Dipeptide γ-secretase inhibitor treatment enhances the anti-tumor effects of cisplatin against gastric cancer by suppressing cancer stem cell properties.

The γ-secretase inhibitor blocks Notch activity by preventing its cleavage at the cell surface. In the present study, the effect of the γ-secretase inhibitor on the viability of gastric cancer cells when administered in combination with cisplatin was investigated, with particular focus on CD44highLgr-5high cancer cells. The four gastric cancer cell lines, MKN45, MKN74, SC-6-JCK and SH-10-TC, were used for the experiments. In the MTT assay, treatment with 25 µM dipeptide γ-secretase inhibitor (DAPT) alone did not affect cell proliferation in any of the four cell lines. Gastric cancer cells subjected to combination treatment with DAPT and cisplatin exhibited decreased viability when compared with those treated with cisplatin alone. Flow cytometry was performed to evaluate the expression of cluster of differentiation (CD)-44 and leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr-5), two cancer stem cell markers in gastric cancers. Treatment with cisplatin alone significantly increased the proportion of CD44highLgr-5high cells. However, the addition of DAPT to cisplatin reduced the CD44highLgr-5high fraction, suggesting that DAPT reduced the number of gastric cancer cells. In conclusion, the present study demonstrated the synergistic effects of DAPT in combination with cisplatin by decreasing the survival of gastric cancer cells. In addition, combination treatment with DAPT reduced the number of CD44highLgr-5high cells, which are thought to exhibit cancer stem cell properties. These results highlight the therapeutic potential of DAPT in gastric cancer treatment.

[1]  L. Qin,et al.  Upregulated miR‐132 in Lgr5+ gastric cancer stem cell‐like cells contributes to cisplatin‐resistance via SIRT1/CREB/ABCG2 signaling pathway , 2017, Molecular carcinogenesis.

[2]  Tetsuji Yamaguchi,et al.  Circulating tumor cells expressing cancer stem cell marker CD44 as a diagnostic biomarker in patients with gastric cancer , 2016, Oncology letters.

[3]  X. Yang,et al.  Gastric Lgr5+ stem cells are the cellular origin of invasive intestinal-type gastric cancer in mice , 2016, Cell Research.

[4]  Yong-zhong Wu,et al.  Gastric tumor-initiating CD44+ cells and epithelial-mesenchymal transition are inhibited by γ-secretase inhibitor DAPT. , 2015, Oncology letters.

[5]  Chao Liu,et al.  Lgr5-Positive Cells are Cancer-Stem-Cell-Like Cells in Gastric Cancer , 2015, Cellular Physiology and Biochemistry.

[6]  E. Keller,et al.  Notch Pathway Inhibition Using PF-03084014, a γ-Secretase Inhibitor (GSI), Enhances the Antitumor Effect of Docetaxel in Prostate Cancer , 2015, Clinical Cancer Research.

[7]  I. Choi,et al.  Targeting Notch signaling by γ-secretase inhibitor I enhances the cytotoxic effect of 5-FU in gastric cancer , 2015, Clinical & Experimental Metastasis.

[8]  Guiyu Wang,et al.  Colorectal cancer stem cell and chemoresistant colorectal cancer cell phenotypes and increased sensitivity to Notch pathway inhibitor , 2015, Molecular medicine reports.

[9]  M. Cristofanilli,et al.  Cancer stem cells: implications for cancer therapy. , 2014, Oncology.

[10]  A. Capobianco,et al.  Notch signaling drives stemness and tumorigenicity of esophageal adenocarcinoma. , 2014, Cancer research.

[11]  J. Medema,et al.  Cancer stem cells – important players in tumor therapy resistance , 2014, The FEBS journal.

[12]  Zongguang Zhou,et al.  Role of Notch signaling pathway in gastric cancer: a meta-analysis of the literature. , 2014, World journal of gastroenterology.

[13]  Edward J. Kim,et al.  The Notch Pathway Is Important in Maintaining the Cancer Stem Cell Population in Pancreatic Cancer , 2014, PloS one.

[14]  Guihua Xu,et al.  Cancer stem cells: the ‘heartbeat’ of gastric cancer , 2013, Journal of Gastroenterology.

[15]  H. Xi,et al.  Increased expression of Lgr5 is associated with chemotherapy resistance in human gastric cancer. , 2013, Oncology reports.

[16]  K. Gajiwala,et al.  Specific inhibition of Notch1 signaling enhances the antitumor efficacy of chemotherapy in triple negative breast cancer through reduction of cancer stem cells. , 2013, Cancer letters.

[17]  Edward Kai-Hua Chow,et al.  Mechanisms of chemoresistance in cancer stem cells , 2013, Clinical and Translational Medicine.

[18]  S. Vinogradov,et al.  Cancer stem cells and drug resistance: the potential of nanomedicine. , 2012, Nanomedicine.

[19]  Y. Liang,et al.  Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype , 2012, Oncogene.

[20]  Kun Yang,et al.  Identification and expansion of cancer stem cells in tumor tissues and peripheral blood derived from gastric adenocarcinoma patients , 2011, Cell Research.

[21]  Sik Yoon,et al.  Cancer spheres from gastric cancer patients provide an ideal model system for cancer stem cell research , 2011, Cellular and Molecular Life Sciences.

[22]  H. Juan,et al.  Notch1 Expression Predicts an Unfavorable Prognosis and Serves as a Therapeutic Target of Patients with Neuroblastoma , 2010, Clinical Cancer Research.

[23]  Lun Zhang,et al.  Expression of Stat3 and Notch1 is associated with cisplatin resistance in head and neck squamous cell carcinoma. , 2010, Oncology reports.

[24]  Lun Zhang,et al.  Correlation of Notch1 expression and activation to cisplatin-sensitivity of head and neck squamous cell carcinoma. , 2009, Ai zheng = Aizheng = Chinese journal of cancer.

[25]  M. Katoh,et al.  Dysregulation of stem cell signaling network due to germline mutation, SNP, helicobacter pylori infection, epigenetic change, and genetic alteration in gastric cancer , 2007, Cancer biology & therapy.

[26]  S. Artavanis-Tsakonas,et al.  Notch signaling: cell fate control and signal integration in development. , 1999, Science.

[27]  Lun Zhang,et al.  Correlation of Notch 1 expression and activation to cisplatin-sensitivity of head and neck squamous cell carcinoma , 2022 .