Activation of SHIP via a small molecule agonist kills multiple myeloma cells.
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.
Kennah
Michael
M
Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
Yau
Tien Yin
TY
Nodwell
Matt
M
Krystal
Gerald
G
Andersen
Raymond J
RJ
Ong
Christopher J
CJ
Mui
Alice L-F
AL
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
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