title: EGFR inhibitor-driven endoplasmic reticulum stress-mediated injury on intestinal epithelial cells.
abstract: OBJECTIVE
  The aim of this study is to understand the underlying mechanisms regulating the adverse effect of diarrhea caused by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).
  
  
  METHODS
  We comparatively examined the effects of two EGFR-TKIs, gefitinib and icotinib, on intestinal epithelial cells (IEC-6). Cell proliferation was measured using MTT analysis. Expression of multiple cytokines was assayed by real-time PCR. Cell cycle and apoptosis of IEC were evaluated using flow cytometry. Protein levels were determined by Western blot.
  
  
  RESULTS
  These two EGFR-TKIs exerted cytotoxicity to inhibit proliferation and induce apoptosis in IEC-6 cells. These effects are due to the ability of these EGFR-TKIs to cause cell cycle arrest at G0/G1 by regulating the expression of cyclin D1 and p27. In addition, gefitinib and icotinib significantly suppressed the levels of cell adhesion molecules while increasing the expression of the proinflammatory cytokines interleukin (IL)-6 and IL-25. Finally, these EGFR-TKIs triggered an endoplasmic reticulum (ER) stress response, characterized by the activation of the RNA dependent protein kinase-like ER kinase (PERK) pathway and the transcriptional induction of XBP-1 signaling, resulting in ER-mediated cell death. Moreover, gefitinib exerted more cytotoxicity than icotinib on IEC-6 cells.
  
  
  CONCLUSIONS
  Because diarrhea is a common adverse event occurring in patients receiving small-molecular EGFR-TKI chemotherapy, the results of this study are clinically significant. The finding that icotinib exerts less cytotoxic activity than gefitinib on IEC-6 cells indicates its usefulness as a less toxic treatment option for non-small-cell lung cancer.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Shaocheng
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Lele
authors.initials: L
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China. Electronic address: wuxf@nju.edu.cn.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, China. Electronic address: molpharm@163.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D043844:Crown Ethers / Q000009:adverse effects*; D003967:Diarrhea / Q000139:chemically induced* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000077156:Gefitinib; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011799:Quinazolines / Q000009:adverse effects*; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D043844:Crown Ethers; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C531470:icotinib; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Diarrhea; ER stress; Gefitinib; Gefitinib (Pubchem CID: 123631); Icotinib; Icotinib hydrochloride (Pubchem CID: 44609731); Intestinal epithelium injury