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EGFR inhibitor-driven endoplasmic reticulum stress-mediated injury on intestinal epithelial cells.

AbstractAIMS:
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).
MAIN 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.
KEY FINDINGS:
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.
SIGNIFICANCE:
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.
AuthorsShaocheng Hong, Yanhong Gu, Zhenzhen Gao, Lele Guo, Wenjie Guo, Xudong Wu, Yan Shen, Yang Sun, Xuefeng Wu, Qiang Xu
JournalLife sciences (Life Sci) Vol. 119 Issue 1-2 Pg. 28-33 (Dec 05 2014) ISSN: 1879-0631 [Electronic] Netherlands
PMID25445223 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Inc. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Crown Ethers
  • Protein Kinase Inhibitors
  • Quinazolines
  • icotinib
  • ErbB Receptors
  • Gefitinib
Topics
  • Animals
  • Antineoplastic Agents (adverse effects)
  • Apoptosis (drug effects)
  • Cell Cycle Checkpoints (drug effects)
  • Cell Line
  • Crown Ethers (adverse effects)
  • Diarrhea (chemically induced, pathology)
  • Endoplasmic Reticulum Stress (drug effects)
  • ErbB Receptors (antagonists & inhibitors)
  • Gefitinib
  • Intestinal Mucosa (drug effects, pathology)
  • Protein Kinase Inhibitors (adverse effects)
  • Quinazolines (adverse effects)
  • Rats

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