye)
ID Code:126319
Year Published:2018
Web of Science® Times Cited:3
Deposited By:Menzies Institute for Medical Research
Deposited On:2018-06-05
Last Modified:2019-01-18
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