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

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2006
Author
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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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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Abstract
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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http://hdl.handle.net/10459.1/48094
DOI
https://doi.org/10.1038/sj.onc.1209648
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Oncogene, 2006, vol. 25, num. 47, p. 6304-6318
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