Home » Key Scientific Articles » 2-Phenylethynesulfonamide (PES) uncovers a necrotic process regulated by oxidative stress and p53.

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

Mattiolo P1, Barbero-Farran A1, Yuste VJ2, Boix J1, Ribas J3.

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

1Pharmacology Unit, Departament de Medicina Experimental, Universitat de Lleida, IRBLLEIDA, Ed. Biomedicina 1, Av. Rovira Roure 80, 25198 Lleida, Catalunya, Spain.

2Cell 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.

3Pharmacology Unit, Departament de Medicina Experimental, Universitat de Lleida, IRBLLEIDA, Ed. Biomedicina 1, Av. Rovira Roure 80, 25198 Lleida, Catalunya, Spain.

Electronic address: [email protected]

 

Abstract

2-Phenylethynesulfonamide (PES) or pifithrin-u 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.

Copyright © 2014 Elsevier Inc. All rights reserved.

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Additional Information: 

Further research from the authors on PES mechanism of action:

1 .  Ribas J., Mattiolo P. & Boix J. (2015) “Pharmacological modulation of reactive oxygen species in cancer treatment.” Curr. Drug Targets 16: 31-37
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2 .  Mattiolo P., Barbero-Farran A., Amigó J., Ripamonti M., Ribas J. & Boix J. (2014) “Cell death induced by 2-phenylethynesulfonamide uncovers a pro-survival function of BAX.”  Cancer Lett. 354: 115-121.