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: Paolo Mattiolo, Ares Barbero-Farran, Víctor J Yuste, Jacint Boix, Judit Ribas
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 91 Issue 3 Pg. 301-11 (Oct 01 2014) ISSN: 1873-2968 [Electronic] England
• PMID: 25139326 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• 2-phenylacetylenesulfonamide
• Antineoplastic Agents
• Chromatin
• Reactive Oxygen Species
• Sulfonamides
• Buthionine Sulfoximine
• Caspases

Topics

• Antineoplastic Agents (pharmacology)
• Buthionine Sulfoximine (pharmacology)
• Caspases (metabolism)
• Cell Death (drug effects)
• Chromatin (genetics)
• Gene Expression Regulation (drug effects)
• Genes, p53
• HCT116 Cells (drug effects)
• Humans
• Necrosis (chemically induced)
• Oxidative Stress (drug effects)
• Reactive Oxygen Species (metabolism)
• Sulfonamides (pharmacology)