Activation of SHIP via a small molecule agonist kills multiple myeloma cells
| Autor: | Michael Kennah, Alice L.-F. Mui, Christopher J. Ong, Tien Yin Yau, Gerald Krystal, Matt Nodwell, Raymond J. Andersen |
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| Rok vydání: | 2009 |
| Předmět: |
Agonist
DNA Replication Cancer Research medicine.drug_class Inositol Phosphates Antineoplastic Agents Apoptosis Biology Dexamethasone Bortezomib Mice Cell Line Tumor Genetics medicine Animals Humans Polycyclic Compounds Phosphorylation Cytotoxicity Molecular Biology Phosphoinositide-3 Kinase Inhibitors B-Lymphocytes Kinase Inositol Polyphosphate 5-Phosphatases Drug Synergism Cell Biology Hematology Small molecule Boronic Acids Phosphoric Monoester Hydrolases Cell biology Neoplasm Proteins Enzyme Activation Pyrazines Signal transduction Drug Screening Assays Antitumor Multiple Myeloma Protein Processing Post-Translational Proto-Oncogene Proteins c-akt medicine.drug Proto-oncogene tyrosine-protein kinase Src Signal Transduction |
| Zdroj: | Experimental hematology. 37(11) |
| ISSN: | 1873-2399 |
| Popis: | 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. Materials and 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. Conclusion These results provide the basis for the further study of small molecule SHIP activators to improve MM patient outcomes. |
| Databáze: | OpenAIRE |
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