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Changes in the gene expression profile of gastric cancer cells in response to ibuprofen: a gene pathway analysis

The Pharmacogenomics Journal volume 11, pages 412–428 (2011)Cite this article

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Abstract

Nonsteroidal anti-inflammatory drugs possess antiproliferative activities that can affect cancer cells. The aim of this study was to examine the antiproliferative effects of ibuprofen on the MKN-45 cell line. Cells were treated with ibuprofen for 24, 48 or 72 h, and cell proliferation was evaluated by cell counting and [3H]-thymidine incorporation. Using microarray technology, we studied changes in the gene expression profiles over time after ibuprofen treatment. Ibuprofen induced a dose- and time-dependent reduction in cell number without altering cell viability. Genes involved in the ‘biological oxidation’ and ‘G1/S checkpoint’ pathways were the most significantly represented at 24 h, whereas genes involved in the ‘cell cycle’ and ‘DNA replication’ pathways were represented at 48 and 72 h. Genes associated with the ‘apoptosis’ pathway were also significantly represented at 72 h. Modulation of the expression of p53 and p53-induced genes (CDKN1A/p21 and GADD45), which are involved in the G1/S transition, suggested an effect of ibuprofen on cell-cycle progression. Using flow cytometry, we observed an early block in the G1 phase of the cell cycle after ibuprofen treatment. In addition, P450 family transcripts were upregulated and intracellular reactive oxygen species (ROS) was increased following 12 h of ibuprofen treatment. Ibuprofen induced ROS, which resulted in cellular alterations that promoted a p53-dependent G1 blockade. These findings suggest that ibuprofen exerts its antiproliferative actions through cell-cycle control and the induction of apoptosis. Both of these mechanisms appear to be independent of ibuprofen's anti-inflammatory effects.

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Acknowledgements

We thank Microgem s.r.l. for support and help with statistical analysis. This work was funded in part by Ricerca Corrente.

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Authors and Affiliations

  1. Department of Research, Experimental Pharmacology, National Cancer Institute G Pascale, Naples, Italy

    P Bonelli & A De Rosa

  2. Department of Research, Molecular Biology and Viral Oncogenesis, National Cancer Institute G Pascale, Naples, Italy

    F M Tuccillo, A Borrelli & D Esposito

  3. Department of Clinical Immunology, National Cancer Institute G Pascale, Naples, Italy

    R Calemma & G Castello

  4. Department of Histology, Institute of Histology, University of Bologna, Bologna, Italy

    F Pezzetti

  5. CEINGE, Naples, Italy

    R Martinelli

  6. Department of Biochemistry and Medical Biotechnology, University of Naples, Naples, Italy

    R Martinelli

  7. Department of Gastrointestinal–Hepatobiliary–Pancreatic Cancer Oncology Surgery, National Cancer Institute G Pascale, Naples, Italy

    R Palaia

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  1. P Bonelli
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Correspondence to P Bonelli.

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Bonelli, P., Tuccillo, F., Calemma, R. et al. Changes in the gene expression profile of gastric cancer cells in response to ibuprofen: a gene pathway analysis. Pharmacogenomics J 11, 412–428 (2011). https://doi.org/10.1038/tpj.2010.55

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  • DOI: https://doi.org/10.1038/tpj.2010.55

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