Growth inhibition by tyrosine kinase inhibitors in mesothelioma cell lines |
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| Authors: | Joyce E. Nutt Kieran O’Toole David Gonzalez John Lunec |
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| Affiliation: | 1. Departamento de Química Física, Facultad de Farmacia, Universidad de Castilla-La Mancha, Paseo de los Estudiantes, s/n, 02071 Albacete, Spain;2. Departamento de Química Física y Analítica, Facultad de Ciencias Experimentales, Universidad de Jaén, Campus “Las Lagunillas” s/n, 23071 Jaén, Spain;3. Departament de Química Física, Universitat de Barcelona (UB), Institut de Recerca en Quimica Teorica i Computacional (IQTCUB), Martí iFranqués 1, 08028 Barcelona, Spain;4. Departamento de Química Física, Facultad de Ciencias Químicas, Universidad de Castilla-La Mancha, Avenida Camilo José Cela, 10, 13071 Ciudad Real, Spain;1. Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium;2. Department of Oncology, Hematology and Stem Cell Transplantation, RWTH Aachen University Medical School, Aachen, Germany;3. Apoptosis Research Centre, National University of Ireland, Galway, Ireland;4. School of Natural Sciences, National University of Ireland, Galway, Ireland;5. INSERM ERL440, Oncogenesis, Stress and Signaling, Université Rennes 1, Rennes, France;6. Centre de Lutte Contre Le Cancer Eugène Marquis, Rennes, France |
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| Abstract: | Clinical outcome following chemotherapy for malignant pleural mesothelioma is poor and improvements are needed. This preclinical study investigates the effect of five tyrosine kinase inhibitors (PTK787, ZD6474, ZD1839, SU6668 and SU11248) on the growth of three mesothelioma cell lines (NCI H226, NCI H28 and MSTO 211H), the presence of growth factor receptors and inhibition of their downstream signalling pathways. GI50 values were determined: ZD6474 and SU11248, mainly VEGFR2 inhibitors, gave the lowest GI50 across all cell lines (3.5–6.9 μM) whereas ZD1839 gave a GI50 in this range only in H28 cells. All cell lines were positive for EGFR, but only H226 cells were positive for VEGFR2 by Western blotting. ZD6474 and ZD1839 inhibited EGF-induced phosphorylation of EGFR, AKT and ERK, whereas VEGF-induced phosphorylation of VEGFR2 was completely inhibited with 0.1 μM SU11248. VEGFR2 was detected in tumour samples by immunohistochemistry. VEGFR2 tyrosine kinase inhibitors warrant further investigation in mesothelioma. |
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