7-Bromoindirubin-3'-oxime induces caspase-independent cell death.
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.
Ribas
J
J
CNRS, Cell Cycle Group and UPS2682, Station Biologique, Bretagne, France.
Bettayeb
K
K
Ferandin
Y
Y
Knockaert
M
M
Garrofé-Ochoa
X
X
Totzke
F
F
Schächtele
C
C
Mester
J
J
Polychronopoulos
P
P
Magiatis
P
P
Skaltsounis
A-L
AL
Boix
J
J
Meijer
L
L
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors; D020169:Caspases / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology; D002467:Cell Nucleus / Q000648:ultrastructure; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor / Q000378:metabolism; D018411:Spodoptera; D013215:Starfish; D013329:Structure-Activity Relationship; D013552:Swine; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D051020:bcl-X Protein / Q000502:physiology
C514974:7-bromoindirubin-3'-oxime; D000590:Amino Acid Chloromethyl Ketones; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015853:Cysteine Proteinase Inhibitors; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011804:Quinolines; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; C468548:quinoline-val-asp(OMe)-CH2-OPH; D016203:CDC2 Protein Kinase; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3; D020169:Caspases