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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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Related in: MedlinePlus

Effects of vinflunine on Bcl-2 phosphorylation. (A) Neither vinflunine, nor taxol induced Bcl-2 phosphorylation in P388 leukaemia cells. Western blot analyses of P388 cells after a 24-h exposure to either 0.1–0.5 μM vinflunine (A1) or 0.04–0.4 μM taxol (A2), or to 0.3 μM vinflunine for 3–24 h (A2). (B) Vinflunine and taxol induced Bcl-2 phosphorylation in human CEM leukaemia cells. Western blot analyses of CEM cells after a 24-h exposure to either 0.08–1.6 μM vinflunine or 0.005–0.1 μM taxol.
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fig5: Effects of vinflunine on Bcl-2 phosphorylation. (A) Neither vinflunine, nor taxol induced Bcl-2 phosphorylation in P388 leukaemia cells. Western blot analyses of P388 cells after a 24-h exposure to either 0.1–0.5 μM vinflunine (A1) or 0.04–0.4 μM taxol (A2), or to 0.3 μM vinflunine for 3–24 h (A2). (B) Vinflunine and taxol induced Bcl-2 phosphorylation in human CEM leukaemia cells. Western blot analyses of CEM cells after a 24-h exposure to either 0.08–1.6 μM vinflunine or 0.005–0.1 μM taxol.

Mentions: Neither vinflunine (0.1–0.5 μM) nor taxol (0.04 and 0.4 μM), at equi-cytotoxic concentrations, induced any alteration of the Bcl-2 electrophoretic pattern in P388 cells after a 24-h exposure (Figure 5AFigure 5


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)

Effects of vinflunine on Bcl-2 phosphorylation. (A) Neither vinflunine, nor taxol induced Bcl-2 phosphorylation in P388 leukaemia cells. Western blot analyses of P388 cells after a 24-h exposure to either 0.1–0.5 μM vinflunine (A1) or 0.04–0.4 μM taxol (A2), or to 0.3 μM vinflunine for 3–24 h (A2). (B) Vinflunine and taxol induced Bcl-2 phosphorylation in human CEM leukaemia cells. Western blot analyses of CEM cells after a 24-h exposure to either 0.08–1.6 μM vinflunine or 0.005–0.1 μM taxol.
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Effects of vinflunine on Bcl-2 phosphorylation. (A) Neither vinflunine, nor taxol induced Bcl-2 phosphorylation in P388 leukaemia cells. Western blot analyses of P388 cells after a 24-h exposure to either 0.1–0.5 μM vinflunine (A1) or 0.04–0.4 μM taxol (A2), or to 0.3 μM vinflunine for 3–24 h (A2). (B) Vinflunine and taxol induced Bcl-2 phosphorylation in human CEM leukaemia cells. Western blot analyses of CEM cells after a 24-h exposure to either 0.08–1.6 μM vinflunine or 0.005–0.1 μM taxol.
Mentions: Neither vinflunine (0.1–0.5 μM) nor taxol (0.04 and 0.4 μM), at equi-cytotoxic concentrations, induced any alteration of the Bcl-2 electrophoretic pattern in P388 cells after a 24-h exposure (Figure 5AFigure 5

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