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Título:
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7-Bromoindirubin-3'-oxime induces caspase-independent cell death
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Autor/a:
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Ribas i Fortuny, Judit; Bettayeb, Karima; Ferandin, Yoan; Knockaert, Marie; Garrofé Ochoa, Xènia; Totzke, Frank; Schächtele, Christoph; Mester, Jan; Polychronopoulos, Panagiotis; Magiatis, Prokopios; Skaltsounis, Alexios-Leandros; Boix Torras, Jacint; Meijer, Laurent
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Notas:
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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. |
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Materia(s):
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-Apoptosis
-Autophagy
-Kinases
-Indirubins
-Caspases
-Apoptosi
-Proteïnes quinases
-Càncer
-Autofàgia
-Mort cel·lular
-Apoptosis
-Protein kinases
-Cancer
-Autophagy
-Cell death |
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Derechos:
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(c) Nature Publishing Group, 2006
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Tipo de documento:
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Artículo
Artículo - Versión aceptada |
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Editor:
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Nature Publishing Group
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Compartir:
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