title: Activation of SHIP via a small molecule agonist kills multiple myeloma cells.
abstract: OBJECTIVE
  Multiple myeloma (MM) is a B-lymphocyte neoplasia that is presently incurable because the tumor cells become resistant to currently available drugs. The growth and survival signals resulting from interactions between the malignant clones and the bone marrow microenvironment are mediated chiefly through the phosphoinositide 3'-kinase/Akt kinase signaling pathway. Thus agents that can abrogate this pathway have great potential as targeted therapies. A novel approach in this regard is through activation of the Src homology 2-containing inositol 5'-phosphatase (SHIP), using the small molecule agonist, AQX-MN100.
  
  
  METHODS
  The SHIP agonist AQX-MN100 was tested in vitro for its ability to inhibit DNA synthesis, induce apoptosis in MM cell lines, as well as inhibit phosphorylation of the kinases in the phosphoinositide 3'-kinase/Akt kinase cascade. The ability of AQX-MN100 to enhance the cytotoxicity of the current MM therapeutic drugs dexamethasone and bortezomib was also examined.
  
  
  RESULTS
  We demonstrate herein that activation of SHIP using AQX-MN100 is sufficient to prevent growth and induce cytotoxicity of MM cell lines, while having no significant effects on nonhematopoietic cells lacking SHIP. AQX-MN100 also augments the effects of the established agents dexamethasone and bortezomib.
  
  
  CONCLUSIONS
  These results provide the basis for the further study of small molecule SHIP activators to improve MM patient outcomes.
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Kennah
authors.forename: Tien Yin
authors.initials: TY
authors.lastname: Yau
authors.forename: Matt
authors.initials: M
authors.lastname: Nodwell
authors.forename: Gerald
authors.initials: G
authors.lastname: Krystal
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ong
authors.forename: Alice L-F
authors.initials: AL
authors.lastname: Mui
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor / Q000187:drug effects / Q000201:enzymology; D004261:DNA Replication / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007295:Inositol Phosphates / Q000502:physiology; D000072181:Inositol Polyphosphate 5-Phosphatases; D051379:Mice; D009101:Multiple Myeloma / Q000473:pathology*; D009363:Neoplasm Proteins / Q000819:agonists; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011083:Polycyclic Compounds / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011719:Pyrazines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C544924:AQX MN100; D000970:Antineoplastic Agents; D001897:Boronic Acids; D007295:Inositol Phosphates; D009363:Neoplasm Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011083:Polycyclic Compounds; D011719:Pyrazines; C118500:inositol 3,4,5-trisphosphate; D000069286:Bortezomib; D003907:Dexamethasone; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases