TY - JOUR T1 - Low Concentrations of Vinflunine Induce Apoptosis in Human SK-N-SH Neuroblastoma Cells through a Postmitotic G<sub>1</sub> Arrest and a Mitochondrial Pathway JF - Molecular Pharmacology JO - Mol Pharmacol SP - 580 LP - 591 VL - 66 IS - 3 AU - Bertrand Pourroy AU - Manon Carré AU - Stéphane Honoré AU - Véronique Bourgarel-Rey AU - Anna Kruczynski AU - Claudette Briand AU - Diane Braguer Y1 - 2004/09/01 UR - http://molpharm.aspetjournals.org/content/66/3/580.abstract N2 - 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. ER -