title: 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.affiliation: Department of Plastic and Reconstructive Surgery, Hand Surgery, and Burn Center, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Volkmar
authors.forename: Britta
authors.initials: B
authors.lastname: Vukadinović-Walter
authors.forename: Christian
authors.initials: C
authors.lastname: Opländer
authors.forename: Ahmet
authors.initials: A
authors.lastname: Bozkurt
authors.forename: Hans-Gert
authors.initials: HG
authors.lastname: Korth
authors.forename: Michael
authors.initials: M
authors.lastname: Kirsch
authors.forename: Csaba
authors.initials: C
authors.lastname: Mahotka
authors.forename: Norbert
authors.initials: N
authors.lastname: Pallua
authors.forename: Christoph V
authors.initials: CV
authors.lastname: Suschek
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002839:Chromans / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D009573:Nitrites / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011701:PUVA Therapy; D010636:Phenols / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D002839:Chromans; D009573:Nitrites; D010636:Phenols; D011838:Radiation-Sensitizing Agents; C042329:phenoxy radical; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid