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Low Concentrations of Vinflunine Induce Apoptosis in Human SK-N-SH Neuroblastoma Cells through a Postmitotic G₁ Arrest and a Mitochondrial Pathway

Formation de Recherche en Evolution–Centre National de la Recherche Scientifique 2737, Université de la Méditerranée, Marseille, France (B.P., M.C., S.H., V.B.-R., C.B., D.B.); and Division of Experimental Cancer Research, Centre de Recherche Pierre Fabre, Castres, France (A.K.)

Vinflunine, the newest fluorinated Vinca alkaloid, currently in phase III clinical trials, targets the microtubule network to induce mitotic block and apoptosis by mechanisms that remain unclear. In the current study, we investigated the apoptotic pathways induced by a wide range of vinflunine concentrations in SK-N-SH neuroblastoma cells. The concentrations of vinflunine that inhibited 50 and 70% of cell growth (IC₅₀ and IC₇₀) induced high extents of apoptosis but failed to depolymerize microtubule network and to block cells in G₂/M. It is interesting that the IC₅₀ and IC₇₀ concentrations suppressed microtubule dynamics, slowed down mitotic progression from metaphase to anaphase, and induced a postmitotic G₁ arrest. This G₁ arrest was associated with an increase in p53 and p21 expression and with their nuclear translocation. A high concentration of vinflunine (500 nM) induced both microtubule depolymerization and a canonical G₂/M block. Mitochondria were involved in apoptotic pathways because all studied concentrations induced cytochrome c release. Bcl-2 family members were differently modulated by the different drug concentrations. Bax was up-regulated and translocated to mitochondria at the IC₅₀ and IC₇₀ concentrations, whereas Bcl-2 was phosphorylated only at the highest vinflunine concentration examined (500 nM). Our findings can be extended to other Vinca alkaloids, because similar results were obtained with vinblastine. All together, our results show that low concentrations of vinflunine fail to promote a G₂/M arrest but are sufficient to induce suppression of microtubule dynamics and subsequent apoptosis. Moreover, mitochondria constitute the point of convergence of apoptotic signals induced by both low and high concentrations of vinflunine.

Address correspondence to: Dr. Diane Braguer, FRE-CNRS 2737, UFR Pharmacie, 27 boulevard Jean Moulin, 13385 Marseilles cedex 05, France. E-mail: diane.braguer{at}pharmacie.univ-mrs.fr

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