Erlotinib promotes endoplasmic reticulum stress-mediated injury in the intestinal epithelium

Journal Article · Tue Jul 01 00:00:00 EDT 2014 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2014.04.015· OSTI ID:22439749

Fan, Lu; Hu, Lingna; Yang, Baofang; Fang, Xianying; Gao, Zhe; Li, Wanshuai; Sun, Yang; Shen, Yan; Wu, Xuefeng ^[1]; Shu, Yongqian ^[2]; Gu, Yanhong ^[2]; Wu, Xudong ^[1]; Xu, Qiang ^[1]

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1. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093 (China)
2. Department of Clinical Oncology, The First Affiliated Hospital of Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029 (China)

Erlotinib, a popular drug for treating non-small cell lung cancer (NSCLC), causes diarrhea in approximately 55% of patients receiving this drug. In the present study, we found that erlotinib induced barrier dysfunction in rat small intestine epithelial cells (IEC-6) by increasing epithelial permeability and down-regulating E-cadherin. The mRNA levels of various pro-inflammatory cytokines (Il-6, Il-25 and Il-17f) were increased after erlotinib treatment in IEC-6 cells. Erlotinib concentration- and time-dependently induced apoptosis and endoplasmic reticulum (ER) stress in both IEC-6 and human colon epithelial cells (CCD 841 CoN). Intestinal epithelial injury was also observed in male C57BL/6J mice administrated with erlotinib. Knockdown of C/EBP homologous protein (CHOP) with small interference RNA partially reversed erlotinib-induced apoptosis, production of IL-6 and down-regulation of E-cadherin in cultured intestinal epithelial cells. In conclusion, erlotinib caused ER stress-mediated injury in the intestinal epithelium, contributing to its side effects of diarrhea in patients. - Highlights: • Erlotinib destroyed barrier integrity both in vitro and in vivo. • Erlotinib induced inflammation both in vitro and in vivo. • Erlotinib induced apoptosis both in vitro and in vivo. • ER stress contributed to erlotinib-induced barrier dysfunction.

• OSTI ID: 22439749
• Journal Information: Toxicology and Applied Pharmacology, Vol. 278, Issue 1; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
DIARRHEA
DRUGS
ENDOPLASMIC RETICULUM
EPITHELIUM
INFLAMMATION
INJURIES
LARGE INTESTINE
LUNGS
LYMPHOKINES
MESSENGER-RNA
MICE
NEOPLASMS
PERMEABILITY
RATS
SIDE EFFECTS
SMALL INTESTINE
STRESSES
TIME DEPENDENCE
VENTILATION BARRIERS