, Volume 70, Issue 2, pp 865–877 | Cite as

Combination treatment of all-trans retinoic acid (ATRA) and γ-secretase inhibitor (DAPT) cause growth inhibition and apoptosis induction in the human gastric cancer cell line



Current medication for gastric cancer patients has a low success rate with resistance and side effects. According to recent studies, γ-secretase inhibitors is used as therapeutic drugs in cancer. Moreover, all-trans retinoic acid (ATRA) is a natural compound proposed for the treatment/chemo-prevention of cancers. The aim of this study was to explore the effects of ATRA in combination with N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t-butyl ester (DAPT) as γ-secretase inhibitor on viability and apoptosis of the AGS and MKN-45 derived from human gastric cancer. AGS and MKN-45 gastric cancer cell lines were treated with different concentrations of ATRA or DAPT alone or ATRA plus DAPT. The viability, death detection and apoptosis of cells was examined by MTT assay and Ethidium bromide/acridine orange staining. The distribution of cells in different phases of cell cycle was also evaluated through flow cytometry analyses. In addition, caspase 3/7 activity and the expression of caspase-3 and bcl-2 were examined. DAPT and ATRA alone decreased gastric cancer cells viability in a concentration dependent manner. The combination of DAPT and ATRA exhibited significant synergistic inhibitory effects. The greater percentage of cells were accumulated in G0/G1 phase of cell cycle in combination treatment. The combination of DAPT and ATRA effectively increased the proportion of apoptotic cells and the level of caspase 3/7 activities compared to single treatment. Moreover, augmented caspase-3 up-regulation and bcl-2 down-regulation were found following combined application of DAPT and ATRA. The combination of DAPT and ATRA led to more reduction in viability and apoptosis in respect to DAPT or ATRA alone in the investigated cell lines.


DAPT ATRA Gastric cancer Caspase 3/7 bcl-2 Combination therapy 



This research was supported by a thesis grant for Master of Science from Ardabil University of Medical Sciences. The authors also appreciate Mrs. Sheri Lynn Jalalian as an English expert for reviewing the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


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© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biochemistry, School of MedicineArdabil University of Medical SciencesArdabilIran
  2. 2.Research Laboratory for Embryology and Stem Cells, Department of Anatomical Sciences, School of MedicineArdabil University of Medical SciencesArdabilIran
  3. 3.Molecular Medicine Laboratory, Department of MedicineThe University of Kansas Medical School (KUMC)Kansas CityUSA
  4. 4.Department of Medicinal Chemistry, School of PharmacyArdabil University of Medical SciencesArdabilIran

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