2-Phenylethynesulfonamide (PES) uncovers a necrotic process regulated by oxidative stress and p53.

Mattiolo, Paolo; Barbero-Farran, Ares; Yuste, Víctor J; Boix, Jacint; Ribas, Judit

Mattiolo, Paolo; Barbero-Farran, Ares; Yuste, Víctor J; Boix, Jacint; Ribas, Judit.

Afiliación

Mattiolo P; Pharmacology Unit, Departament de Medicina Experimental, Universitat de Lleida, IRBLLEIDA, Ed. Biomedicina 1, Av. Rovira Roure 80, 25198 Lleida, Catalunya, Spain.
Barbero-Farran A; Pharmacology Unit, Departament de Medicina Experimental, Universitat de Lleida, IRBLLEIDA, Ed. Biomedicina 1, Av. Rovira Roure 80, 25198 Lleida, Catalunya, Spain.
Yuste VJ; 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.
Boix J; Pharmacology Unit, Departament de Medicina Experimental, Universitat de Lleida, IRBLLEIDA, Ed. Biomedicina 1, Av. Rovira Roure 80, 25198 Lleida, Catalunya, Spain.
Ribas J; 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.

Biochem Pharmacol ; 91(3): 301-11, 2014 Oct 01.

Article en En | MEDLINE | ID: mdl-25139326

RESUMEN

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.

Asunto(s)

Antineoplásicos/farmacología; Genes p53; Estrés Oxidativo/efectos de los fármacos; Sulfonamidas/farmacología; Butionina Sulfoximina/farmacología; Caspasas/metabolismo; Muerte Celular/efectos de los fármacos; Cromatina/genética; Regulación de la Expresión Génica/efectos de los fármacos; Células HCT116/efectos de los fármacos; Humanos; Necrosis/inducido químicamente; Especies Reactivas de Oxígeno/metabolismo

Palabras clave

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

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sulfonamidas / Genes p53 / Estrés Oxidativo / Antineoplásicos Límite: Humans Idioma: En Revista: Biochem Pharmacol Año: 2014 Tipo del documento: Article País de afiliación: España Pais de publicación: Reino Unido

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