2-phenylethynesulfonamide (PES) uncovers a necrotic process regulated by oxidative stress and p53
Yuste Mateos, Víctor J. (Víctor José)
MetadataShow full item record
2-Phenylethynesulfonamide (PES) or pifithrin-μ is a promising anticancer agent with preferential toxicity for cancer cells. The type of cell death and the molecular cascades activated by this compound are controversial. Here, we demonstrate PES elicits a caspase- and BAX/BAK-independent non-necroptotic necrotic cell death, since it is not inhibited by necrostatin-1. This process is characterized by an early generation of reactive oxygen species (ROS) resulting in p53 up-regulation. Accordingly, thiolic antioxidants protect cells from PES-induced death. Furthermore, inhibiting the natural sources of glutathione with l-buthionine-sulfoximine (BSO) strongly cooperates with PES in triggering cytotoxicity. Genetically modified p53-null or p53 knocked-down cells show resistance to PES-driven necrosis. The predominant localization of p53 in chromatin-enriched fractions added to the up-regulation of the p53-responsive gene p21, strongly suggest the involvement of a transcription-dependent p53 program. On the other hand, we report an augmented production of ROS in p53-positive cells that, added to the increased p53 content in response to PES-elicited ROS, suggests that p53 and ROS are mutually regulated in response to PES. In sum, p53 up-regulation by ROS triggers a positive feedback loop responsible of further increasing ROS production and reinforcing PES-driven non-necroptotic necrosis.
Is part ofBiochemical Pharmacology, 2014, vol. 91, num. 3, p. 301-311
European research projects
Showing items related by title, author, creator and subject.
Mattiolo, Paolo; Barbero-Farran A.; Amigó J.; Ripamonti M.; Ribas i Fortuny, Judit; Boix Torras, Jacint (Elsevier, 2014)PES (2-phenylethynesulfonamide) was initially identified as an inhibitor of p53 translocation to mitochondria and named Pifithrin-µ. Further studies showed that PES selectively killed tumour cells and was thus a promising ...
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. ...
Mattiolo, Paolo; Yuste Mateos, Víctor J. (Víctor José); Boix Torras, Jacint; Ribas i Fortuny, Judit (Elsevier, 2015-12)Autophagy is generally regarded as a mechanism to promote cell survival. However, autophagy can occasionally be the mechanism responsible of cell demise. We have found that a concomitant depletion of glucose, nutrients and ...