title: Combination of arginine deprivation with TRAIL treatment as a targeted-therapy for mesothelioma.
abstract: In the present study we present data to show that certain tumor cells including malignant pleural mesothelioma (MPM) cells do not express argininosuccinate synthetase (ASS), and thus are unable to synthesize arginine from citrulline. Exposure of these ASS-negative cells to the arginine degrading enzyme, arginine deiminase (ADI-PEG20), for 72 h results in significant increases in cleaved caspase-3. Importantly, this apoptotic signal is further strengthened by the addition of TNF-related apoptosis-inducing ligand (TRAIL). Using flow cytometry, we showed that the combination treatment (ADI-PEG20 at 50 ng/ml and TRAIL at 10 ng/ml) for 24 h resulted in profound cell death with 67% of cells positive for caspase-3 activity, while ADI-PEG20 alone or TRAIL alone resulted in only 10-15% cell death. This positive amplification loop is mediated through the cleavage of proapototic protein "BID".
  
  
  CONCLUSIONS
  Our work represents a new strategy for treating patients with malignant pleural mesothelioma using targeted molecular therapeutics based on selected tumor markers, thus avoiding the use of potentially cytotoxic chemotherapy.
authors.affiliation: Miami VA Healthcare System, Department of Veterans Affairs, Miami, FL, U.S.A. Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, U.S.A. mwangpaichitr@med.miami.edu.
authors.forename: Medhi
authors.initials: M
authors.lastname: Wangpaichitr
authors.affiliation: Miami VA Healthcare System, Department of Veterans Affairs, Miami, FL, U.S.A.
authors.forename: Chunjing
authors.initials: C
authors.lastname: Wu
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami, Miller School of Medicine, Miami, FL, U.S.A.
authors.forename: Gregory
authors.initials: G
authors.lastname: Bigford
authors.affiliation: Miami VA Healthcare System, Department of Veterans Affairs, Miami, FL, U.S.A.
authors.forename: George
authors.initials: G
authors.lastname: Theodoropoulos
authors.affiliation: Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, U.S.A.
authors.forename: Min
authors.initials: M
authors.lastname: You
authors.affiliation: Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, U.S.A.
authors.forename: Ying Ying
authors.initials: YY
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, U.S.A.
authors.forename: Javier
authors.initials: J
authors.lastname: Verona-Santos
authors.affiliation: Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, U.S.A.
authors.forename: Lynn G
authors.initials: LG
authors.lastname: Feun
authors.affiliation: Department of Surgery, University of Miami, Miller School of Medicine, Miami, FL, U.S.A.
authors.forename: Dao M
authors.initials: DM
authors.lastname: Nguyen
authors.affiliation: Miami VA Healthcare System, Department of Veterans Affairs, Miami, FL, U.S.A. Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, U.S.A.
authors.forename: Niramol
authors.initials: N
authors.lastname: Savaraj
mesh_terms: D017209:Apoptosis; D001120:Arginine / Q000172:deficiency*; D001124:Argininosuccinate Synthase / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D006867:Hydrolases / Q000494:pharmacology / Q000627:therapeutic use*; D008654:Mesothelioma / Q000188:drug therapy*; D058990:Molecular Targeted Therapy / Q000379:methods*; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D034622:RNA Interference; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000627:therapeutic use*
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D011092:Polyethylene Glycols; D001120:Arginine; D006867:Hydrolases; D053148:Caspase 3; C512527:ADI PEG20; C019723:arginine deiminase; D001124:Argininosuccinate Synthase
keywords: Arginine deprivation; TNF-related apoptosis-inducing ligand (TRAIL); mesothelioma