RT Journal Article SR Electronic T1 Low Concentrations of Vinflunine Induce Apoptosis in Human SK-N-SH Neuroblastoma Cells through a Postmitotic G1 Arrest and a Mitochondrial Pathway JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 580 OP 591 VO 66 IS 3 A1 Bertrand Pourroy A1 Manon Carré A1 Stéphane Honoré A1 Véronique Bourgarel-Rey A1 Anna Kruczynski A1 Claudette Briand A1 Diane Braguer YR 2004 UL http://molpharm.aspetjournals.org/content/66/3/580.abstract AB 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.