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Vandetanib combined with a p38 MAPK inhibitor synergistically reduces glioblastoma cell survival

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Abstract

The survival for patients with high-grade glioma is poor, and only a limited number of patients respond to the therapy. The aim of this study was to analyze the significance of using p38 MAPK phosphorylation as a prognostic marker in high-grade glioma patients and as a therapeutic target in combination chemotherapy with vandetanib. p38 MAPK phosphorylation was analyzed with immunohistochemistry in 90 high-grade glioma patients. Correlation between p38 MAPK phosphorylation and overall survival was analyzed with Mann–Whitney U test analysis. The effects on survival of glioblastoma cells of combining vandetanib with the p38 MAPK inhibitor SB 203580 were analyzed in vitro with the median-effect method with the fluorometric microculture cytotoxicity assay. Two patients had phosphorylated p38 MAPK in both the cytoplasm and nucleus, and these two presented with worse survival than patients with no detectable p38 MAPK phosphorylation or phosphorylated p38 MAPK only in the nucleus. This was true for both high-grade glioma patients (WHO grade III and IV, n = 90, difference in median survival: 6.1 months, 95 % CI [0.20, 23], p = 0.039) and for the subgroup with glioblastoma patients (WHO grade IV, n = 70, difference in median survival: 6.1 months, 95 % CI [0.066, 23], p = 0.043). The combination of vandetanib and the p38 MAPK inhibitor SB 203580 had synergistic effects on cell survival for glioblastoma-derived cells in vitro. In conclusion, p38 MAPK phosphorylation may be a prognostic marker for high-grade glioma patients, and vandetanib combined with a p38 MAPK inhibitor may be useful combination chemotherapy for glioma patients.

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Acknowledgments

The authors would like to thank Dr. H Hedman, Umea University, the UCSF Tissue Bank, and Dr. JS Guillamo for providing us with the glioma cell lines used in the experiments. We would also like to thank Dr. E. Freyhult at Bioinformatics Infrastructure for Life Sciences for statistical support. In addition, we would also like to express our gratitude for the financial support from the Cancer Foundation at Gavle Hospital, the Research Fund at the Department of Oncology, Uppsala University Hospital, the Swedish Cancer Society, the Swedish Research Council, and the Knut and Alice Wallenberg Foundation.

Conflict of interest

The authors declare that we have no conflict of interest.

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Authors and Affiliations

  1. Section of Oncology, Department of Radiology, Oncology and Radiation Sciences, Rudbeck Laboratory, 751 85, Uppsala, Sweden

    Linda Sooman, Michael Bergqvist, Georgios Tsakonas, Fredrik Johansson, Erik Blomquist & Simon Ekman

  2. Ludwig Institute for Cancer Research, Uppsala University, Box 595, 751 24, Uppsala, Sweden

    Johan Lennartsson

  3. Section of Clinical Pharmacology, Department of Medical Sciences, Uppsala University Hospital, 751 85, Uppsala, Sweden

    Joachim Gullbo

  4. Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85, Uppsala, Sweden

    Per-Henrik Edqvist, Fredrik Pontén, Irina Alafuzoff & Svetlana Popova

  5. The Human Protein Atlas Project, Mumbai Site, Lab Surgpath, 204 Bombay Market, 731/1 Tardeo Main Road, Mumbai, 400034, India

    Archita Jaiswal & Sanjay Navani

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  1. Linda Sooman
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Corresponding author

Correspondence to Linda Sooman.

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12032_2013_638_MOESM1_ESM.tif

Dose-effect curves (A) and median-effect plots (B) of vandetanib combined with SB 203580. The combination was tested in a vandetanib sensitive (left panel) and resistant cell line (right panel). fa = affected fraction, fu = unaffected fraction. (TIFF 2987 kb)

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Sooman, L., Lennartsson, J., Gullbo, J. et al. Vandetanib combined with a p38 MAPK inhibitor synergistically reduces glioblastoma cell survival. Med Oncol 30, 638 (2013). https://doi.org/10.1007/s12032-013-0638-0

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  • DOI: https://doi.org/10.1007/s12032-013-0638-0

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