7-Bromoindirubin-3'-oxime induces caspase-independent cell death
Garrofé Ochoa, Xènia
MetadataShow full item record
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.
Is part ofOncogene, 2006, vol. 25, num. 47, p. 6304-6318
European research projects
Showing items related by title, author, creator and subject.
Ribas i Fortuny, Judit; Yuste Mateos, Víctor J. (Víctor José); Garrofé Ochoa, Xènia; Meijer, Laurent; Esquerda Colell, Josep; Boix Torras, Jacint (Elsevier, 2008)The new 7-bromoindirubin-3′-oxime (7BIO) compound induces caspase-independent cell death in all cell lines tested to date. Irrespective of the cell line, a 25 μM treatment for 24 h is lethal for the entire cell population. ...
Garrofé Ochoa, Xènia; Cosialls, Ana M; Ribas i Fortuny, Judit; Gil, Joan; Boix Torras, Jacint (Springer Science Business Media, 2011)Chemical inhibitors of cyclin-dependent kinase (CDK), like roscovitine, are promising drugs in thecontext of new cancer therapies. Roscovitine and related compounds, like seliciclib and olomoucine, are effective inducers ...
Garrofé Ochoa, Xènia; Melero Fernández de Mera, Raquel M; Fernández Gómez, Francisco J.; Ribas i Fortuny, Judit; Jordán Bueso, Joaquín; Boix Torras, Jacint (American Association for Cancer Research, 2008)In previous reports we have shown in SH-SY5 cells that Olomoucine and Roscovitine, two inhibitory drugs of Cyclin Dependent Kinases, caused apoptosis independent of the extrinsic pathway. In this experimental paradigm, ...