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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.

Abstract：

: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 (IC(50) and IC(70)) induced high extents of apoptosis but failed to depolymerize microtubule network and to block cells in G(2)/M. It is interesting that the IC(50) and IC(70) concentrations suppressed microtubule dynamics, slowed down mitotic progression from metaphase to anaphase, and induced a postmitotic G(1) arrest. This G(1) 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 G(2)/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 IC(50) and IC(70) 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 G(2)/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.

journal_name

Mol Pharmacol

journal_title

Molecular pharmacology

authors

Pourroy B,Carré M,Honoré S,Bourgarel-Rey V,Kruczynski A,Briand C,Braguer D

doi

10.1124/mol.66.3.

keywords:

subject

Has Abstract

pub_date

2004-09-01 00:00:00

pages

580-91

issue

eissn

0026-895X

issn

1521-0111

pii

66/3/580

journal_volume

pub_type

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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.