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

• Published in: British journal of cancer Vol. 86; no. 1; pp. 143 - 150
• Main Authors: KRUCZYNSKI, A, ETIEVANT, C, PERRIN, D, CHANSARD, N, DUFLOS, A, HILL, B. T
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 07.01.2002
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; bcl-X Protein; Biological and medical sciences; Caspases - metabolism; Cell death; Experimental Therapeutics; General aspects; Leukemia P388 - pathology; Medical sciences; Mice; Oligopeptides - pharmacology; Pharmacology. Drug treatments; Phosphorylation; Poly(ADP-ribose) Polymerases - metabolism; Proto-Oncogene Proteins c-bcl-2 - analysis; Proto-Oncogene Proteins c-bcl-2 - metabolism; Vinblastine - analogs & derivatives; Vinblastine - pharmacology; Antineoplastic agent; Enzyme; Rodentia; P388-Leukemia; Caspase; Mitogen-activated protein kinase; Malignant hemopathy; Vinflunine; In vitro; Biological activity; Peptidases; Vertebrata; Alkaloid; Mammalia; Mouse; Cell death; Animal; C-Onc gene; Established cell line; Hydrolases; Mechanism of action; Protooncogene; Apoptosis
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6600025

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.