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

Kruczynski A, Etiévant C, Perrin D, Chansard N, Duflos A, Hill BT - Br. J. Cancer (2002)

Bottom Line: 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.Therefore, these data indirectly implicate Bcl-2 and Bfl-1/A1 in vinflunine-induced cell death mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Division of Experimental Cancer Research, Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, 81106 Castres, Cedex 06, France. anna.kruczynski@pierre-fabre.com

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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Comparison of vinflunine-induced DNA fragmentation (A) and PARP cleavage (B) in sensitive P388 and vinflunine-resistant P388/VFL leukaemia cells. See legends to Figure 1 for DNA fragmentation data and to Figure 4 for PARP degradation data.
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fig6: Comparison of vinflunine-induced DNA fragmentation (A) and PARP cleavage (B) in sensitive P388 and vinflunine-resistant P388/VFL leukaemia cells. See legends to Figure 1 for DNA fragmentation data and to Figure 4 for PARP degradation data.

Mentions: In order to detect PARP cleavage and DNA fragmentation after a 24-h exposure of P388/VFL resistant cells to vinflunine, it was necessary to increase the vinflunine concentrations 10-fold (i.e., 2–5 μM) relative to those required to induce comparable effects in the sensitive cells (Figure 6A,BFigure 6


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

Kruczynski A, Etiévant C, Perrin D, Chansard N, Duflos A, Hill BT - Br. J. Cancer (2002)

Comparison of vinflunine-induced DNA fragmentation (A) and PARP cleavage (B) in sensitive P388 and vinflunine-resistant P388/VFL leukaemia cells. See legends to Figure 1 for DNA fragmentation data and to Figure 4 for PARP degradation data.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2746541&req=5

fig6: Comparison of vinflunine-induced DNA fragmentation (A) and PARP cleavage (B) in sensitive P388 and vinflunine-resistant P388/VFL leukaemia cells. See legends to Figure 1 for DNA fragmentation data and to Figure 4 for PARP degradation data.
Mentions: In order to detect PARP cleavage and DNA fragmentation after a 24-h exposure of P388/VFL resistant cells to vinflunine, it was necessary to increase the vinflunine concentrations 10-fold (i.e., 2–5 μM) relative to those required to induce comparable effects in the sensitive cells (Figure 6A,BFigure 6

Bottom Line: 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.Therefore, these data indirectly implicate Bcl-2 and Bfl-1/A1 in vinflunine-induced cell death mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Division of Experimental Cancer Research, Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, 81106 Castres, Cedex 06, France. anna.kruczynski@pierre-fabre.com

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.

Show MeSH
Related in: MedlinePlus