Abstract | AIM: METHODS: Normal human epidermal keratinocytes (NHEK) were incubated for 2 and 24h with different concentrations of EGFRI ( erlotinib) for Western blot analysis and cytokine expression analysis, respectively. Inhibition of EGFR, extracellular-signal-regulated kinase 1/2 (Erk 1/2) and c-Jun was examined by Western blot analysis. Cytokine concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in the NHEK cell supernatant and also in the serum of 186 cancer patients who are followed up for EGFRI induced skin rash. RESULTS: A significant inhibitory effect of EGFRI was seen on EGFR (Y845), Erk 1/2 and c-Jun in a dose dependent manner. Further downstream, increased CC-chemokine ligand 2 (CCL2), CC-chemokine ligand 5 (CCL5) and decreased interleukin-8 (IL-8) or CXCL8 expression was observed in keratinocytes. In EGFRI treated patients, low levels of serum CXCL8 corresponding to stronger EGFR inhibition were associated with a higher grade of skin toxicity (p=0.0016) and a prolonged overall survival (p=0.018). CONCLUSIONS: The results obtained in this study indicate that EGFRI can regulate cytokines by modulating EGFR signalling pathway in keratinocytes. Moreover, serum levels of CXCL8 in EGFRI treated patients may be important for individual EGFRI induced skin toxicity and patient's survival.
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Authors | Tanusree Paul, Christian Schumann, Stefan Rüdiger, Stefan Boeck, Volker Heinemann, Volker Kächele, Michael Steffens, Catharina Scholl, Vivien Hichert, Thomas Seufferlein, Julia Carolin Stingl |
Journal | European journal of cancer (Oxford, England : 1990)
(Eur J Cancer)
Vol. 50
Issue 11
Pg. 1855-63
(Jul 2014)
ISSN: 1879-0852 [Electronic] England |
PMID | 24857781
(Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2014 Elsevier Ltd. All rights reserved. |
Chemical References |
- CXCL8 protein, human
- Cytokines
- Interleukin-8
- Protein Kinase Inhibitors
- EGFR protein, human
- ErbB Receptors
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Topics |
- Adult
- Aged
- Aged, 80 and over
- Cells, Cultured
- Cytokines
(biosynthesis, metabolism)
- Disease-Free Survival
- ErbB Receptors
(antagonists & inhibitors, metabolism)
- Female
- Humans
- Interleukin-8
(blood)
- Keratinocytes
(cytology, drug effects)
- Male
- Middle Aged
- Neoplasms
(drug therapy, enzymology, metabolism)
- Prospective Studies
- Protein Kinase Inhibitors
(administration & dosage, adverse effects)
- Signal Transduction
(drug effects)
- Skin Diseases
(chemically induced, metabolism)
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