2026-04-17T21:26:43Zhttps://recercat.cat/oai/request

oai:recercat.cat:10459.1/480942024-12-05T22:33:35Zcom_2072_3622col_2072_479130

7-Bromoindirubin-3'-oxime induces caspase-independent cell death Ribas i Fortuny, Judit Bettayeb, Karima Ferandin, Yoan Knockaert, Marie Garrofé Ochoa, Xènia Totzke, Frank Schächtele, Christoph Mester, Jan Polychronopoulos, Panagiotis Magiatis, Prokopios Skaltsounis, Alexios-Leandros Boix Torras, Jacint Meijer, Laurent Apoptosis Autophagy Kinases Indirubins Caspases Apoptosi Proteïnes quinases Càncer Autofàgia Mort cel·lular Apoptosis Protein kinases Cancer Autophagy 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. 2015-03-23T19:16:07Z 2015-03-23T19:16:07Z 2006 2015-03-23T19:16:07Z info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion https://doi.org/10.1038/sj.onc.1209648 0950-9232 http://hdl.handle.net/10459.1/48094 http://hdl.handle.net/10459.1/48094 eng Versió postprint del document publicat a: https://doi.org/10.1038/sj.onc.1209648 Oncogene, 2006, vol. 25, num. 47, p. 6304-6318 (c) Nature Publishing Group, 2006 info:eu-repo/semantics/openAccess application/pdf Nature Publishing Group