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.
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.
Authors: Gwenny M Fuhler; Robert Brooks; Bonnie Toms; Sonia Iyer; Elizabeth A Gengo; Mi-Young Park; Matthew Gumbleton; Dennis R Viernes; John D Chisholm; William G Kerr Journal: Mol Med Date: 2012-02-10 Impact factor: 6.354
Authors: Elizabeth A Lemm; Beatriz Valle-Argos; Lindsay D Smith; Johanna Richter; Yohannes Gebreselassie; Matthew J Carter; Jana Karolova; Michael Svaton; Karel Helman; Nicola J Weston-Bell; Laura Karydis; Chris T Williamson; Georg Lenz; Jeremy Pettigrew; Curtis Harwig; Freda K Stevenson; Mark Cragg; Francesco Forconi; Andrew J Steele; Jennifer Cross; Lloyd Mackenzie; Pavel Klener; Graham Packham Journal: Clin Cancer Res Date: 2019-12-12 Impact factor: 12.531