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.
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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)
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Copyright | Copyright © 2014 Elsevier Inc. All rights reserved. |
Chemical References |
- 2-phenylacetylenesulfonamide
- Antineoplastic Agents
- Chromatin
- Reactive Oxygen Species
- Sulfonamides
- Buthionine Sulfoximine
- Caspases
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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)
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