Research Papers:

Oxidative stress mediates an increased formation of vascular endothelial growth factor in human hepatocarcinoma cells exposed to erlotinib

Nataliya Rohr-Udilova _, Florian Klinglmüller, Martha Seif, Hubert Hayden, Martin Bilban, Matthias Pinter, Klaus Stolze, Wolfgang Sieghart, Markus Peck-Radosavljevic and Michael Trauner

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Oncotarget. 2017; 8:57109-57120. https://doi.org/10.18632/oncotarget.19055

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Nataliya Rohr-Udilova1, Florian Klinglmüller2, Martha Seif1, Hubert Hayden1, Martin Bilban3, Matthias Pinter1, Klaus Stolze4, Wolfgang Sieghart1, Markus Peck-Radosavljevic5 and Michael Trauner1

1Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria

2Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, A-1090 Vienna, Austria

3Clinical Institute for Laboratory Medicine, Medical University of Vienna, A-1090 Vienna, Austria

4Institute of Animal Nutrition and Functional Plant Compounds, Department for Farm Animals and Veterinary Public Health,University of Veterinary Medicine, A-1220 Vienna, Austria

5Clinic Klagenfurth, Division of Gastroenterology and Hepatology, 9020 Klagenfurt am Wörthersee, Austria

Correspondence to:

Nataliya Rohr-Udilova, email: [email protected]

Keywords: tyrosine kinase inhibitors, erlotinib, vascular endothelial growth factor, cytochrome P450, hepatocarcinoma cell lines

Received: May 10, 2017     Accepted: June 19, 2017     Published: July 06, 2017


The tyrosine kinase inhibitor erlotinib targets the receptor of epidermal growth factor (EGFR) involved in development of hepatocellular carcinoma (HCC).

Although inefficient in established HCC, erlotinib has been recently proposed for HCC chemoprevention. Since Cyp3A4 and Cyp1A2 enzymes metabolize erlotinib in the liver, the insights into the mechanisms of erlotinib effects on liver cells with maintained drug metabolizing activity are needed.

We applied erlotinib to both commercially available (SNU398, Huh7) and established in Austria HCC cell lines (HCC-1.2, HCC-3). Cyp3A4 and Cyp1A2, microarray gene expression, cell viability, LDH release, DHFC fluorescence were assessed. VEGF expression was analysed by real-time RT-PCR and ELISA.

Higher cumulative expression of erlotinib metabolizing enzymes was observed in HCC-1.2 and HCC-3 cells. Gene expression microarray analysis showed upregulation of VEGF signalling by erlotinib. VEGF was increased up to 134 ± 14% (n = 5, p = 0.002) in HCC-1.2, HCC-3 and Huh7 cells. Interventions by Cyp1A2 and Mek2siRNA, MEK inhibitor UO126, diphenylene iodonium, as well as a combination of N-acetylcysteine with selenium all inhibited VEGF upregulation caused by erlotinib.

Thus, erlotinib increases VEGF production by mechanisms involving Cyp1A2, oxidative stress and MEK1/2. VEGF may favour angiogenesis and growth of early HCC tumours limiting the therapeutic and chemopreventive effects of erlotinib.

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