UVA-induced phenoxyl radical formation: A new cytotoxic principle in photodynamic therapy.

Abstract

Psoralens are regularly used in therapy in combination with ultraviolet A light irradiation (PUVA) to treat skin diseases such as psoriasis, vitiligo, and mycosis fungoides. PUVA therapy is also used within the scope of extracorporeal photopheresis to treat a variety of diseases that have a suspected involvement of pathogenic T cells, including rejection of organ transplants, graft-vs-host disease, cutaneous T cell lymphoma, and autoimmune disorders. Because psoralens are the only photosensitizers used in PUVA therapies and are considered to be responsible for a number of side effects, the identification of alternative drugs is of practical interest. Here we investigated the impact of activated Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), a hydrophilic vitamin E analog lacking the phytyl tail, as an alternative photoactivatable agent with T cell cytotoxic properties. Despite the well-known antioxidative capacity of Trolox, we found that at low UVA doses and in the presence of supraphysiological concentration of nitrite, a natural constituent of human skin, this compound selectively enhances radical-mediated cytotoxicity toward T cells but not toward human skin fibroblasts, keratinocytes, or endothelial cells. The cytotoxic mechanism comprises a reaction of Trolox with photo-decomposition products of nitrite, which leads to increased Trolox phenoxyl radical formation, increased intracellular oxidative stress, and a consecutive induction of apoptosis and necrosis in fast proliferating T cells. Thus, the identified UVA/nitrite-induced phenoxyl radical formation provides an opportunity for a new cytotoxic photodynamic therapy.

• Authors: Christine M Volkmar, Britta Vukadinović-Walter, Christian Opländer, Ahmet Bozkurt, Hans-Gert Korth, Michael Kirsch, Csaba Mahotka, Norbert Pallua, Christoph V Suschek
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 49 Issue 6 Pg. 1129-37 (Sep 15 2010) ISSN: 1873-4596 [Electronic] United States
• PMID: 20619338 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Inc. All rights reserved.

Chemical References

• Chromans
• Nitrites
• Phenols
• Radiation-Sensitizing Agents
• phenoxy radical
• 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid

Topics

• Apoptosis (drug effects, radiation effects)
• Chromans (pharmacology)
• Humans
• Jurkat Cells
• Nitrites (metabolism)
• Oxidative Stress (drug effects)
• PUVA Therapy
• Phenols (metabolism)
• Radiation-Sensitizing Agents (pharmacology)
• Skin (drug effects, metabolism, pathology, radiation effects)
• T-Lymphocytes (drug effects, metabolism, pathology, radiation effects)
• Ultraviolet Rays (adverse effects)