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Characterization of cell death induced by vinflunine, the most recent Vinca alkaloid in clinical development

  • Experimental Therapeutics
  • Published:
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Abstract

Vinflunine, the most recent Vinca alkaloid in clinical development, demonstrated superior antitumour activity to other Vincas in preclinical tumour models. This study aimed to define its molecular mechanisms of cell killing in both parental sensitive and vinflunine-resistant P388 leukaemia cells. Vinflunine treatment of these cells resulted in apoptosis characterized by DNA fragmentation and proteolytic cleavage of poly-(ADP-ribose) polymerase. Apoptosis-inducing concentrations of vinflunine caused c-Jun N-terminal kinase 1 stimulation, as well as caspases-3/7 activation. This activation of caspases and the induction of apoptosis could be inhibited by the caspase inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde. Interestingly, the apoptosis signal triggered by vinflunine in these P388 cells was not mediated through Bcl-2 phosphorylation. In addition, when vinflunine resistance was developed in P388 cells, it was associated with resistance to vinflunine-induced apoptosis, as reflected by a loss of capacity to induce DNA fragmentation and PARP degradation, and characterized by increased levels of Bcl-2 and Bfl-1/A1. Therefore, these data indirectly implicate Bcl-2 and Bfl-1/A1 in vinflunine-induced cell death mechanisms.

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Acknowledgements

We thank Nathalie Cabrol, Jacqueline Astruc, Eric Chazottes, Valérie Cassabois and Stéphane Gras for their skilled technical assistance.

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Authors and Affiliations

  1. Division of Experimental Cancer Research, Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, Castres, 81106, Cedex 06, France

    A Kruczynski, C Etiévant, D Perrin, N Chansard & B T Hill

  2. Division of Medicinal Chemistry V, Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, Castres, 81106, Cedex 06, France

    A Duflos

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  1. A Kruczynski
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  2. C Etiévant
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  3. D Perrin
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  4. N Chansard
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  5. A Duflos
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  6. B T Hill
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Correspondence to A Kruczynski.

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Kruczynski, A., Etiévant, C., Perrin, D. et al. Characterization of cell death induced by vinflunine, the most recent Vinca alkaloid in clinical development. Br J Cancer 86, 143–150 (2002). https://doi.org/10.1038/sj.bjc.6600025

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  • DOI: https://doi.org/10.1038/sj.bjc.6600025

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