Abstract |
Multiple myeloma (MM) is still an incurable disease and adhesion of MM cells to bone marrow stromal cells is one of the hallmarks of the disease. Lymphocyte function associated antigen 1 (LFA-1) is an adhesion molecule that mediates lymphocyte adhesion, but its role in MM is only poorly understood. The aim of the presented study was to improve knowledge on LFA-1 and associated pathways in MM for the development of molecular targeted therapies. We demonstrate that LFA-1 is expressed in U266, RPMI-8226, OPM-2, and NCI-H929 MM cell lines and in primary cells of eight tested patients. The LFA-1 inhibitor LFA878 induces apoptosis in all four cell lines as revealed by annexin V staining and caspase 3 cleavage. Apoptosis is not hampered by adhesion to stromal cells. Additionally, the soluble ligand, intracellular adhesion molecule 1 (ICAM-1), which is increased in the serum of MM patients, does not protect from melphalan-induced apoptosis. Western blots demonstrate downregulation of FAK, PI3-K, and Akt upon LFA878 treatment. Additionally, sequential inhibition of the pathway by simultaneous application of Src family kinase or PI3-K inhibitors significantly increases LFA878 induced apoptosis. We conclude that LFA-1/FAK/PI3-K/Akt is a survival pathway in MM and that targeted inhibition may provide new therapeutic options.
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Authors | Ralf Schmidmaier, Sonja Mandl-Weber, Leander Gaul, Philipp Baumann, Irmgard Bumeder, Christian Straka, Bertold Emmerich |
Journal | International journal of oncology
(Int J Oncol)
Vol. 31
Issue 4
Pg. 969-76
(Oct 2007)
ISSN: 1019-6439 [Print] Greece |
PMID | 17786331
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cyclins
- LFA 878
- Lymphocyte Function-Associated Antigen-1
- Naphthalenes
- Oxazines
- Phosphatidylinositol 3-Kinases
- Focal Adhesion Kinase 1
- Proto-Oncogene Proteins c-akt
- Caspases
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Topics |
- Apoptosis
(drug effects)
- Caspases
(metabolism)
- Cell Cycle
(drug effects)
- Cyclins
(metabolism)
- Down-Regulation
- Enzyme-Linked Immunosorbent Assay
- Flow Cytometry
- Focal Adhesion Kinase 1
(metabolism)
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- Immunoblotting
- Lymphocyte Function-Associated Antigen-1
(chemistry, metabolism)
- Multiple Myeloma
(drug therapy, metabolism, pathology)
- Naphthalenes
(pharmacology)
- Oxazines
(pharmacology)
- Phosphatidylinositol 3-Kinases
(metabolism)
- Proto-Oncogene Proteins c-akt
(metabolism)
- Signal Transduction
(drug effects)
- Tumor Cells, Cultured
(drug effects)
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