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Everolimus enhances cellular cytotoxicity of lapatinib via the eukaryotic elongation factor-2 kinase pathway in nasopharyngeal carcinoma cells

Authors Liu L, Wang ZH, Han J, Tang C, Chen N, Lin Z, Peng PJ

Received 19 June 2016

Accepted for publication 7 September 2016

Published 11 October 2016 Volume 2016:9 Pages 6195—6201


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 3

Editor who approved publication: Dr XuYu Yang

Lin Liu,1,* Zhi-Hui Wang,1,* Jun Han,1 Con Tang,2 Nan Chen,1 Zhong Lin,1 Pei-Jian Peng1,*

1Department of Medical Oncology, 2Department of Surgical Oncology, The Fifth Affiliated Hospital of Sun-Yat-Sen University, Zhu Hai, Guangdong Province, People’s Republic of China

*These authors contributed equally to this work

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.
Conclusion: 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.

Keywords: lapatinib, eEF-2K, everolimus, nasopharyngeal carcinoma

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