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

摘要: Abstract Aims The aim of this study is to understand the underlying mechanisms regulating adverse effect diarrhea caused by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Main methods We comparatively examined effects two EGFR-TKIs, gefitinib and icotinib, on intestinal epithelial cells (IEC-6). Cell proliferation was measured using MTT analysis. Expression multiple cytokines assayed real-time PCR. cycle apoptosis IEC were evaluated flow cytometry. Protein levels determined Western blot. Key findings These EGFR-TKIs exerted cytotoxicity inhibit induce in IEC-6 cells. are due ability these cause cell arrest at G0/G1 expression cyclin D1 p27. In addition, icotinib significantly suppressed adhesion molecules while increasing proinflammatory interleukin (IL)-6 IL-25. Finally, triggered an endoplasmic reticulum (ER) stress response, characterized activation RNA dependent protein kinase-like ER (PERK) pathway transcriptional induction XBP-1 signaling, resulting ER-mediated death. Moreover, more than Significance Because a common event occurring patients receiving small-molecular EGFR-TKI chemotherapy, results clinically significant. finding that exerts less cytotoxic activity indicates its usefulness as toxic treatment option for non-small-cell lung cancer.