title: Improved Anti-Tumor Activity of Novel Highly Bioactive Liposome-Bound TRAIL in Breast Cancer Cells.
abstract: BACKGROUND
  Apo2-ligand/TRAIL, a member of the TNF cytokine superfamily capable of inducing apoptosis on tumor cells while sparing normal cells, is a promising anti-tumor agent. However, about 50% of human cancer are TRAIL resistant. Consequently, future TRAIL-based therapies will require the use of novel highly bioactive forms of TRAIL and/or the addition of sensitizing agents to TRAIL-induced apoptosis. Recently, we demonstrated that artificial lipid nanoparticles coated with bioactive TRAIL (LUV-TRAIL) greatly improved TRAIL activity and were able to induce apoptosis in chemoresistant hematological tumor cells.
  
  
  OBJECTIVE
  In this study, we have tested LUV-TRAIL-pro-apoptotic potential in human breast cancer.
  
  
  METHODS
  Comparative analysis of cytotoxicity induced by sTRAIL and LUV-TRAIL was performed using several human breast tumor cell lines with different sensitivity to TRAIL. In vivo anti-tumor activity of LUV-TRAIL was also studied using a xeno-graft tumor model.
  
  
  RESULTS
  LUV-TRAIL improved not only sTRAIL in vitro cytotoxicity in all breast tumor cell lines tested but also showed more anti-tumor activity than sTRAIL in an in vivo xeno-graft tumor model. On the other hand, the concomitant treatment of LUV-TRAIL with the sensitizing agent flavopiridol (FVP) induced a higher level of cell death in TRAIL-resistant cell lines. TRAIL-sensitization induced by FVP was mediated by DR5 up-regulation, and interestingly TRAIL-apoptotic signaling was completely shifted towards DR5 upon FVP treatment. LUV-TRAIL could especially take advantage of this DR5 up-regulation, while sTRAIL was not able.
  
  
  CONCLUSIONS
  To date, no special attention had been paid to this aspect of FVP-induced TRAIL-sensitization, may be because sTRAIL used were not able to take advantage of this DR5 up-regulation. Hence, LUV-TRAIL could be a better choice than sTRAIL to be used in combination with anti-tumor drugs inducing DR5 over-expression, since LUV-TRAIL is especially effective activating this death-receptor.
authors.forename: Diego
authors.initials: D
authors.lastname: De Miguel
authors.forename: Ana
authors.initials: A
authors.lastname: Gallego-Lleyda
authors.forename: José M
authors.initials: JM
authors.lastname: Ayuso
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Pawlak
authors.forename: Blanca
authors.initials: B
authors.lastname: Conde
authors.forename: Ignacio
authors.initials: I
authors.lastname: Ochoa
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Fernández
authors.forename: Alberto
authors.initials: A
authors.lastname: Anel
authors.affiliation: Departamento de Bioquímica, Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, C/ Pedro Cerbuna 12, Zaragoza, 50009 Spain. lumartin@unizar.es.
authors.forename: Luis
authors.initials: L
authors.lastname: Martinez-Lostao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004339:Drug Compounding; D005260:Female; D006801:Humans; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human