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Pro-apoptotic effect of a nitric oxide-donating NSAID, NCX 4040, on bladder carcinoma cells

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Abstract

Nitric oxide-releasing non steroidal anti-inflammatory drugs (NO-NSAIDs) are a promising class of compounds that cause cell cycle perturbations and induce apoptosis in cell lines from different tumors. We investigated the activity of a recently developed NO-NSAID (NCX 4040) in bladder cancer cell lines (HT1376 and MCR). Cells were treated with different drug concentrations for different exposure times. Cytostatic and cytocidal activity was tested by SRB assay and apoptosis was evaluated by TUNEL analysis, ANNEXIN V assay and fluorescence microscopy. To further investigate the cell death-inducing mechanisms of NCX 4040, we analyzed gp-170, caspase expression and mitochondrial membrane potential (Δ Ψ) depolarization. NCX 4040 showed a striking cytocidal activity in both cell lines, reaching LC50 at a 10-μ M and 50-μ M concentrations in HT1376 and in MCR cells, respectively, after an exposure of only 6 h followed by an 18-h washout. Apoptosis was triggered in up to 90% of cells and was associated with active caspase-3 expression and Δ Ψ depolarization in both cell lines after a 6-h exposure. In conclusion, NCX 4040, which probably causes apoptosis via a mitochondrial-dependent mechanism, could prove to be a useful agent for improving bladder cancer treatment.

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Authors and Affiliations

  1. Istituto Oncologico Romagnolo, Forlì, Italy

    F. Fabbri, G. Brigliadori, P. Ulivi, A. Tesei, I. Vannini, M. Rosetti & S. Bravaccini

  2. Division of Oncology and Diagnostics, Morgagni-Pierantoni Hospital, Via Forlanini 34, 47100, Forlì, Italy

    D. Amadori & W. Zoli

  3. Interdisciplinary Center for the Study of Inflammation , NicOx SA, Sophia-Antipolis, France

    M. Bolla

Authors
  1. F. Fabbri
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  2. G. Brigliadori
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  3. P. Ulivi
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  4. A. Tesei
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  5. I. Vannini
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  6. M. Rosetti
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  7. S. Bravaccini
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  8. D. Amadori
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  9. M. Bolla
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  10. W. Zoli
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Corresponding author

Correspondence to W. Zoli.

Additional information

This study was supported by Istituto Oncologico Romagnolo, Forlì, and by the Italian Ministry of Health, 2002.

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Fabbri, F., Brigliadori, G., Ulivi, P. et al. Pro-apoptotic effect of a nitric oxide-donating NSAID, NCX 4040, on bladder carcinoma cells. Apoptosis 10, 1095–1103 (2005). https://doi.org/10.1007/s10495-005-0619-7

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  • DOI: https://doi.org/10.1007/s10495-005-0619-7

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