Abstract
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.
Highlights
Erlotinib is supposed to act mainly through the inhibition of tyrosine kinase domain of epidermal growth factor (EGF) receptor [1]
Based on microarray gene expression analysis, we identified VEGF as proangiogenic cytokine induced by erlotinib in hepatocellular carcinoma (HCC) cells by oxidative stress dependent mechanism (Figure 6B)
Our data suggest that the VEGF increase caused by erlotinib may counteract the inhibitory effects of erlotinib on tumour growth contributing to therapy resistance, which almost all patients develop over time
Summary
Erlotinib is supposed to act mainly through the inhibition of tyrosine kinase domain of epidermal growth factor (EGF) receptor [1]. Since erlotinib has been approved for treatment of non-small cell lung cancer, its efficiency to treat other cancers with deregulated EGFR signalling pathway has been investigated. Upregulation of EGFR signalling pathway in hepatocellular carcinoma (HCC) is supported by several lines of evidences. Erlotinib diminished viability of HCC cells in vitro [5, 6], the in vivo data were quite sobering. We have reported the lack of erlotinib efficacy in an orthotopic HCC rat model [7]. Erlotinib monotherapy showed modest effect in clinical HCC studies [8, 9]. Erlotinib failed to increase the efficiency of sorafenib in a phase III study in a first line HCC therapy [10]. Case reports suggest that erlotinib could still be a treatment option for certain patients [11]
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