title: Immunotherapy with liposome-bound TRAIL overcomes partial protection to soluble TRAIL-induced apoptosis offered by down-regulation of Bim in leukemic cells.
abstract: OBJECTIVE
  Human Apo2-Ligand/TRAIL secreted by natural killer cells and cytotoxic T lymphocytes plays an important role immunosurveillance controlling tumor growth and metastasis. Moreover, the fact that Apo2L/TRAIL is capable of inducing cell death in tumor cells but not in normal cells makes this death ligand a promising anti-tumor agent. Previous data from our group demonstrated that Apo2L/TRAIL was physiologically released as transmembrane protein inserted in lipid vesicles, called exosomes. Recently, we demonstrated that artificial lipid nanoparticles coated with bioactive Apo2L/TRAIL (LUV-TRAIL) resembling the natural exosomes, greatly improved Apo2L/TRAIL activity and were able to induce apoptosis in hematological malignancies. In this study, we have deepened in the underlying mechanism of action of LUV-TRAIL in hematologic cells.
  
  
  METHODS
  Cytotoxic ability of LUV-TRAIL was assessed on Jurkat cells either over-expressing the anti-apoptotic protein Mcl1 or down-regulating the pro-apoptotic protein Bim previously generated in our laboratory. We also tested LUV-TRAIL cytotoxic ability against primary human leukemic cells from T-cell ALL patient.
  
  
  RESULTS
  Silencing Bim but not Mcl-1 over-expression partially protects Jurkat cells from apoptosis induced by sTRAIL. LUV-TRAIL induced caspase-8 and caspase-3 activation and killed Jurkat-Mcl1 and Jurkat-shBim more efficiently than sTRAIL independently of the mitochondrial pathway. On the other hand, LUV-TRAIL were clearly more cytotoxic against primary leukemic cells from a T-cell ALL patient than sTRAIL.
  
  
  CONCLUSIONS
  Tethering Apo2L/TRAIL to the surface of lipid nanoparticles greatly increases its bioactivity and could be of potential use in anti-tumor therapeutics.
authors.affiliation: Departamento de Bioquímica, Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, C/Pedro Cerbuna 12, 50009, Zaragoza, Spain, diego_demiguel@hotmail.com.
authors.forename: D
authors.initials: D
authors.lastname: De Miguel
authors.forename: A
authors.initials: A
authors.lastname: Gallego-Lleyda
authors.forename: P
authors.initials: P
authors.lastname: Galan-Malo
authors.forename: C
authors.initials: C
authors.lastname: Rodriguez-Vigil
authors.forename: I
authors.initials: I
authors.lastname: Marzo
authors.forename: A
authors.initials: A
authors.lastname: Anel
authors.forename: L
authors.initials: L
authors.lastname: Martinez-Lostao
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D007124:Immunoenzyme Techniques; D007167:Immunotherapy; D007938:Leukemia / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D008081:Liposomes; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008081:Liposomes; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human