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Molecular Biology Reports

, Volume 41, Issue 1, pp 165–177 | Cite as

Cisplatin associated with LY294002 increases cytotoxicity and induces changes in transcript profiles of glioblastoma cells

  • P. O. Carminati
  • F. S. Donaires
  • M. M. Marques
  • E. A. Donadi
  • G. A. S. Passos
  • E. T. Sakamoto-Hojo
Article

Abstract

Glioblastoma, one of the deadliest forms of brain tumor, responds poorly to available therapies. This highlights the intense search for new treatment approaches, and an emerging strategy is based on molecular targets. In the present work, we aimed to study whether glioblastoma cells can be sensitized by cisplatin combined with LY294002 (LY), which is an inhibitor of PI3K-related family (ATM, ATR, DNA-PK). We observed that cisplatin caused a pronounced reduction in cell proliferation in U343 and U87 cells, and LY significantly increased the cytotoxic effects caused by cisplatin under these conditions. Differently of U343, U87 cells did not show a significant induction of apoptosis. The phosphorylation level of damage response proteins was analyzed after drug-treatment either with/without LY. The presence of γH2AX foci and phosphorylation of TP53(ser15) and CHK1(ser317) were shown in U343 cells, compatible with cisplatin-induced DNA damage. Similarly, the level of ATR phosphorylation (ser428) was also increased (24 h). The transcript expression profiles of drug-treated compared with untreated U343 cells showed significant changes in the expression of 108 genes, while 274 genes were modulated by cisplatin+LY. The combined treatment caused a high proportion of down-regulated genes, which were mainly involved with DNA repair, cell death and cell cycle control/proliferation, metabolism, transcription regulation and cellular adhesion. Altogether, the present results indicate that most probably, PI3K-related kinases may play an important role in the resistance of glioblastomas cells to cisplatin, and the combination with LY can, at least in part, sensitize these cells to drug treatment.

Keywords

Glioblastoma Cisplatin LY294002 Microarrays DNA-PK DNA repair 

Notes

Acknowledgments

This work was supported by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo [Proc. 2005/02900-2] and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico).

Supplementary material

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Supplementary material 1 (PDF 99 kb)
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Supplementary material 4 (PDF 66 kb)
11033_2013_2849_MOESM5_ESM.pdf (136 kb)
Supplementary material 5 (PDF 136 kb)

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Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • P. O. Carminati
    • 1
  • F. S. Donaires
    • 1
  • M. M. Marques
    • 1
  • E. A. Donadi
    • 2
  • G. A. S. Passos
    • 1
    • 3
  • E. T. Sakamoto-Hojo
    • 1
    • 4
  1. 1.Department of Genetics, Faculty of Medicine of Ribeirão PretoUniversity of São Paulo (USP)Ribeirão PretoBrazil
  2. 2.Department of Medical Clinic, Faculty of Medicine of Ribeirão PretoUniversity of São Paulo (USP)Ribeirão PretoBrazil
  3. 3.Department of Morphology (DMEF)School of Dentistry of Ribeirão Preto,University of São Paulo (USP)Ribeirão PretoBrazil
  4. 4.Department of Biology, Faculty of Philosophy, Sciences and Letters of Ribeirão PretoUniversity of São Paulo (USP)Ribeirão PretoBrazil

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