title: 2-Phenylethynesulfonamide (PES) uncovers a necrotic process regulated by oxidative stress and p53.
abstract: 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.
authors.affiliation: Pharmacology Unit, Departament de Medicina Experimental, Universitat de Lleida, IRBLLEIDA, Ed. Biomedicina 1, Av. Rovira Roure 80, 25198 Lleida, Catalunya, Spain.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mattiolo
authors.affiliation: Pharmacology Unit, Departament de Medicina Experimental, Universitat de Lleida, IRBLLEIDA, Ed. Biomedicina 1, Av. Rovira Roure 80, 25198 Lleida, Catalunya, Spain.
authors.forename: Ares
authors.initials: A
authors.lastname: Barbero-Farran
authors.affiliation: Cell Death, Senescence, and Survival Group, Departament de Bioquímica i Biologia Molecular and Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona, Campus de Bellaterra, 08193 Bellaterra, Catalunya, Spain.
authors.forename: Víctor J
authors.initials: VJ
authors.lastname: Yuste
authors.affiliation: Pharmacology Unit, Departament de Medicina Experimental, Universitat de Lleida, IRBLLEIDA, Ed. Biomedicina 1, Av. Rovira Roure 80, 25198 Lleida, Catalunya, Spain.
authors.forename: Jacint
authors.initials: J
authors.lastname: Boix
authors.affiliation: Pharmacology Unit, Departament de Medicina Experimental, Universitat de Lleida, IRBLLEIDA, Ed. Biomedicina 1, Av. Rovira Roure 80, 25198 Lleida, Catalunya, Spain. Electronic address: judit.ribas@mex.udl.cat.
authors.forename: Judit
authors.initials: J
authors.lastname: Ribas
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002843:Chromatin / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D016158:Genes, p53; D045325:HCT116 Cells / Q000187:drug effects; D006801:Humans; D009336:Necrosis / Q000139:chemically induced; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C545747:2-phenylacetylenesulfonamide; D000970:Antineoplastic Agents; D002843:Chromatin; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D019328:Buthionine Sulfoximine; D020169:Caspases
keywords: 2-Phenylethynesulfonamide (PES); 2-Phenylethynesulfonamide (Pubmed CID 327653); 3-Methyladenine (Pubmed CID 1673); Anticancer drug; Dithiothreitol (Pubmed CID 19001); N-acetyl cysteine (Pubmed CID 12035); Necrosis; Necrostatin-1 (Pubmed CID 282833); Pifithrin-μ; Q-VD-OPh (Pubmed CID 11237609); Reactive oxygen species (ROS); l-Buthionine-sulfoximine (Pubmed CID 119565); p53