@article{3094613,
    title = "7-Bromoindirubin-3′-oxime induces caspase-independent cell death",
    author = "Ribas, J. and Bettayeb, K. and Ferandin, Y. and Knockaert, M. and Garrofé-Ochoa, X. and Totzke, F. and Schächtele, C. and Mester, J. and Polychronopoulos, P. and Magiatis, P. and Skaltsounis, A.-L. and Boix, J. and Meijer, L.",
    journal = "Oncogenesis",
    year = "2006",
    volume = "25",
    number = "47",
    pages = "6304-6318",
    issn = "2157-9024",
    doi = "10.1038/sj.onc.1209648",
    keywords = "5 bromoindirubin 3' oxime;  6 bromoindirubin 3' oxime;  7 bromoindirubin 3' oxime;  caspase;  caspase inhibitor;  Chinese drug;  cyclin dependent kinase inhibitor;  cytochrome c;  glycogen synthase kinase 3 inhibitor;  indirubin;  indirubin 3' oxime;  protein bcl 2;  protein bcl xl;  unclassified drug, animal cell;  apoptosis;  article;  autophagy;  cell death;  cell nucleus;  Chinese medicine;  chromatin condensation;  chronic myeloid leukemia;  controlled study;  drug activity;  drug effect;  drug synthesis;  enzyme activation;  human;  human cell;  mouse;  nonhuman;  priority journal, Amino Acid Chloromethyl Ketones;  Animals;  bcl-X Protein;  Caspases;  CDC2 Protein Kinase;  Cell Cycle;  Cell Death;  Cell Line;  Cell Line, Tumor;  Cell Nucleus;  Cyclin-Dependent Kinase Inhibitor p21;  Cyclin-Dependent Kinases;  Cysteine Proteinase Inhibitors;  Female;  Glycogen Synthase Kinase 3;  Humans;  Indoles;  Male;  Mice;  Oximes;  Phosphorylation;  Protein Kinase Inhibitors;  Protein Processing, Post-Translational;  Proto-Oncogene Proteins c-bcl-2;  Quinolines;  Recombinant Fusion Proteins;  Spodoptera;  Starfish;  STAT3 Transcription Factor;  Structure-Activity Relationship;  Swine;  Tumor Suppressor Protein p53",
    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. © 2006 Nature Publishing Group. All rights reserved."
}