n-(n-(3-5-difluorophenacetyl)alanyl)phenylglycine-tert-butyl-ester and Nasopharyngeal-Neoplasms

The cancer stem cell (CSC) is responsible for the initiation, proliferation and radiation resistance. Side population (SP) cells are a rare subset of cells enriched with CSCs. The targeting of key signaling pathways that are active in CSCs is a therapeutic approach to treating cancer. Notch signaling is important for the self-renewal and maintenance of stem cells. Our previous studies demonstrated that downregulation of Notch signaling could enhance radiosensitivity of nasopharyngeal carcinoma (NPC) cells. In this study, we found that Notch signaling was highly activated in SP cells compared with that of non-SP (NSP) cells of NPC. Therefore, Notch inhibition could reduce the proportion of SP cells. As SP cells decreased, proliferation, anti-apoptosis and tumorigenesis were also decreased. This study shows that Notch inhibition may be a promising clinical approach in CSC-targeting therapy for NPC.

Topics: Animals; Carcinoma; Cell Growth Processes; Cell Line, Tumor; Dipeptides; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplastic Stem Cells; Receptors, Notch; Side-Population Cells; Signal Transduction

Currently, the main approach to nasopharyngeal carcinoma (NPC) treatment is radiotherapy (RT), but for many NPC patients, RT is not effective. Increasing RT sensitivity of NPC cells would provide a significant treatment advance for NPC patients. While γ-secretase inhibitors (GSIs) have gained recent attention as novel anticancer drugs, the mechanism of action of GSIs as radiosensitizers is not well understood. In the present study, radiation-induced anti-proliferative effects of the one GSI (N-[(3,5-difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester, DAPT), on CNE2 cells were investigated with the MTT assay; in vitro radiosensitization effects were evaluated by the apoptosis assay and the cell colony formation assay. The activation status of the Notch signaling pathway in DAPT- or dimethyl sulfoxide-treated CNE2 cells was also examined. Notch signaling in NPC cells was found to be down-regulated by DAPT; therefore, DAPT could significantly inhibit CNE2 growth and improve NPC radiosensitization, thus, enhancing RT-induced anti-proliferative effects and apoptosis. Taken together, our data show that Notch signaling down-regulation by GSIs could enhance radiosensitivity of NPC cells, suggesting clinical applications for GSIs as radiosensitizers for NPC therapy.

Topics: Amyloid Precursor Protein Secretases; Carcinoma; Cell Line, Tumor; Combined Modality Therapy; Dipeptides; Down-Regulation; Humans; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Radiation Tolerance; Receptors, Notch; Signal Transduction