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oai:recercat.cat:10459.1/478502024-12-05T22:19:42Zcom_2072_3622col_2072_479130

2-phenylethynesulfonamide (PES) uncovers a necrotic process regulated by oxidative stress and p53 Mattiolo, Paolo Barbero-Farran A. Yuste Mateos, Víctor J. (Víctor José) Boix Torras, Jacint Ribas i Fortuny, Judit Necrosis p53 oxidative stress pifithrin-mu PES (2-phenylethynesulfonamide) Necrosi Estrès oxidatiu Necrosis Oxidative stress 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. 2024-12-05T22:19:42Z 2024-12-05T22:19:42Z 2024-12-05T22:19:42Z 2015-02-03T17:23:08Z 2015-02-03T17:23:08Z 2014 info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion http://hdl.handle.net/10459.1/47850 Versió postprint del document publicat a: https://doi.org/10.1016/j.bcp.2014.08.005 Biochemical Pharmacology, 2014, vol. 91, num. 3, p. 301-311 cc-by-nc-nd (c) Elsevier, 2014 info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-nd/3.0/ Elsevier