title: The novel organic arsenical darinaparsin induces MAPK-mediated and SHP1-dependent cell death in T-cell lymphoma and Hodgkin lymphoma cells and human xenograft models.
abstract: OBJECTIVE
  Darinaparsin (Zio-101) is a novel organic arsenical compound with encouraging clinical activity in relapsed/refractory T-cell lymphoma (TCL) and Hodgkin lymphoma (HL); however, little is known about its mechanism of action.
  
  
  METHODS
  TCL cell lines (Jurkat, Hut78, and HH) and HL cell lines (L428, L540, and L1236) were examined for in vitro cell death by MTT assay and Annexin V-based flow cytometry. Jurkat and L540-derived xenografts in SCID mice were examined for in vivo tumor inhibition and survival. Biologic effects of darinaparsin on the MAPK pathway were investigated using pharmacologic inhibitors, RNAi and transient transfection for overexpression for SHP1 and MEK.
  
  
  RESULTS
  Darinaparsin treatment resulted in time- and dose-dependent cytotoxicity and apoptosis in all TCL and HL cell lines. In addition, darinaparsin had more rapid, higher, and sustained intracellular arsenic levels compared with arsenic trioxide via mass spectrometry. In vivo experiments with Jurkat (TCL) and L540 (HL)-derived lymphoma xenografts showed significant inhibition of tumor growth and improved survival in darinaparsin-treated SCID mice. Biologically, darinaparsin caused phosphorylation of ERK (and relevant downstream substrates) primarily by decreasing the inhibitory SHP1 phosphatase and coimmunoprecipitation showed significant ERK/SHP1 interaction. Furthermore, ERK shRNA knockdown or constitutive overexpression of SHP1 resulted in increased apoptosis, whereas cotreatment with pharmacologic MEK inhibitors resulted in synergistic cell death. Conversely, SHP1 blockade (via pharmacologic inhibition or RNAi) and MEK constitutive activation decreased darinaparsin-related cell death.
  
  
  CONCLUSIONS
  Altogether, these data show that darinaparsin is highly active in HL and TCL and its activity is dependent primarily on MAPK mechanisms.
authors.affiliation: Molecular Oncology Research Institute and Division of Hematology Oncology, Tufts Medical Center, Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Dashnamoorthy
authors.initials: D
authors.lastname: Ravi
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Savita
authors.initials: S
authors.lastname: Bhalla
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, Department of Medicine, University of Maryland, Baltimore, Maryland.
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Gartenhaus
authors.affiliation: Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Crombie
authors.affiliation: Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois.
authors.forename: Irawati
authors.initials: I
authors.lastname: Kandela
authors.affiliation: Molecular Oncology Research Institute and Division of Hematology Oncology, Tufts Medical Center, Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Jaya
authors.initials: J
authors.lastname: Sharma
authors.affiliation: Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois. Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mazar
authors.affiliation: Molecular Oncology Research Institute and Division of Hematology Oncology, Tufts Medical Center, Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts. AEvens@tuftsmedicalcenter.org.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Evens
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001151:Arsenic / Q000378:metabolism; D001152:Arsenicals / Q000008:administration & dosage / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005978:Glutathione / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006689:Hodgkin Disease / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D001152:Arsenicals; C515055:darinaparsin; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D005978:Glutathione; D001151:Arsenic