title: Down-regulation of Notch signaling by a γ-secretase inhibitor enhances the radiosensitivity of nasopharyngeal carcinoma cells.
abstract: 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.
authors.affiliation: Department of Otolaryngology, Huadong Hospital, Fudan University, Shanghai 200040, PR China.
authors.forename: Shudong
authors.initials: S
authors.lastname: Yu
authors.forename: Ruxin
authors.initials: R
authors.lastname: Zhang
authors.forename: Fenye
authors.initials: F
authors.lastname: Liu
authors.forename: Hua
authors.initials: H
authors.lastname: Hu
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Yu
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D002277:Carcinoma; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004151:Dipeptides / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D011836:Radiation Tolerance / Q000187:drug effects; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases