RESUMEN
BACKGROUND: Photodynamic therapy (PDT) is used to treat cutaneous cancers. It may induce cell death through direct and indirect means, including apoptosis, inflammation and certain immune mechanisms, with the depth of penetration as a potential modifying factor. OBJECTIVES: To examine the pathways of apoptosis in the intralesional PDT of basal cell carcinoma (BCC) and intraepidermal squamous cell carcinoma (Bowen's disease). METHODS: Sixteen patients with superficial or nodular BCC and Bowen's disease were treated with intralesional aminolevulinic acid-PDT. Biopsies were taken at baseline and 24 h post-PDT, and sections were examined by immunohistochemistry for the expression of markers of apoptosis, such as caspase 3, involved in the intrinsic apoptotic pathway, granzyme B, a caspase-independent apoptotic mediator, and the proapoptotic markers BAX and BAK. RESULTS: Apoptotic cells stained with TUNEL showed statistically significant staining at 24 h post PDT (p < 0.01 in both BCC and Bowen's lesions). Caspase 3 (p < 0.01 in BCC and p < 0.05 in Bowen's) and granzyme B (p < 0.01 in BCC and p < 0.01 in Bowen's) were significantly increased at 24 h post-PDT. BAX expression was apparently increased compared to baseline in Bowen's lesions at 24 h post-PDT, whereas Bak was upregulated both in BCC and Bowen's disease at baseline and at 24 h post-PDT. CONCLUSION: Intralesional PDT induces apoptosis in BCC and Bowen's disease via common and alternative apoptotic pathways involving granzyme B. Proapoptotic factors Bak in both BCC and Bowen and Bax in Bowen's disease appear to increase by intralesional PDT at 24 h.
Asunto(s)
Enfermedad de Bowen , Carcinoma Basocelular , Fotoquimioterapia , Neoplasias Cutáneas , Humanos , Enfermedad de Bowen/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Caspasa 3/uso terapéutico , Granzimas/uso terapéutico , Proteína X Asociada a bcl-2/uso terapéutico , Carcinoma Basocelular/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Ácido Aminolevulínico/uso terapéutico , ApoptosisRESUMEN
BACKGROUND: Psoriasis is a chronic inflammatory skin disease associated with abnormal vascular expansion in the papillary dermis. Tumour necrosis factor (TNF)-α is a proinflammatory cytokine that can induce antiapoptotic proteins and endothelial cell activation factors in psoriasis. OBJECTIVES: The present study investigated the effect of the anti-TNF-α agent etanercept on the expression of endothelial nuclear factor-κB (NF-κB), angiogenic vascular endothelial growth factor (VEGF), endothelial cell marker CD31, antiangiogenic factor thrombospondin-1 (TSP-1), and antiapoptotic factors Bcl-2 and Bcl-xL in psoriasis. METHODS: Sixteen patients with moderate-to-severe psoriasis were included in the study and treated with etanercept 50 mg twice weekly subcutaneously for 12 weeks. Biopsies of lesional skin (baseline, weeks 3, 6 and 10) were obtained and immunohistochemically stained with antibodies for CD31, VEGF, TSP-1, NF-κB, Bcl-2 and Bcl-xL. Double immunofluorescence staining for VEGF and CD31 was evaluated with confocal laser microscopy. The terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling (TUNEL) assay was applied for apoptosis detection. RESULTS: Etanercept caused a statistically significant time-dependent reduction in the number of dermal blood vessels, the number of CD31+ cells and VEGF in psoriatic lesions, with induction of endothelial cell apoptosis and statistically significant upregulation of TSP-1 in psoriatic vessels. Immunohistochemical analysis showed significant reduction of NF-κB, Bcl-2 and Bcl-xL expression in endothelial cells during treatment. These changes were accompanied by a marked clinical response. CONCLUSIONS: The present findings suggest that treatment with etanercept induces apoptosis, reduces apoptosis-inhibiting factors in psoriatic endothelial cells, and decreases angiogenesis in psoriatic skin.
Asunto(s)
Apoptosis/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Inmunoglobulina G/farmacología , Factores Inmunológicos/farmacología , Psoriasis/tratamiento farmacológico , Adulto , Biopsia , Células Endoteliales/metabolismo , Etanercept , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , FN-kappa B/metabolismo , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Psoriasis/metabolismo , Psoriasis/patología , Receptores del Factor de Necrosis Tumoral , Trombospondina 1/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteína bcl-X/metabolismoRESUMEN
A series of new analogues of trifluralin (TFL) were synthesized and characterized in view of changing the unfavorable properties that limits its use as antileishmanial agent. Some of the TFL analogues display more activity than a standard drug (miltefosine) against the promastigote forms of Leishmania infantum and Leishmania donovani and the intracellular form (THP-1 infected with L. infantum). All analogues showed a clear advantage over miltefosine, as they are not hemolytic. Some analogues can conjugate these characteristics with reduced cell toxicity and improved intracellular activity.