Luis Martínez-Lostao de CliNK en el Congreso "V International Conference BIFI 2012"“Protein Targets: Discovery of Bioactive Compounds”

3 de Febrero a las 10 h.

Luis Martínez-Lostao, Profesor Ayudante Doctor en la Universidad de Zaragoza presentará el tema titulado "Tethering to liposomes results in a dramatic increase in Apo2L/TRAIL effectiveness on human leukemic cells" ("El anclaje a liposomas resulta en un incremento dramático de la efectividad de Apo2L/TRAIL contra células leucémicas humanas") en "The V International Conference of the Institute for Biocomputation and Physics of Complex Systems" (BIFI).

Se centrará en los liposomas con Apo2L/TRAIL, un tratamiento que ha dado buenos resultados en un modelo de artritis reumatoide en conejos, y que ahora se ha probado en células leucémicas. Los resultados están siendo muy efectivos y el siguiente paso será experimentar en ratones con tumores humanos. Estos procesos están patentados pero todavía no hay ninguna empresa que los explote, lo que podrá ser factible en cuanto se demuestre que no hay efectos secundarios.

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Abstract

Luis Martinez-Lostao, Diego De Miguel, Patricia Galán, Diego Sánchez, Julián Pardo, Isabel Marzo, Javier Naval & Alberto Anel

TETHERING TO LIPOSOMES RESULTS IN A DRAMATIC INCREASE IN APO2L/TRAIL EFFECTIVENESS ON HUMAN HEMATOLOGIC TUMOR CELLS

Apo2L/TRAIL is a member of the TNF cytokine super-family capable of inducing apoptosis in a Fas-independent manner. Besides its anti-tumor activity, Apo2L/TRAIL is also implicated in immune regulation. Apo2L/TRAIL is stored inside activated T cells in cytoplasmic multivesicular bodies and it is physiologically released to the extracellular compartment associated with the internal exosomes. The aim of this study has been to generate artificial lipid vesicles resembling the natural exosomes and associate bioactive Apo2L/TRAIL to assay their ability in inducing apoptosis in vitro in a variety of hematological human tumor cell lines. To achieve this goal, we have used a novel Ni2+-(N-5-amino-1-carboxylpentyl)-iminodiacetic acid, NTA)-containing liposomal system. We find that tethering Apo2L/TRAIL to the liposome membrane by this means increases its bioactivity, inducing apoptosis more effectively at lower doses in the hematological human tumor cell line Jurkat. More importantly, the association of Apo2L/TRAIL with liposomes overcomes the resistance to Apo2L/TRAIL in soluble phase of tumor cells lines that over-express anti-apoptotic proteins, such as Jurkat-CrmA, Jurkat-Bcl2 and Jurkat-BclxL. This increase in bioactivity correlates with a higher ability of LUV-Apo2L/TRAIL to induce caspase-3 activation at the same protein dose. Our results suggest that this increased bioactivity of is due to an increases in the local concentration of the recombinant protein, augmenting its receptor cross-linking efficiency.