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

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.

Bcl-2 down-regulation and tubulin subtype composition are involved in resistance of ovarian cancer cells to vinflunine

“…Inactivation of Bcl-2, through hyperphosphorylation (47), leads to mitochondrial membrane permeability and apoptosis triggering by MTDs, including vinflunine (10,11). A relationship has been established between Bcl-2 overexpression and clinical resistance to MTDs (48).…”

Upregulation of bfl-1 is a potential mechanism of chemoresistance in B-cell chronic lymphocytic leukaemia

“…In fact, bfl-1 has previously been implicated in chemotherapy resistance development in model systems. Increased expression of bfl-1 has been found in an in vivo established vinflunineresistant murine leukaemia cell line as well as in in vitro established cisplatin-resistant bladder cancer cell lines compared to their respective sensitive parental cell lines (Kruczynski et al, 2002;Kim et al, 2004). We have found that fludarabine did not induce increased bfl-1 expression in B-CLL cells in a short-term culture (Olsson, unpublished observation).…”

Need of an Ancient Roots to Modern Medicine in the Treatment of Cancer- A review

“…Vinblastine has been modified to vinflunine, which is a novel fluorinated vinca alkaloid. Vinflunine is more efficacious than the parent drug and is undergoing clinical trial [113]. Exatecan, a novel synthetic camptothecin derivative with a unique hexacyclic structure has been synthesized.…”