title: Everolimus enhances cellular cytotoxicity of lapatinib via the eukaryotic elongation factor-2 kinase pathway in nasopharyngeal carcinoma cells.
abstract: BACKGROUND
  Nasopharyngeal carcinoma (NPC) has a high relapse and metastatic rates; hence, development of new therapeutics is an immediate requirement. Lapatinib and everolimus have been demonstrated to be effective in the treatment of several carcinomas. This preclinical study aimed to investigate the effect and mechanism of lapatinib combined with everolimus on NPC cells.
  
  
  METHODS
  The Cell Counting Kit 8 and colony formation assay were used to detect the effect of lapatinib alone or lapatinib combined with everolimus on the growth and proliferation of cells. Apoptosis was tested by flow cytometry and was further confirmed by western blot. The targets of lapatinib and the effects of lapatinib or everolimus on the eukaryotic elongation factor-2 (eEF-2) kinase pathway were analyzed by western blot, which also evaluated autophagy activity.
  
  
  RESULTS
  Lapatinib inhibited the cellular viability and colony formation in NPC cells. At 24-72 h, the average half maximal inhibitory concentration (IC50) values of lapatinib were ranging from 3 to 5 μM. This study further found that lapatinib induced both apoptosis and autophagy in NPC cells, and this autophagic activity was described as type II programmed cell death via an eEF-2 kinase-dependent pathway. In addition, augmentation of lapatinib-induced autophagy by mammalian target of rapamycin (mTOR) inhibitor everolimus enhanced the cytocidal effect of lapatinib in NPC cells via the mTOR/S6 kinase/eEF-2 kinase pathway.
  
  
  CONCLUSIONS
  This study reveals that everolimus can sensitize NPC cells to lapatinib by the activation of eEF-2 kinase and provides a potential model of combination therapy.
authors: Department of Medical Oncology.
authors: Lin
authors: L
authors: Liu
authors: Department of Medical Oncology.
authors: Zhi-Hui
authors: ZH
authors: Wang
authors: Department of Medical Oncology.
authors: Jun
authors: J
authors: Han
authors: Department of Surgical Oncology, The Fifth Affiliated Hospital of Sun-Yat-Sen University, Zhu Hai, Guangdong Province, People's Republic of China.
authors: Con
authors: C
authors: Tang
authors: Department of Medical Oncology.
authors: Nan
authors: N
authors: Chen
authors: Department of Medical Oncology.
authors: Zhong
authors: Z
authors: Lin
authors: Department of Medical Oncology.
authors: Pei-Jian
authors: PJ
authors: Peng
keywords: eEF-2K; everolimus; lapatinib; nasopharyngeal carcinoma