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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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Induction of JNK1 activation by vinflunine in P388 cells. P388 cells were treated with 0.025 to 0.5 μM vinflunine for 6 h. JNK1 activity was determined in cell lysates by immunocomplex assay, as described in Materials and methods. Results, from two independent experiments, are expressed as average increase of JNK1 activity relative to the controls±s.e.m. Statistical evaluation using the Student t-test showed that the values for 0.25 and 0.5 μM were significant, with respective P values of 0.015 and <0.001.
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fig2: Induction of JNK1 activation by vinflunine in P388 cells. P388 cells were treated with 0.025 to 0.5 μM vinflunine for 6 h. JNK1 activity was determined in cell lysates by immunocomplex assay, as described in Materials and methods. Results, from two independent experiments, are expressed as average increase of JNK1 activity relative to the controls±s.e.m. Statistical evaluation using the Student t-test showed that the values for 0.25 and 0.5 μM were significant, with respective P values of 0.015 and <0.001.

Mentions: A 6-h treatment with 0.025, 0.25 or 0.5 μM vinflunine resulted in the activation of JNK1 in these P388 cells in a dose-dependent manner, as illustrated in Figure 2Figure 2


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)

Induction of JNK1 activation by vinflunine in P388 cells. P388 cells were treated with 0.025 to 0.5 μM vinflunine for 6 h. JNK1 activity was determined in cell lysates by immunocomplex assay, as described in Materials and methods. Results, from two independent experiments, are expressed as average increase of JNK1 activity relative to the controls±s.e.m. Statistical evaluation using the Student t-test showed that the values for 0.25 and 0.5 μM were significant, with respective P values of 0.015 and <0.001.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Induction of JNK1 activation by vinflunine in P388 cells. P388 cells were treated with 0.025 to 0.5 μM vinflunine for 6 h. JNK1 activity was determined in cell lysates by immunocomplex assay, as described in Materials and methods. Results, from two independent experiments, are expressed as average increase of JNK1 activity relative to the controls±s.e.m. Statistical evaluation using the Student t-test showed that the values for 0.25 and 0.5 μM were significant, with respective P values of 0.015 and <0.001.
Mentions: A 6-h treatment with 0.025, 0.25 or 0.5 μM vinflunine resulted in the activation of JNK1 in these P388 cells in a dose-dependent manner, as illustrated in Figure 2Figure 2

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