Τίτλος:
7-Bromoindirubin-3′-oxime induces caspase-independent cell death
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
Ribas, J.
Bettayeb, K.
Ferandin, Y.
Knockaert, M.
Garrofé-Ochoa, X.
Totzke, F.
Schächtele, C.
Mester, J.
Polychronopoulos, P.
Magiatis, P.
Skaltsounis, A.-L.
Boix, J.
Meijer, L.
Λέξεις-κλειδιά:
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
DOI:
10.1038/sj.onc.1209648
