PUVA‐induced apoptosis involves mitochondrial dysfunction caused by the opening of the permeability transition pore

Abstract

The mechanism of cell death was investigated in Jurkat cells exposed to the combination of psoralen and UVA irradiation (PUVA). Apoptosis was by far prevailing over necrosis and involved mitochondrial dysfunction. The collapse of mitochondrial membrane potential, appears to be caused by the opening of the mitochondrial permeability transition pore since its inhibitor, cyclosporin A, prevented mitochondrial dysfunction and largely attenuated apoptosis. Apoptosis also occurred in cells treated with the photoproducts generated by irradiating psoralen in vitro with an oxygen-dependent process. Thus, the involvement of reactive oxygen species in the onset of PUVAinduced apoptosis appears mostly related to psoralen photooxidation. ß 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.

The mitochondrial effects of novel apoptogenic molecules generated by psoralen photolysis as a crucial mechanism in PUVA therapy

“…22 To exclude artefacts due to the different loading capacity of the various cells which can be erroneously interpreted as ⌬ m differences, after each treatment the cells were added with an uncoupler of oxidative phosphorylation (FCCP) that abolishes ⌬ m . 9 Thus, in each cell the difference of fluorescence intensities obtained before and after FCCP provided a reliable assessment of ⌬ m . At 4 hours after POP treatment an extensive decrease of ⌬ m was measured (Figure 2A).…”

“…[15][16][17][18] Here we show that POPs caused apoptosis in Jurkat cells, thus highlighting the relevance of long-lasting toxic molecules generated by psoralen photodegradation. 9 The apoptogenic potency of the mixture was reduced-but not suppressed-by irradiating the psoralen solution in the absence of oxygen, suggesting that both oxygen-dependent and oxygen-independent reactions are relevant during the process of POP generation. 9 The present study was aimed at both investigating the mechanism of cell death induced by POP treatment and identifying the novel apoptogenic compounds which are generated by the photodegradation of psoralen.…”

“…7 More recently, PUVA treatment has been reported to cause cell death by apoptosis, 8 and we have demonstrated that the underlying mechanism involves mitochondrial dysfunction caused by opening of the permeability transition pore (PTP). 9 On the other hand, upon UVA irradiation, psoralen photoproducts (POPs) are generated, which are likely to contribute to PUVA cytotoxicity. 10 In fact, POP were reported to elicit a wide variety of effects, such as oxidation of proteins and unsaturated lipids, modulation of the immunologic response, 10,11 and inhibition of the growth of an EL4 tumor, which represents an experimental murine model of human CTCL.…”

“…9 The apoptogenic potency of the mixture was reduced-but not suppressed-by irradiating the psoralen solution in the absence of oxygen, suggesting that both oxygen-dependent and oxygen-independent reactions are relevant during the process of POP generation. 9 The present study was aimed at both investigating the mechanism of cell death induced by POP treatment and identifying the novel apoptogenic compounds which are generated by the photodegradation of psoralen. Among POPs, 3 cytotoxic molecules were purified and characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS), namely a pyrone-pyrone and a furan-pyrone dimer of psoralen, and 6-formyl-7-hydroxycoumarin (FHC).…”

Histone Deacetylase Inhibitor Sodium Butyrate Enhances the Cell Killing Effect of Psoralen plus UVA by Attenuating Nucleotide Excision Repair

“…PUVA-induced ICL in chromosomal DNA induces an antiproliferative effect convenient for skin therapy. Some studies found that PUVA showed a cell killing effect (apoptosis) in cultured lymphoma cell lines (17,18); however, the application of PUVA to melanoma and carcinoma has not been realized because the cell killing power is not as strong as that of anticancer drugs and radiation.…”