TY - JOUR
TI - 7-Bromoindirubin-3′-oxime induces caspase-independent cell death
AU - Ribas, J.
AU - Bettayeb, K.
AU - Ferandin, Y.
AU - Knockaert, M.
AU - Garrofé-Ochoa, X.
AU - Totzke, F.
AU - Schächtele, C.
AU - Mester, J.
AU - Polychronopoulos, P.
AU - Magiatis, P.
AU - Skaltsounis, A.-L.
AU - Boix, J.
AU - Meijer, L.
JO - Oncogenesis
PY - 2006
VL - 25
TODO - 47
SP - 6304-6318
PB - 
SN - 2157-9024
TODO - 10.1038/sj.onc.1209648
TODO - 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
TODO - 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.
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