Novel o-naphthoquinones induce apoptosis of EL-4 T lymphoma cells through the increase of reactive oxygen species

• Autores: Di Rosso, María Emilia; Barreiro Arcos, María Laura; Elingold, Igal; Sterle, Helena Andrea; Baptista Ferreira, Sabrina; Ferreira, Vitor Francisco; Galleano, Mónica; Cremaschi, Graciela A.; Dubin, Marta
• Año de publicación: 2013
• Idioma: inglés
• Tipo de recurso: artículo
• Fuente: Toxicology in Vitro. 2013;27(7):2094-2104
• Materia: APOPTOSIS; BENZODIAZEPINAS; OXIGENO; IONES; RADICALES LIBRES; CELULAS
• Institución: Pontificia Universidad Católica Argentina

Fil: Di Rosso, María Emilia. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Di Rosso, María Emilia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Barreiro Arcos, María Laura. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Elingold, Igal. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Elingold, Igal. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Sterle, Helena Andrea. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Baptista Ferreira, Sabrina. Universidade Federal do Río de Janeiro. Instituto de Química. Departamento de Química Orgânica; Brasil
Fil: Galleano, Mónica. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Bioquímica y Medicina Molecular; Argentina
Fil: Galleano, Mónica. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Cremaschi, Graciela A. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Dubin, Marta. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Abstract: Novel β-lapachone analogs 2-phenyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (NQ1), 2-p-tolyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (NQ3) and 2-methyl-2-phenyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (NQ7), which have trypanocidal activity, were assayed for cytotoxic effects on murine EL-4 T lymphoma cells. The NQs inhibited the proliferation of EL-4 cells at concentrations above 1μM. Nuclear staining of the EL-4 cells revealed chromatin condensation and a nuclear morphology compatible with the induction of apoptosis. Flow cytometry assays with annexin V-FITC and propidium iodide confirmed the cell death by apoptosis. Using electron paramagnetic resonance (EPR), a semiquinone radical was detected in EL-4 cells treated with NQs. In addition, a decrease in the GSH level in parallel with reactive oxygen species (ROS) production was observed. Preincubation with n-acetyl-l-cysteine (NAC) was able to reverse the inhibitory effects of the NQs on cell proliferation, indicating that ROS generation is involved in NQ-induced apoptosis. In addition, the NQs induced a decrease in the mitochondrial membrane potential and increased the proteolytic activation of caspases 9 and 3 and the cleavage of Poly (ADP-Ribose) Polymerase (PARP). In conclusion, these results indicate that redox cycling is induced by the NQs in the EL-4 cell line, with the generation of ROS and other free radicals that could inhibit cellular proliferation as a result of the induction of the intrinsic apoptosis pathway.