title: Molecular targets for selective killing of TRAIL-resistant leukemic cells.
abstract: BACKGROUND
  TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, and shows promising therapeutic activity against solid tumors and lymphomas, in a variety of Phase I and II clinical trials. In contrast, primary leukemias have shown poor susceptibility to TRAIL-mediated cytotoxicity, suggesting the need for sensitizing TRAIL-resistant leukemic cells, by combining soluble recombinant TRAIL either with chemotherapeutic drugs, or with targeted small molecules.
  
  
  METHODS
  This review discusses potential therapeutic applications of combinations able to restore the sensitivity of leukemic cells to either recombinant TRAIL or anti-TRAIL-receptor agonistic antibodies for the treatment of hematological malignancies.
  
  
  CONCLUSIONS
  Up-to-date knowledge of the most innovative anti-leukemic therapies including functional screening of specific-sensitizers, enhancing TRAIL-mediated cytotoxicity. Strategies aimed to enhance TRAIL-mediated apoptosis, include the combination of novel sensitizers, functionally identified from libraries of pharmaceutically active, synthetic or naturally derived compounds. Other approaches aim to employ the administration of stem cells engineered to express TRAIL, in the leukemic stem cell niche, and promise to be a successful treatment with reduced specific toxicity.
authors.affiliation: Institute for Maternal and Child Health , IRCCS Burlo Garofolo, Trieste , Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zauli
authors.forename: Raffaella
authors.initials: R
authors.lastname: Bosco
authors.forename: Paola
authors.initials: P
authors.lastname: Secchiero
mesh_terms: D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology / Q000378:metabolism*
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human