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

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2006Author
Bettayeb, Karima
Ferandin, Yoan
Knockaert, Marie
Garrofé Ochoa, Xènia
Totzke, Frank
Schächtele, Christoph
Mester, Jan
Polychronopoulos, Panagiotis
Magiatis, Prokopios
Skaltsounis, Alexios-Leandros
Meijer, Laurent
Suggested citation
Ribas i Fortuny, Judit;
Bettayeb, Karima;
Ferandin, Yoan;
Knockaert, Marie;
Garrofé Ochoa, Xènia;
Totzke, Frank;
...
Meijer, Laurent.
(2006)
.
7-Bromoindirubin-3'-oxime induces caspase-independent cell death.
Oncogene, 2006, vol. 25, num. 47, p. 6304-6318.
https://doi.org/10.1038/sj.onc.1209648.
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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.