title: Synergistic antitumor activity of recombinant human Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in combination with carboplatin and pemetrexed in malignant pleural mesothelioma.
abstract: BACKGROUND
  Malignant pleural mesothelioma (MPM) is an aggressive, currently incurable tumor with increasing incidence in industrialized countries. Tumor necrosis factor-related, apoptosis-inducing ligand (TRAIL) is a member of the TNF family, which induces cancer cell death through extrinsic apoptotic pathway, while sparing normal cells. The aim of this study was to investigate the antitumor activity of recombinant human Apo2L/TRAIL (dulanermin) in combination with chemotherapy in MPM in vitro and in vivo.
  
  
  METHODS
  In the present studies, we employed a panel of MPM cell lines to test the antitumor activity of recombinant human Apo2L/TRAIL (T) in combination with carboplatin and pemetrexed (CP) in vitro and SCID mice.
  
  
  RESULTS
  Results demonstrated a significant increase of apoptosis in cell lines treated with CPT compared with those receiving CP or T as single agents. This synergistic effect was dependent on the ability of CP to increase the expression of the TRAIL receptors DR4 and DR5 in a p53 manner. The CPT combination was also effective in blocking the growth of MPM cell lines in a SCID mice preclinical model.
  
  
  CONCLUSIONS
  CPT increases MPM cell death in vitro and in vivo compared with CP. In vitro results suggest that chemotherapy sensitizes MPM to TRAIL-dependent apoptosis through p53 activation and subsequent upregulation of DRs.
authors.affiliation: Second Medical Oncology Unit, Istituto Oncologico Veneto, Padua, Italy. Electronic address: giulia.pasello@ioveneto.it.
authors.forename: Giulia
authors.initials: G
authors.lastname: Pasello
authors.affiliation: Second Medical Oncology Unit, Istituto Oncologico Veneto, Padua, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Urso
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, Padova, Italy.
authors.forename: Micol
authors.initials: M
authors.lastname: Silic-Benussi
authors.affiliation: Thoracic Surgery Unit, University of Padua, Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Schiavon
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, Padova, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Cavallari
authors.affiliation: Thoracic Surgery Unit, University of Padua, Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Marulli
authors.affiliation: Pathology Department, University of Padua, Padova, Italy.
authors.forename: Nazarena
authors.initials: N
authors.lastname: Nannini
authors.affiliation: Thoracic Surgery Unit, University of Padua, Padova, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Rea
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, Padova, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Ciminale
authors.affiliation: Second Medical Oncology Unit, Istituto Oncologico Veneto, Padua, Italy.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Favaretto
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D016190:Carboplatin / Q000008:administration & dosage; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D000068437:Pemetrexed; D010997:Pleural Neoplasms / Q000188:drug therapy*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism*
chemical_list: D005971:Glutamates; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D016159:Tumor Suppressor Protein p53; D000068437:Pemetrexed; D006147:Guanine; D016190:Carboplatin