inositol-3-4-5-trisphosphate and Multiple-Myeloma

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.. 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.. 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.. These results provide the basis for the further study of small molecule SHIP activators to improve MM patient outcomes.

Topics: Animals; Antineoplastic Agents; Apoptosis; B-Lymphocytes; Boronic Acids; Bortezomib; Cell Line, Tumor; Dexamethasone; DNA Replication; Drug Screening Assays, Antitumor; Drug Synergism; Enzyme Activation; Humans; Inositol Phosphates; Inositol Polyphosphate 5-Phosphatases; Mice; Multiple Myeloma; Neoplasm Proteins; Phosphoinositide-3 Kinase Inhibitors; Phosphoric Monoester Hydrolases; Phosphorylation; Polycyclic Compounds; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Pyrazines; Signal Transduction