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

Hu,Bi‑Dan; Guo,Jia; Ye,Yuan‑Zi; Du,Ting; Cheng,Chun‑Song; Jiang,Qian; Liu,Ruo‑Nan; Zhang,Yan‑Bei

doi:10.3892/or.2018.6448

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

Authors:
- Bi‑Dan Hu
- Jia Guo
- Yuan‑Zi Ye
- Ting Du
- Chun‑Song Cheng
- Qian Jiang
- Ruo‑Nan Liu
- Yan‑Bei Zhang
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Affiliations: Department of Respiratory and Critical Care, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China, Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, SAR, P.R. China
Published online on: May 16, 2018 https://doi.org/10.3892/or.2018.6448
Pages: 155-164
Copyright: © Hu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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