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Synergistic interactions between camptothecin and EGFR or RAC1 inhibitors and between imatinib and Notch signaling or RAC1 inhibitors in glioblastoma cell lines

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Abstract

Purpose

The current treatment strategies for glioblastoma have limited health and survival benefits for the patients. A common obstacle in the treatment is chemoresistance. A possible strategy to evade this problem may be to combine chemotherapeutic drugs with agents inhibiting resistance mechanisms. The aim with this study was to identify molecular pathways influencing drug resistance in glioblastoma-derived cells and to evaluate the potential of pharmacological interference with these pathways to identify synergistic drug combinations.

Methods

Global gene expressions and drug sensitivities to three chemotherapeutic drugs (imatinib, camptothecin and temozolomide) were measured in six human glioblastoma-derived cell lines. Gene expressions that correlated to drug sensitivity or resistance were identified and mapped to specific pathways. Selective inhibitors of these pathways were identified. The effects of six combinations of inhibitors and chemotherapeutic drugs were evaluated in glioblastoma-derived cell lines. Drug combinations with synergistic effects were also evaluated in non-cancerous epithelial cells.

Results

Four drug combinations had synergistic effects in at least one of the tested glioblastoma-derived cell lines; camptothecin combined with gefitinib (epidermal growth factor receptor inhibitor) or NSC 23766 (ras-related C3 botulinum toxin substrate 1 inhibitor) and imatinib combined with DAPT (Notch signaling inhibitor) or NSC 23766. Of these, imatinib combined with DAPT or NSC 23766 did not have synergistic effects in non-cancerous epithelial cells. Two drug combinations had at least additive effects in one of the tested glioblastoma-derived cell lines; temozolomide combined with gefitinib or PF-573228 (focal adhesion kinase inhibitor).

Conclusion

Four synergistic and two at least additive drug combinations were identified in glioblastoma-derived cells. Pathways targeted by these drug combinations may serve as targets for future drug development with the potential to increase efficacy of currently used/evaluated chemotherapy.

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Acknowledgments

The authors would like to thank Prof. Aristidis Moustakas, Ludwig Institute for Cancer Research, Uppsala for kindly providing the p12xCSL-luciferase and pCMV-β-galactosidase plasmids and Dr. H Hedman, Umea University, the UCSF/Neurosurgery Tissue Bank, and Dr. JS Guillamo for providing us with the glioma cell lines used in the experiments The authors would like to express their 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 and the Swedish Research Council.

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Authors and Affiliations

  1. Rudbeck Laboratory, Department of Radiation, Oncology and Radiation Science, Section of Oncology, Uppsala University, Dag Hammarskjölds väg 20, 751 85, Uppsala, Sweden

    Linda Sooman, Simon Ekman, Fredrik Johansson, Michael Bergqvist, Erik Blomquist & Joachim Gullbo

  2. Division of Clinical Pharmacology, Department of Medical Sciences, Uppsala University Hospital, 751 85, Uppsala, Sweden

    Claes Andersson & Joachim Gullbo

  3. Science for Life Laboratory, Department of Medical Sciences, Uppsala University, 751 85, Uppsala, Sweden

    Hanna Göransson Kultima & Anders Isaksson

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

    Johan Lennartsson

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  1. Linda Sooman
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Correspondence to Linda Sooman.

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The microarray probes with gene expression-drug activity correlations (permutation p < 0.05) to the three therapeutic drugs.(PDF 738 kb)

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Sooman, L., Ekman, S., Andersson, C. et al. Synergistic interactions between camptothecin and EGFR or RAC1 inhibitors and between imatinib and Notch signaling or RAC1 inhibitors in glioblastoma cell lines. Cancer Chemother Pharmacol 72, 329–340 (2013). https://doi.org/10.1007/s00280-013-2197-7

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  • DOI: https://doi.org/10.1007/s00280-013-2197-7

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