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Published on: May 15, 2019
Activation of SHIP via a small molecule agonist kills multiple myeloma cells
Michael Kennah1, Tien Yin Yau, Matt Nodwell
1Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
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.
Insights
A novel drug, AQX-MN100, activates SHIP to combat multiple myeloma (MM) by inhibiting cancer cell growth and enhancing existing therapies. This targeted approach shows promise for improving patient outcomes in MM treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Multiple myeloma (MM) is an incurable B-lymphocyte cancer.
- Tumor cell resistance limits current MM therapies.
- The phosphoinositide 3'-kinase/Akt pathway is crucial for MM cell survival.
Purpose of the Study:
- To investigate AQX-MN100, a novel small molecule agonist for Src homology 2-containing inositol 5'-phosphatase (SHIP).
- To evaluate AQX-MN100's potential as a targeted therapy for multiple myeloma by targeting the phosphoinositide 3'-kinase/Akt pathway.
Main Methods:
- In vitro testing of AQX-MN100 on multiple myeloma cell lines.
- Assessing AQX-MN100's effects on DNA synthesis and apoptosis.
- Examining AQX-MN100's impact on the phosphoinositide 3'-kinase/Akt cascade.
- Evaluating AQX-MN100's synergy with dexamethasone and bortezomib.
Main Results:
- AQX-MN100 activation of SHIP inhibited multiple myeloma cell growth and induced cytotoxicity.
- AQX-MN100 demonstrated selective toxicity, sparing nonhematopoietic cells lacking SHIP.
- AQX-MN100 enhanced the efficacy of dexamethasone and bortezomib.
Conclusions:
- Activation of SHIP with AQX-MN100 is a viable strategy against multiple myeloma.
- Small molecule SHIP activators warrant further investigation for improving MM patient outcomes.
