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The pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma cells for apoptosis by inhibiting DNA repair

Oncogene volume 28, pages 3586–3596 (2009)Cite this article

Abstract

The failure of conventional therapies in glioblastoma (GBM) is largely due to an aberrant activity of survival cascades, such as PI3 kinase (PI3K)/Akt-mediated signaling. This study is the first to show that the class I PI3K inhibitor, PI-103, enhances chemotherapy-induced cell death of GBM cells. Concurrent treatment with PI-103 and DNA-damaging drugs, in particular doxorubicin, significantly increases apoptosis and reduces colony formation compared with chemotherapy treatment alone. The underlying molecular mechanism for this chemosensitization was shown by two independent approaches, that is, pharmacological and genetic inhibition of PI3K, DNA-PK and mTOR, to involve inhibition of DNA-PK-mediated DNA repair. Accordingly, blockage of PI3K or DNA-PK, but not of mTOR, significantly delays the resolution of doxorubicin-induced DNA damage and concomitantly increases apoptosis. Importantly, not only are several GBM cell lines chemosensitized by PI-103 but also GBM stem cells. Clinical relevance was further confirmed by the use of primary cultured GBM cells, which also exhibit increased cell death and reduced colony formation on combined treatment with PI-103 and doxorubicin. By identifying class I PI3K inhibitors as powerful agents in enhancing the lethality of DNA-damaging drugs, to which GBMs are usually considered unresponsive, our findings have important implications for the design of rational combination regimens in overcoming the frequent chemoresistance of GBM.

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Acknowledgements

We thank H Lane (Novartis Institute for BioMedical Research, Oncology Basel, Novartis Pharma AG, Basel, Switzerland) for providing everolimus, R Pallini and R De Maria for glioblastoma-initiating cells and S Piater for expert technical assistance. This work was supported by grants from Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, European Community (ApopTrain, APO-SYS), Novartis Stiftung für therapeutische Forschung and IAP6/18 (to SF), and the University of Ulm junior research grant (to JAK).

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  1. M -A Westhoff and J A Kandenwein: These authors contributed equally to this work.

Authors and Affiliations

  1. University Children's Hospital, Ulm, Germany

    M -A Westhoff, J A Kandenwein, S Karl, S H K Vellanki, G Antoniadis, K -M Debatin & S Fulda

  2. Department of Neurosurgery, University of Ulm, Bezirkskrankenhaus Guenzburg, Germany

    J A Kandenwein

  3. Department of Neurosurgery, Evangelisches Jung-Stilling-Krankenhaus, Siegen, Germany

    V Braun

  4. Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Rome, Italy

    A Eramo

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  1. M -A Westhoff
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Correspondence to S Fulda.

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Westhoff, MA., Kandenwein, J., Karl, S. et al. The pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma cells for apoptosis by inhibiting DNA repair. Oncogene 28, 3586–3596 (2009). https://doi.org/10.1038/onc.2009.215

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