7-Bromoindirubin-3'-oxime induces caspase-independent cell death. - Université Pierre et Marie Curie Accéder directement au contenu
Article Dans Une Revue Oncogene Année : 2006

7-Bromoindirubin-3'-oxime induces caspase-independent cell death.

K. Bettayeb
  • Fonction : Auteur
Y. Ferandin
  • Fonction : Auteur
M. Knockaert
  • Fonction : Auteur
X. Garrofé-Ochoa
  • Fonction : Auteur
F. Totzke
  • Fonction : Auteur
C. Schächtele
  • Fonction : Auteur
J. Mester
  • Fonction : Auteur
P. Polychronopoulos
  • Fonction : Auteur
P. Magiatis
  • Fonction : Auteur
A.-L. Skaltsounis
  • Fonction : Auteur
J. Boix
  • Fonction : Auteur

Résumé

Indirubin, an isomer of indigo, is a reported inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3 (GSK-3) as well as an agonist of the aryl hydrocarbon receptor (AhR). Indirubin is the active ingredient of a traditional Chinese medicinal recipe used against chronic myelocytic leukemia. Numerous indirubin analogs have been synthesized to optimize this promising kinase inhibitor scaffold. We report here on the cellular effects of 7-bromoindirubin-3'-oxime (7BIO). In contrast to its 5-bromo- and 6-bromo- isomers, and to indirubin-3'-oxime, 7BIO has only a marginal inhibitory activity towards CDKs and GSK-3. Unexpectedly, 7BIO triggers a rapid cell death process distinct from apoptosis. 7-Bromoindirubin-3'-oxime induces the appearance of large pycnotic nuclei, without classical features of apoptosis such as chromatin condensation and nuclear fragmentation. 7-Bromoindirubin-3'-oxime-induced cell death is not accompanied by cytochrome c release neither by any measurable effector caspase activation. Furthermore, the death process is not altered either by the presence of Q-VD-OPh, a broad-spectrum caspase inhibitor, or the overexpression of Bcl-2 and Bcl-XL proteins. Neither AhR nor p53 is required during 7BIO-induced cell death. Thus, in contrast to previously described indirubins, 7BIO triggers the activation of non-apoptotic cell death, possibly through necroptosis or autophagy. Although their molecular targets remain to be identified, 7-substituted indirubins may constitute a new class of potential antitumor compounds that would retain their activity in cells refractory to apoptosis.

Dates et versions

hal-00169383 , version 1 (03-09-2007)

Identifiants

Citer

J. Ribas, K. Bettayeb, Y. Ferandin, M. Knockaert, X. Garrofé-Ochoa, et al.. 7-Bromoindirubin-3'-oxime induces caspase-independent cell death.. Oncogene, 2006, 25 (47), pp.6304-18. ⟨10.1038/sj.onc.1209648⟩. ⟨hal-00169383⟩
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