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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Abbreviations
- AhR:
-
aryl hydrocarbon receptor
- ARNT:
-
aryl hydrocarbon receptor nuclear translocator
- BIO:
-
bromoindirubin-3′-oxime
- CDK:
-
cyclin-dependent kinase
- FCS:
-
fetal calf serum
- FLT-3:
-
FMS-like tyrosine kinase 3
- GSK-3:
-
glycogen synthase kinase-3
- IFNα:
-
interferon α
- IO:
-
indirubin-3′-oxime
- LDH:
-
lactate dehydrogenase
- MeBIO:
-
1-methyl-bromoindirubin-3′-oxime
- MeIO:
-
1-methyl-indirubin-3′-oxime
- MTS:
-
3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
- RA:
-
retinoic acid
- ROS:
-
reactive oxygen species
- STS:
-
staurosporine
- TCDD:
-
2,3,7,8-tetrachlorodibenzo-p-dioxin
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Acknowledgements
We thank our colleagues for providing reagents: Dr Martin Goëttlicher, Dr Steve Safe, Dr Bert Vogelstein. This research was supported a grant from the EEC (FP6-2002-Life Sciences & Health, PRO-KINASE Research Project) (LM), and a ‘Cancéropole Grand-Ouest’ grant (LM). KB was supported by a fellowship from the ‘Ministère de la Recherche’. The Molecular Pharmacology Group thank the ‘Instituto de Salud Carlos III’ (PI041488, 2005-2007) for financial support.
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Ribas, J., Bettayeb, K., Ferandin, Y. et al. 7-Bromoindirubin-3′-oxime induces caspase-independent cell death. Oncogene 25, 6304–6318 (2006). https://doi.org/10.1038/sj.onc.1209648
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DOI: https://doi.org/10.1038/sj.onc.1209648
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