The inhibition of tyrosine kinase receptor signalling in leiomyosarcoma cells using the small molecule kinase inhibitor PTK787/ZK222584 (Vatalanib®)

Gaumann,Andreas K.A.; Drexler,Hannes C.A.; Lang,Sven A.; Stoeltzing,Oliver; Diermeier‑Daucher,Simone; Buchdunger,Elisabeth; Wood,Jeanette; Bold,Guido; Breier,Georg

doi:10.3892/ijo.2014.2683

The inhibition of tyrosine kinase receptor signalling in leiomyosarcoma cells using the small molecule kinase inhibitor PTK787/ZK222584 (Vatalanib®)

Authors:
- Andreas K.A. Gaumann
- Hannes C.A. Drexler
- Sven A. Lang
- Oliver Stoeltzing
- Simone Diermeier‑Daucher
- Elisabeth Buchdunger
- Jeanette Wood
- Guido Bold
- Georg Breier
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Affiliations: Institute of Pathology, Kaufbeuren‑Ravensburg, 87600 Kaufbeuren, Germany, Department of Molecular Cell Biology, Max Planck Institute for Physiological and Clinical Research, 61231 Bad Nauheim, Germany, Department of Surgery, University Medical Center Regensburg, 93053 Regensburg, Germany, Department of Obstetrics and Gynecology, University Medical Center Regensburg, 93053 Regensburg, Germany, Novartis Oncology, CH‑4002 Basel, Switzerland
Published online on: September 29, 2014 https://doi.org/10.3892/ijo.2014.2683
Pages: 2267-2277
Copyright: © Gaumann et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Leiomyosarcomas remain challenging tumors to manage and novel therapy strategies besides radiation and conventional chemotherapy are needed. Targeting angiogenesis by inhibition of vascular endothelial growth factor (VEGF) receptor tyrosine kinases (RTKs) of the tumor vasculature with small molecules is a promising new therapy. It has been shown recently that these receptors are not only expressed on tumor endothelium but also on tumor cells themselves. Thus, we investigated the expression of members of the VEGF receptor (VEGFR) family and corresponding growth factors in leiomyosarcoma tissue specimens and in the leiomyosarcoma cell lines SK‑LMS‑1 and SK‑UT‑1. We evaluated the influence of the VEGFR inhibitor PTK787/ZK222584 (PTK787) on cell growth, migration, apoptosis and phosphorylation of intracellular signalling molecules. In human leiomyosarcoma tissue specimens VEGFR‑1/‑2 and platelet‑derived growth factor receptor (PDGFR‑β) were strongly expressed. Both leiomyosarcoma cell lines expressed VEGFR‑1/‑3 and PDGFR‑β but VEGFR‑2 protein expression was positive only in SK‑UT‑1. SK‑LMS‑1 and SK‑UT‑1 cells secreted high and low amounts of VEGF‑A, respectively, whereas PDGF‑BB secretion was similar in both cell lines. Application of PTK787 led to partial inhibition of PDGF‑BB‑activated AKT/p90RSK and ERK1/2 signalling pathways. In contrast, protein phosphorylation was not affected by PTK787 in VEGF‑A‑treated cells. PTK787 turned out to inhibit cell migration even though no effects were observed upon stimulation with VEGF‑A or PDGF‑BB. In line, cell growth in leiomyosarcoma cell lines remained unchanged upon PTK787 treatment alone and with subsequent VEGF‑A‑ or PDGF‑BB‑stimulation. However, VEGF‑A, but not PDGF‑BB‑treated cells showed increased cell death upon PTK787 treatment. VEGFR family members are expressed in leiomyosarcomas in vivo and in vitro. Upon receptor stimulation, PTK787 is able to inhibit subsequent phosphorylation events and influences cell survival but not metabolic activity and migration. Thus, the inhibitor is possibly an additional option in the treatment of leiomyosarcomas.

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